第19章P437-467

CHAPTER NINETEEN




Antimicrobial Treatment Based Upon The Specific Plaque Hypothesis (SPH)





I. Introduction

II. Diagnosis of a Cariogenic Infection

A. Clinical

B. Saliva

C. Bacteriological Tests

1. Snyder Test Agar

2. Diagnostic Broths for S. mutans

3. Semi-quantitative Tests for S. mutans

4. Summary of Diagnostic Criteria

III. Chemical Agents Directed Against S. mutans

A. What Topical Antimicrobial Agent to Use

1. Substantivity

2. Taste

3. Stability

4. Safety

B. Delivery of the Agent

1. Dentifrices

2. Mouthwashes

3. Applicator Trays

4. Chewing gums, Tablets, Adherent Pastes and Lozenges

5. Depot Devices

C. Dosages and Treatment Schedules

IV. Clinical Studies

A. Topical Fluorides

1. Anti S. mutans Studies

2. Anti Caries Studies

B. Vancomycin

C. Furadroxyl

D. Iodine

E. Kanamycin

1. The White Spot Hypothesis

2. Testing the While Spot Hypothesis

V. Risk-Benefit and Cost-Benefit Considerations

A. Short Term Fluoride Treatments

B. Combined Treatment Modalities

VI. Antimicrobial Resistant Bacteria

A. Unique Aspects of Microbial Resistance on Mucous Membranes

B. Fluoride Resistance in S. mutans

VII. Summary





第十九章

根據特定性牙菌斑假說(SPH的抗菌治療

I. 前言

II. 蛀牙感染的診斷

III. A. 臨床

B. 唾液

C. 細菌學的測試

1. Snyder Test Agar　

2. Diagnostic Broths for S. mutans

　　　　　　診斷S. mutans的培養液

3. Semi-quantitative Tests for S. mutans

S. mutans的半定量測試

4. 診斷準則的總結

III. 抗S. mutans的化學藥劑

A. 使用什麼局部抗菌藥劑

1. Substantivity

2. 味道

3. 穩定性

4. 安全性

B. 藥劑的給予

1. 牙膏

2. 漱口水

3. 牙托

4. 口香糖, 藥片, 黏膠和錠劑

5. 儲存裝置

C. 劑量與使用時間表

IV. 臨床研究

A. 局部塗氟

1. 抗S. mutans 研究

2. 抗蛀牙研究

B. Vancomycin 萬古黴素

C. Furadroxyl

D. 碘

E. Kanamycin

1. 白斑假說

2. 測試白斑假說

V. 風險與益處和花費與益處的考量

A. 短期氟化物治療

B. 合併治療療法

VI. Antimicrobial Resistant Bacteria抗菌抵抗細菌?

A. 在黏膜表面微生物抵抗力的特殊面

B. S. mutans對的氟化物抵抗力

VII. 總結







INTRODUCTION



The efficacy of antimicrobial treatment increases to the extent that it can be focused upon those patients with an odontopathic infection or at risk to this infection. This is the essential tenet of the specific plaque hypothesis (SPH). The procedures described in previous chapters, whether mechanical or chemical, can be used with greater efficacy and at less cost, if they are properly targeted on individuals with an odontopathic infection. The same criteria used to identify these individuals can be used to monitor the response to the therapeutic regimen employed. The dosages and treatment schedules, after initial empirical trials, can be optimized to give the most favorable benefit to risk ratio. In this manner, the clinician will be better able to control the prognosis for a given individual's odontopathic infection.



Treatment according to the SPH is in its infancy. In this chapter some of the exploratory investigations, which seek to verify this concept, will be described.



前言



抗菌治療的效用增加對牙科病變感染或對這些感染有風險的病患的重視程度，是特定性牙菌斑假說必要的宗旨，這些程序在之前的章節有描述過，不管是機械性或化學性，可以有更好的效率且花費較低，如果他們被適當地把有牙科病變感染的個體選為目標，可使用相同用來辨別這些個體的標準，來監控使用治療療法的反應。在起初經驗法則的試驗之後，劑量與時間表可被有效的給予最佳的風險益處比例?，所以，使臨床醫師更能夠控制有牙科病變感染的個體的癒後。



根據SPH的治療還在未發達的階段，在本章，將會描述一些探究如何證實此想法的研究調查。



DIAGNOSIS OF A CARIOGENIC INFECTION



Clinical



The diagnosis of an odontopathic infection is the indispensable entry criterion for treatment according to the SPH. This diagnosis can be made clinically by the presence of multiple carious lesions and a high DMFS score. A dental history should reveal whether the patient's parents or siblings have had a high caries morbidity, or if they are wearing dentures. If the mother or older siblings have a high DMFS score, then the child being examined most likely has been infected with S. mutans and other odontopathic organisms. Diet histories that indicate frequent between-meal eating of sucrose would identify those children with a high caries risk. Unusual oral sucrose retention or low salivary flow should be suspected when smooth surface decay is observed on anterior teeth.



蛀牙感染的診斷



臨床



根據SPH，牙齒病變感染的診斷對治療的準則是必不可缺的，診斷以臨床上由多種蛀牙損害及高DMFS分數取得，牙科病史會顯示是否此患者的父母或兄弟姐妹有高蛀牙率，或是他們是否有配帶假牙，如果母親或年長的哥哥姐姐有高DMFS分數，則此孩童會有很高機會被檢查出有S. mutans的感染，或其他造成牙齒病變的微生物。飲食紀錄指出正餐間有高頻率的蔗糖攝取，將辨別出這些孩童有高蛀牙率，當發現前牙有平滑面蛀牙，可預知這些孩童有不常見的口腔蔗糖殘留或低唾液分泌。



Saliva



Decreased salivary flow resulting in a dry mouth can usually be elicited from the dental history given by a patient. The clinician can confirm this and quantify the patient's salivary secretion rate by asking the patient to expectorate saliva into a test tube or cup, either with (stimulated) or without (unstimulated) the concurrent chewing of a piece of paraffin wax for a fixed time interval. The salivary flow rate per unit time for a population of Swedish schoolchildren is shown in Table 19-1 About 30 percent of these children had what appeared to be a low salivary flow, i.e., less than 1.0 ml/min. These children could comprise a subpopulation that would be at risk to an odontopathic infection because of inadequate salivary defense mechanisms.



唾液



唾液流量的減少造成口腔乾燥時常可經由患者提供的牙科病史得到，臨床醫師可以確認且測量病患的唾液分泌速率，經由在固定時間內咀嚼蠟片(刺激)或不咀嚼蠟片(非刺激)測得，表19-1顯示瑞典學齡孩童每單位時間的唾液分泌速率，約30%的孩童顯示低唾液流量，例如少於1.9ml/min，這些孩童因為他們不全的唾液防禦機制，組成一個得到牙齒病變感染的subpopulation次級的高危險群組?，



Bacteriological Tests



These clinical and historical data should be supplemented by bacteriological evidence of an odontopathic infection. The Lactobacillus Index (See "Lactobacillus Index" in Chap. 16) was shown to be a reliable indicator of an odontopathic infection when it was applied to rampant caries patients (Tables 16-2 and 16-3). However, its reliability in identifying a high-caries-risk patient prior to the onset of clinical caries has not been demonstrated. The diagnostic value of a saliva culture can be enhanced if S. mutans is also examined for. This was not possible until the advent of the selective MSB medium (See "Selective Media" in Chap. 2), which permits reliable estimates of the salivary levels of S. mutans to be made. The salivary levels of S. mutans are related to the tooth levels of S. mutans and correlate with the number of carious lesions and the DMFS scores. This is understandable as the tooth surface and the carious lesion are the main, if not only, niche for S. mutans in the oral cavity. S. mutans levels above 100,000 per ml of saliva have been associated with active decay and may provide an accurate indication of a S. mutans infection.



細菌學實驗



這些臨床及病史資料應該以牙齒病變感染的細菌學證據來補充，實施在猛爆性蛀牙的患者身上，Lactobacillus Index指標(查閱第十六章"Lactobacillus Index)被認為是一個牙齒病變感染可靠的指標，然而，在辨認臨床蛀牙發生前的高蛀牙率病人的可靠性還未被證明，若S. mutans也被檢察，則唾液培養的診斷價值可被提高，直到selective MSB medium(查閱第二章"Selective Media")出現才有其診斷價值，其提供可靠的唾液中S. mutans預估量，唾液中S. mutans的量與牙齒表面S. mutans的量有關，且與其蛀牙的數目和DMFS有關聯，可了解的是，因為牙齒表面和蛀牙是主體，不只是S. mutans在口腔中活動範圍?，若唾液中每毫升有超過100,000的S. mutans的量，則與蛀牙活躍性有關，且能提供一個切確S. mutans感染的徵兆。



The enumeration of S. mutans and lactobacilli in salivary samples, while capable of being incorporated into a routine culturing procedure in a hospital microbiology laboratory is, as of 1981, not cost efficient in a private practice clinical situation. In an effort to transfer some of the knowledge that could be obtained from these bacteriological procedures to the clinical sector, the selective media have been simplified or modified so as to give information which, though less reliable, is nonetheless useful as a first approximation of risk to caries.



S. mutans和lactobacili在唾液樣本中的細目，將其合併當作醫院微生物實驗室常規培養程序，在1981年代私人臨床現狀成本很高，從這些細菌學過程得到的知識，轉移到臨床部分，簡單化或修改selective media，可給予一些雖然較不可靠，但對評估蛀牙的風險是有效的資料。



Snyder Test Agar. The first successful effort in this regard was the Snyder Test Agar which added a pH indicator to a glucose agar that had been adjusted to a pH of 4.7 to 5.0. Bromocresol green was chosen as the indicator dye because its pK is below pH 5.0, and therefore, it would change from green to yellow only if growth of aciduric organisms occurred. As aciduricity is a characteristic of both lactobacilli and S. mutans, this diagnostic medium was well designed to detect the presence of these organisms. Accuracy was lost because the medium was designed in a yes-no configuration and could not differentiate reliably along a spectrum of microbial levels in the saliva. Thus, one ml of saliva, which contained 1,000,000 CFU of lactobacilli might give the same positive reaction as one ml of saliva which contained only 100 CFU of lactobacilli. The correlation with salivary lactobacilli levels improved with the rapidity of the onset of color change. Thus, a color change after one or two days of incubation was more likely to indicate high levels of lactobacilli than was a change after 7 days of incubation.



Snyder Test Agar

最初成功的例子是加入pH值偵測並調整在pH值4.7-5.0的一個葡萄糖培養基Synder Test Agar，選擇三溴甲酚綠當做偵測的染色工具，因為其pK值是低於pH 5.0，所以，只有當產酸微生物存在時，會從綠色變成黃色，由於產酸能力是lactobacilli與S. mutans的特質，設計這種診斷培養基來偵測是否有這些微生物的出現，因為此培養基是設計成非是及非的型態，且無法在唾液中單憑微生物量的範圍來分辨其可靠性，使得準確性不被重視。因此，一毫升的唾液含1,000,000 CFU的lactobacilli可能與一毫升的唾液只含100 CFU的lactobacilli有相同的正反應，與唾液中lactobacilli量的關係加快了出現顏色變化的速度，所以，一或兩天培養後出現顏色變化，會較七天培養後出現顏色變化，顯示其所含lactobacilli的量更高。



In retrospect, it was unreasonable to expect that such a complex inoculum, as saliva, could yield easily interpretable data on caries susceptibility when placed into a single diagnostic medium. The fact that it seemed to do so in many instances, indicated that the trait selected for, i.e., aciduricity, was a prime requirement of a cariogenic organism.



回朔以往，這無法合理的預期，像唾液如此複雜的接種體，當放在一個單一診斷培養基中，容易產生可解釋的蛀牙敏感性資料，事實上，這似乎在很多情況下都顯示其選擇的特性，例如產酸性，是致蛀牙微生物的主要必須條件。



Diagnostic Broths for S. Mutans . Diagnostic media that give information concerning S. mutans would be of greater value in assigning individuals to high and low caries risk groups. Several broth media, which relied upon pH changes and which contained bromocresol purple as a pH indicator, were designed to give yes-no information concerning S. mutans in plaque samples. The 20 percent sucrose and 0.2 units/ml bacitracin formulation that was responsible for the success of the MSB agar medium, were added to thioglycolate broth. In another medium one percent mannitol was substituted for the sucrose, while retaining the bacitracin. Because of the instability of the bacitracin, these broths had to be used within a week after preparation, which meant that they would be of little value in a clinical setting.



診斷S. Mutans的培養液

診斷培養基提供分配辨認高低蛀牙率的組別，其S. mutans的資料，一些培養液，靠著pH值變化，以三溴甲酚紫當做pH值指示劑，設計來提供使否在牙菌斑樣本中含有S. mutans，含20%的蔗糖和0.2 units/ml的崔西桿菌素bacitracin加入thioglycolate培養液中，可成功的做成MSB培養基，其他的培養基以1%的mannitol代替蔗糖，保留崔西桿菌素，因為崔西桿菌素的不穩定性，這些培養液必須在配置後一星期內使用完，這意味著在臨床上其使用價值不高。



A third medium contained one percent mannitol and one percent arginine HC1 in a dilute trypticase base. The mannitol was added to permit the growth of mannitol fermenters such as S. mutans and L. casei, while the arginine permitted the growth of arginine fermenters and/or arginine hydrolyzers, such as S. sanguis. This medium was designed to exploit the inverse relationship, seen in plaques, between S. mutans and S. sanguis (See "Longitudinal Studies" in Chap. 12). If S. mutans dominated in the plaque, the mannitol-arginine broth would turn yellow, whereas if S. sanguis and other amino-acid-fermenting bacteria dominated, enough ammonia would be released so as to neutralize any acid production from mannitol and the broth would remain purple.



第三種培養基是在稀釋的trypticase基底含1%mannitol和1% arginine蛋白胺酸HC1，當蛋白胺酸容許蛋白胺酸發酵物及/或蛋白胺酸水解物生長，加入mannitol使得mannitol發酵物，例如S. mutans和L. casei生長，這種培養基設計來開發在牙菌斑中，S. mutans和S. sanguis間的反轉關係(查閱第十二章"Longitudinal縱向實驗")。如果在牙菌斑中，S. mutans是主要的，則mannitol-arginine培養液會變成黃色，相反的若S. sanguis或其他胺基酸發酵性細菌是主要的，會釋放出足夠的氨，去中和從mannitol產生出的酸性產物，則培養液會維持紫色。



The color changes in these diagnostic broths were evaluated according to the proportions of S. mutans in the plaque and according to the S. mutans-S. sanguis ratio. The frequency distribution of the positive results obtained with the mannitol-arginine (MA) and the sucrose-bacitracin (SB) broths were highly significant (Table 19-2). However, none of these broths was so specific that it separated out all those plaques with high and low proportions of S. mutans and high and low mutans-sanguis ratios. The MA broth was slightly better statistically primarily because of the lower levels of false positives encountered, i.e., samples in which the color changes, but S. mutans was not detectable or present in low proportions.



根據在牙菌斑中S. mutans的比例和S. mutans-S. sanguis的比率來評估這些診斷培養液的顏色變化，在mannitol-arginine(MA)及sucrose-bacitracin(SB)培養液中，得到正反應結果的分佈頻率有很高的指標意義（表19-2)。然而，沒有一種培養液有足夠特定性來分別牙菌斑中高或低比例的S. mutans，及高或低Nutans-sanguis比率，MA培養液有較高的統計學上意義，因為他的偽陽性比率較低，例如，在顏色變化的樣本中，S. mutans沒有被偵測到或表現出比例較低。



These comparisons were performed on single site occlusal plaque samples taken from individual teeth and were more likely to reflect the caries risk status of the sampled tooth rather than the patient. Accordingly the study was extended to compare the salivary levels of S. mutans with color changes in the MA, SB and a third broth, thallium acetate (TA). The TA broth contained 0.5 percent mannitol, which permits growth of S. mutans and 0.5 percent thallium acetate and 1 ppm crystal violet, which inhibits the growth of the other oral organisms. Unstimulated saliva was collected from 109, twelve to thirteen-year-old children, and inoculated into each of the diagnostic broths and onto MSB agar. One hundred of these salivas had detectable levels of S. mutans on the MSB agar, and the SB broth was positive in 95 percent of these samples; the MA broth in 70 percent, and the TA broth in 25 percent. The SB broth was thus extremely sensitive for detecting S. mutans but was not able to differentiate between the levels of S. mutans (Table 19-2). The TA broth appeared to be insensitive to S. mutans levels, whereas the MA broth was best able to distinguish between high and low proportions of S. mutans in the saliva.



這些對照以從個體取出牙齒咬合面的單一位置牙菌斑樣本完成，且較易反映出樣本牙齒的蛀牙風險狀況而不是病人個體，於是，這些研究延伸以在MA、SB和第三個培養液醋酸鉈thallium acetate(TA)的顏色變化，來比較唾液中的S. mutans的量，TA培養液含有0.5%的mannitol，可使S. mutans生長，還有0.5% thallium acetate與1ppm的紫羅蘭晶，能抑制其他口腔為生物的生長，從109個12-13歲孩童身上取得非刺激分泌的唾液，灌輸進入每個診斷培養液及MSB培養基中，發現在MSB培養基中可探測到100個唾液樣本有S. mutans存在，SB培養液中95%的樣本表現出正反應，在MA培養液中有70%，而在TA培養液中有23%。所以SB培養液對偵測S. mutans是最敏感的，但無法分辨S. mutans量的不同(表19-2)，TA培養液對S. mutans的量是不敏感的，MA培養液則是最能夠分別唾液中不同高低比率的S. mutans。



Semi-quantitative Tests for S. mutans . The diagnostic broths sacrifice diagnostic accuracy for simplicity. Bratthall, Kohler and their associates have sought to overcome these deficiencies by introducing a semiquantative salivary culturing procedure using the MSB agar. The subject chews a piece of paraffin to increase the shedding of bacteria from the teeth into the saliva. A wooden tongue depressor (spatula) is turned around ten times in the mouth in order to wet it with saliva. The tongue depressor is removed from the mouth and pressed directly against the MSB agar, thereby inoculating the agar with the saliva. A comparison of this technique with conventional cultivation of the saliva showed that more than 100 CFUs obtained with the tongue depressor corresponded to more than 1,000,000 S. mutans per ml of saliva (Table 19-3). No colonies indicated fewer than 400 CFUs of S. mutans per ml of saliva.



S. mutans的半定量測試

診斷培養液因為其簡單性犧牲了診斷的正確性，Bratthall、Kohler與其同事引進採用了一個使用MSB培養基的半定量唾液培養程序，來尋找克服這些短處的方法，個體咀嚼一片蠟片來增加細菌從牙齒脫落而進入唾液中，一個木頭製壓舌板在口中翻轉約十次使其被唾液浸濕，壓舌板從口中取出直接壓在MSB培養基上，以唾液灌輸在培養基上，與傳統培養唾液方式比較，顯示以壓舌板會取得大於100 CFUs相當於每毫升的唾液有大於1,000,000 的S. mutans (表19-3)，沒有菌落顯示其每毫升唾液少於400 CFUs的S. mutans。



This methodology was then used to survey select groups of subjects residing in Sweden for their salivary S. mutans levels. About 20 percent of the school children and military recruits sampled had high salivary S. mutans levels and were considered on the basis of a clinical examination to belong to a high caries risk group (Table 19-3). Only three percent of the dental students sampled were considered to be at risk to caries, a finding that is consistent in general with the caries status of dental students. A group of Vietnam refugees was also sampled. The individuals had a low caries experience in the past, but were developing caries in the Swedish environment. About 50 percent of the 14 to 21-year-old individuals were, on bacteriological criteria, placed in the high risk group, a finding which was confirmed by clinical examination.



這種方法論後來被使用在測量選取出居住在瑞典的個體，其唾液中S. mutans的量，約有20%學童和徵募軍人的唾液樣本有高含量的S. mutans，且以臨床實驗為基礎來考慮其屬於高蛀牙危險的組別(表19-3)，一般而言，一個牙科學生連續的蛀牙情況發現，只有3%的牙科學生樣本是有蛀牙危險的，一群越南徵召軍人也被取得樣本，在瑞典社會中，那些以往有低蛀牙率的個體，但漸漸發展出蛀牙的個體，以細菌學準則來說，臨床實驗確認在14-21歲的個體，約有20%屬於高蛀牙率組別。



These investigators are using the same culturing procedure to identify mothers with high salivary levels of S. mutans. They hope that by eliminating or reducing the S. mutans infection in the mothers, that their children will not become infected with S. mutans and accordingly will have a low caries experience. Preliminary results indicate that a comprehensive treatment program for the mothers, which included professional tooth cleaning, excavation of carious lesions, fluoride varnish and discussions about the role of sucrose, have reduced the incidence of a S. mutans infection in their children compared to children in a control group whose mothers had not received similar treatment. This type of protocol, with its apparent positive results, demonstrates the efficiency of treatment when directed according to the SPH.



這些研究者使用相同的培養程序，來辨認唾液中有高含量S. mutans的母親，他們希望藉由限制或減低母親口中S. mutans的感染，使得他們的孩子不會被S. mutans感染，也就會有較低的蛀牙率，初步的結果發現，在母親廣泛的治療計畫，包含專業潔牙，挖掘蛀牙，塗氟漆及討論蔗糖扮演的角色，與對照組中母親的小孩比較，實驗組中母親的小孩，其S. mutans感染的發生會下降，這種療程，有很明顯良好的結果，顯示當根據SPH治療的效果是很好的。



Summary of Diagnostic Criteria. Diagnosis of a cariogenic infection is essential in order to focus treatment upon those individuals either infected or at risk to infection. This selectivity is what distinguishes the SPH from the NSPH and provides for a greater efficiency and intensity of treatment. Clinical symptomatology can serve to identify those patients who should receive preventive treatment. This approach was introduced by Jay and Becks, (See "Diet Therapy" in Chap. 16) who directed their dietary therapy at rampant caries patients. They introduced the Lactobacillus Index as a means of monitoring patient compliance with the dietary regimens, and as the basis for increasing, decreasing or stopping the preventive therapy. Tests for lactobacilli can now be supplemented with tests for S. mutans, such as the semiquantitative salivary MSB cultures and the qualitative mannitol-arginine broth. In the following sections, the efficacy of various antimicrobial agents to combat an S. mutans infection and/or dental caries will be discussed. These studies were conceivable only in the context of a diagnosable cariogenic infection.



診斷準則的總結

為了針對不論是被感染的或是有危險被感染的個體治療，診斷蛀牙感染是必要的，這種選擇方法能辨別SPH與NSPH的不同，且提供了高效率及高強度的治療。臨床樣本學sympomotology可提供辨認須接受預防性治療的患者。此方法由Jay和Becks提出(查閱第十六章"飲食治療")，指引猛爆性蛀牙的患者飲食治療。他們提出以Lactobacillus為指標當作監視病人對飲食療法的合作度，且視為增加、減少或停止預防性治療的基礎。檢查lactobacilli現今可使用檢查S. mutans的方法來補充，像是半定量測試唾液MSB培養，及定性mannitol-arginine培養液。在接下來的段落文章，會討論不同的抗菌藥物對抗S. mutans感染或蛀牙的效率。這些研究只在診斷性蛀牙感染的文章中出現是可理解想見的。



CHEMICAL AGENTS DIRECTED AGAINST S. MUTANS



The ecological niche of S. mutans is the tooth surface. This has important implications for antimicrobial therapy as treatment need only be applied on the teeth, and if successful, may lead to a prolonged period without a S. mutans reinfection, as there are apparently no other oral soft tissue reservoirs of this organism. The therapist can, under these conditions, use topical agents, thereby avoiding certain problems related to the usage of systemic agents. In regard to the topical agents, a series of questions need to be answered before their usage can be considered routine. In this section investigations will be described which address such issues as 1. What topical agents to use? 2. How is this agent delivered to the dento-gingival surfaces? 3. What dosages should be used? 4. When do you stop treatment?



抗S. mutans的化學藥物



S. mutans的致病因所在在牙齒表面，這對抗為生物治療有重大含意，因為治療只需要侷限在牙齒，且如果治療成功，可能導致延長沒有S. mutans重新感染的時間，因為顯然沒有其他口腔軟組織儲存這個微生物。此治療在此狀況下可以，使用局部藥物，避免一些與使用系統性藥物相關的問題，至於局部藥物，在被視為常規使用之前，必須回答一系列的問題，在這個段落會闡述以下論點的研究，1. 使用哪一種局部藥物？2. 此藥物如何被傳遞到牙齒及牙齦表面？3. 須使用多少劑量？4. 何時停止治療？



What Topical Antimicrobial Agent to Use?



Substantivity. Any agent recommended for usage in dentistry must possess antibacterial activity against S. mutans and lactobacilli in vivo. The killing action of an agent is a function of the chemistry of the compound, but perhaps more importantly, of the contact time of the agent with the bacteria. This aspect is well recognized in medicine where the goal of antimicrobial treatment is to maintain a 24-hour level of the agent in the blood that is above the minimal inhibitory concentration (MIC) determined in vitro. This concept has not been appreciated in dentistry, since most antimicrobial agents have been packaged in mouthrinses, gels and dentifrices which by design, are present for only minutes per day in the oral cavity. If the agent is not immediately bactericidal and/or capable of penetrating the depth of the plaque, it will have a minimal and/or transient effect on the oral flora. From this consideration alone, the failures of most oral antimicrobial agents can be explained. Thus when chlorhexidine was shown to prevent plaque (See "Chlorhexidine" in Chap. 18), it meant that there was something unique about chlorhexidine. This appears now to be the substantivity of chlorhexidine in the oral cavity due to its basic charges, which allow it to adsorb to the mainly negatively-charged tooth and mucosal surfaces.



使用哪一種局部藥物？



獨立自力性? Substantivity

任何被建議使用在牙科上的藥物必須在人體，具備抗S. mutans 和lactobacilli的抗菌能力，藥物的殺菌作用是一個複合體的化學功效，但更重要的是，此藥物與細菌接觸的時間，在藥物上此觀點被認可，抗菌治療的目標是在血液中，24小時維持定量藥物，需高過體外實驗的最低抗菌濃度(MIC)。此論點在牙科不被賞識，因為多數抗菌藥物被包裝入漱口水、膠或牙膏中，且被設計使用在口腔中一天只有數分鐘時間，如果藥物沒有立刻殺菌或深入牙菌斑中，其作用在口腔微生物的效果只是侷限且短暫的。單獨考慮到此，可以解釋為什麼大部分抗菌藥物會失敗。所以當chlorhexidine顯示可預防牙菌斑(查閱第十八章"Chlorhexidine")，這表示chlorhexidine有一種獨特性，這顯然是在口腔中，chlorhexidine的substantivity，因為其鹼性帶電荷，能使其附著到主要帶負電的牙齒及黏膜表面。



The experience with chlorhexidine indicates that substantivity on the dentogingival surfaces should be a characteristic of a topical agent. Accordingly, potential oral antimicrobial agents should be evaluated for release in an active form. A demanding in vitro test for the substantivity and prolonged antimicrobial activity has been described by Turesky et al. Extracted teeth are polished and immersed into a one percent solution of the test agent for one minute. The tooth is air dried, immersed again for one minute, and again air dried. The tooth is placed into 250 ml of distilled water for five minutes to remove any loosely-bound agent. At this point the tooth is sequentially placed for various periods of time into a series of broth media inoculated with S. mutans. Chlorhexidine and dodecylamine were the most potent inhibitors in this system, as after four serial passages totaling 25 hours in broth, the teeth treated with these agents were still capable of inhibiting growth.



使用chlorhexidine的經驗顯示，在牙齒牙齦表面的substantivity應該是局部用藥的一種特性，因此，必須評估以活性型態釋放可能的口內抗菌藥物，Turesky及其同事描述，在體外高要求標準的研究substantivity，及延長的抗菌活性的實驗，研磨拔出的牙齒並將其包埋入1%實驗用藥的溶液中一分鐘，將牙齒風乾，再次浸泡在250 ml蒸餾水五分鐘，去除任何零星附著的用藥，此時，依序將牙齒放入且灌輸入S. mutans不同系列的培養液，以不同時間期間點放入，在此系統中，chlorhexidine與dodycylamine是最顯著的抑制劑，在培養液中25小時通過四個系列過程後，以這兩種藥物治療的牙齒還是能夠抑制微生物的生長。



Substantivity may be enhanced by pretreating the enamel so as to make it more receptive for the retention of the agent. Acid treatment of the enamel permits more fluoride to penetrate the enamel layer and as discussed in Chapter 18, this fluoride could act as a reservoir of antimicrobial activity (See "Fluoride-Antimicrobial Effects" in Chap. 18). The enamel could be treated in other ways so as to increase substantivity of other agents. When enamel slabs were treated in vitro with chelating agents, such as oxalate and fumarate and then exposed to hexachloraphene, the enamel levels of hexachloraphene increased by six- to seven-fold. These slabs exhibited marked inhibition of plaque formation compared to controls when incubated with S. mutans. These results warrant clinical testing of the enamel conditioning system in the caries-susceptible patient.



經由穿越牙釉質可加強substantivity，使其藥物的保留更能被容納接受，在第十八章討論到，牙釉質的酸治療容許更多氟化物穿越牙釉質表面，氟可以扮演抗菌能力的儲藏室(查閱第十八章"氟化物的抗菌作用")，牙釉質能夠以其他方法治療，像是增加其他藥物的substantivity，當牙釉質切片在體外，用螯合劑，像是草酸鹽oxalate和反丁西二酸鹽fumarate治療，接著暴露在六氯酚hexachloraphene，則牙釉質的六氯酚量會提高六到七倍，這些切片顯示，當與S. mutans培養在一起，跟對照組比較，實驗組顯著可抑制牙菌斑的生長。這些結果證明在蛀牙敏感的患者上，臨床牙釉質處理系統的臨床測試。



Taste. The usage of a topical agent in the oral cavity and especially in children requires that the agent possess a taste that is acceptable. The organoleptic properties of the agent will thus assume importance out of proportion to its therapeutic efficacy. Little information regarding the taste characteristics of antimicrobial agents is provided by the pharmaceutical industry, because this information was never important in the design of products that were used in medicine. A topical agent such as bacitracin has such an objectionable taste that some of its anticariogenic activity in animal models (See Table 8-3) could be attributed to the animals' refusal to eat food containing this agent. Other topical antibiotics, such as kanamycin, vancomycin, neomycin and puromycin, do not possess a disagreeable taste. Many of the agents used in the oral cavity, such as chlorhexidine, fluorides and iodine, have undesirable taste characteristics. Fortunately in many instances these taste(s) can be masked. More information on the gustatory sensations of these topical antimicrobial agents is needed.



味道

在口腔中使用局部用藥特別是在孩童身上，藥物需要具備可接受的味道，這些用藥的感官特性，除其治療效用外將是重點，藥物廠商提供非常少考慮到抗菌藥物味道特性的資訊，因為這些資訊在設計視為藥物的這些商品，從不是最重要的，像是崔西桿菌素bacitracin，此局部用藥就有令人反感的味道，其可歸因於一些在抗菌作用的動物模型上(查閱表8-3)，動物拒絕食用含這些藥物的食物，其他局部抗生素，像是卡那黴素kanamycin、萬古黴素vancomycin、nemycin和puromycin，就沒有這種無法接受的味道，很多使用在口腔的藥物，像是chlorhexidine、氟和碘就有此反感的味道，幸好在很多時候，這種味道可被隱藏，我們需要致力於取得更多這些局部抗菌藥物味覺的資料。



Stability. The oral antimicrobial agents should be stable at room temperatures for considerable periods of time. Most antiseptics, fluorides and some antibiotics, i.e., kanamycin, neomycin and polymyxin possess this stability. Vancomycin and bacitracin, after solubilization, remain active for only a few weeks at room temperature. Chlorhexidine can be inactivated by anionic substances, such as phosphates, carbonates, sulfates and anionic detergents. Since these compounds are often found in toothpastes, it is possible that the addition of chlorhexidine to such a delivery vehicle will render it inactive. Thus, in addition to stability, the bioavailability of the agent in various dentifrices, gels and mouthrinses will have to be determined.



穩定性

口腔抗菌藥物必須在室溫下相當的時間內保持穩定，多數的消毒劑、氟化物及一些抗生素，像是卡那黴素、neomycin和polymycin具備此穩定性。萬古黴素和崔西桿菌素，在溶解後，室溫下只能維持幾周的活躍性，Chlorhexidine因為其負離子物質，像是磷酸、碳酸、硫酸及負離子去汙劑，可以保持非活性，既然這些複合物時常發現在牙膏中，也可能加在chlorhexidine中成為傳遞媒介，使其保持非活躍性，所以，除了穩定性，必須決定在不同牙膏、牙膠或漱口水中，此藥物的生物利用度。



Safety. The safety of any oral antimicrobial agent will have to be established on the basis of animal studies and carefully monitored human trials. Chlorhexidine has been extensively used in various medical fields with no serious toxicity found. After two years of continuous use in two separate dental studies, no evidence of reduced effectiveness, bacterial resistance, yeast overgrowth or other signs of toxicity were found. Flotra et al. noted that epithelial desquamation may occur in any occasional patient. A brown stain appears unavoidable and may irreversibly discolor silicate restorations. The stain on the natural surfaces is readily removed by dental polishing.



安全性

任何口腔抗菌藥物必須以動物實驗及仔細監控的人類連續研究為基礎，chlorhexidine是最常用在不同醫學領域，且沒有重大毒性的抗菌藥物，在兩個獨立的牙科研究連續兩年的使用後，沒有證據顯示其效用減低，細菌產生抗藥性，或有酵母菌的增生，或其他毒性徵兆的產生，Flotra及其同事發現，上皮脫削可能會偶而發生在患者身上，棕色染色無可避免會發生，且含矽的填補物可能會有不可逆的變色，這些在天然正常的表面形成的染色可用牙科打磨移除。



Fluoride has a more extensive safety record, as water fluoridation and fluoride dentifrices have been used for 20 to 30 years without obvious evidence of toxicity. The dentifrices are formulated to deliver about 1 mg of fluoride per gram of toothpaste. If approximately 0.5 g of toothpaste is used per brushing, then about 0.5-1 ppm are applied to the tooth surfaces. Eighty percent of the dentifrice can be recovered in the rinsing water, so that 0.1 to 0.2 ppm are either swallowed or absorbed to oral surfaces. If the APF gels which contain 0.5 percent fluoride are used, considerably more fluoride is available both for adsorption to the teeth and for swallowing. If approximately 3 to 5 ml of gel are applied per treatment, this would contain about 15 to 25 ppm of fluoride. If eighty percent of the gel is expectorated, this leaves behind 3 to 5 ppm of fluoride. Some of this goes into the tooth, as judged by the analysis of the enamel surface, and some is swallowed. In the Cheektowaga study, over 200 applications of gels containing 0.5 percent fluoride were not associated with any signs of toxicity. Nevertheless, the use of topicals with 0.5 percent or 1.23 percent fluoride requires a prescription and should be carefully monitored. The treatment should be for short periods so as to minimize any signs of chronic fluoride toxicity. Continuous doses of fluoride in the range of 20 to 30 ppm over a period of years has been associated with osteosclerosis and thyroid changes.



氟有更大規模安全的歷史記錄，飲水加氟及含氟牙膏已使用了20-30年，並沒有發現明顯的毒性，牙膏每公克約傳遞1毫克的氟，若每次刷牙使用約0.5克的牙膏，則約0.5-1ppm會被使用在牙齒表面上，80%的牙膏可以在漱口沖掉的水中發現，所以有0.1-0.2ppm的氟不是被吞下就是被口腔表面吸收，如果使用含有0.5%氟的APF氟膠，可想而知更多的氟會被牙齒吸附或吞下，如果每次治療使用約3-5 ml的氟膠，則會包含約15-25 ppm的氟，如果80%的氟膠被咳出，這會留下3-5 ppm的氟，一些會進入牙齒，如同進入牙釉質表面?，另一些則會被吞下，在Cheektowaga研究中，多於200次0.5%的塗氟膠與任何毒性徵兆無關，然而，局部使用0.5%或1.23%的氟需要處方籤才能使用，且必須嚴格的監控，治療必須是短期才能減少任何長期氟中毒的發生，氟劑量在20-30 ppm的範圍連續使用幾年，與軟骨症及甲狀腺的病變有關。



Regulations related to safety and efficacy have proved to be a major obstacle in the development of new topical antimicrobial agents in the United States. Since 1962, when the legislation was enacted, only a toothpaste with monoflurophosphate, has been approved by the dental division of the FDA. The necessary toxicology studies in animals which must be done prior to human studies may cost about one million dollars. Most dental pharmaceutical companies are seeking approval for an over-the-counter product, which can be used frequently, if not daily. The safety requirements for a compound with such unrestricted usage have to be stringent, and this apparently accounts for the essentially zero approval rate. FDA approval for prescription-type agents that are used in individuals diagnosed as having an odontogenic infection should not be as difficult to obtain. However, neither the dental profession nor industry have approached the FDA from this perspective. Only a few clinical trails have been performed according to the specific plaque hypothesis, and these have been done with agents that had been introduced to the market prior to 1962.



與安全性及效用有關的法規證明是美國新的局部抗菌藥物發展的重要阻礙，自1962年起，當有立法制定，只有含monoflurophosphate的牙膏被FDA的牙科部門認可，必要的動物毒性實驗必須在需花費約一百萬美金的人體實驗之前完成，大多牙科藥材廠商尋求在賣場可得，不是每天但時常被使用的商品認可，這無限制使用的複合物，其安全要求必須是嚴厲且令人信服的，但顯然的其說明認可率幾乎是零。FDA對處方簽藥物的認可，使用在診斷為牙科病變感染的個體，不應該太困難取得。然而，牙科專業人士或工業皆沒有達到FDA的此觀點，在1962年之前上市的藥物，只有一些臨床連續實驗是根據特定性牙菌斑假說來實行。



Delivery of the Agent



Antimicrobial therapy should bring the drug into contact with the infecting bacteria for a time period sufficient to eliminate the bacteria, or to reduce the bacterial load to a level where host defense mechanisms can control the infection. In systemic infections, the drug is given orally or is injected. These delivery systems have not been used in dentistry, except where overt dental abscesses are present. Instead, mouthrinses and dentifrices have been almost exclusively used as delivery systems. Convenient as these may be, they fail as vehicles for therapeutic agents, except in those instances where the drug has unusual substantivity. In the discussion which follows, we will examine the various delivery systems available for oral chemotherapeutic agents.



藥劑的給予

抗菌治療必須將藥物帶到與引起感染的細菌接觸一段足夠時間來抑制細菌，或是減少細菌承載量到一定的量，宿主抵抗機制可以控制感染，當系統性感染時，藥物以口服或注射給予，除了當明顯的牙齒膿殤出現，牙科上並沒有使用這些傳遞系統，取而代之，漱口水跟牙膏幾乎是唯一的使用途徑，雖然使用方便，除了在這些藥物有不常見的substantivity情況下，它們無法做為治療藥物的傳達媒介?，在接下來的討論中，我們會檢視口腔化學治療藥物不同的傳遞媒介系統。



Dentifrices. Dentifrices are pleasant-tasting pastes containing abrasive ingredients, which were designed to be used with toothbrushes, in order to facilitate the debriding of the dentogingival surfaces of food particles and plaque. Approximately 0.5 to 1 g of dentifrice is used for a brushing which takes less than one minute. There is the possibility that the dentifrice ingredients could inactivate the therapeutic agent, as occurred in certain trials involving chlorhexidine. Dentifrices remain a popular choice for the delivery of chemotherapeutic agents, probably due to the success of the fluoridated dentifrices and the public and professional acceptance of toothbrushing as a valid oral hygiene procedure. However, toothbrushing with abrasive dentifrices should be an adjunct to antimicrobial therapy, with the brushing preceding the application of the antimicrobial agent.



牙膏

牙膏是含有研磨劑且味道良好的膏狀物，設計以牙刷使用，來促進去除牙齒牙齦表面的食物殘渣及牙菌班，使用約0.5-1克的牙膏刷牙耗時不會超過一分鐘，在一些含chlorhexidine的實驗，牙膏分子有可能會阻止治療藥物，牙膏依舊是常見的化學治療藥物傳遞媒介的選擇，可能因為含氟牙膏的成功，及大眾和專業人士接受刷牙仍是良好的口腔衛生維持的程序，然而，用研磨牙膏刷牙應該是抗菌治療的助手，伴隨刷牙動作會優於抗菌藥物的給予?。



Mouthrinses. Mouthrinses are inefficient delivery systems for a plaque antimicrobial agent because the one minute or more rinsing time is not adequate for the agent to penetrate and kill bacteria located in the deeper layers of supragingival plaque, occlusal fissures, the gingival sulcus, the periodontal pocket and the interproximal spaces. Stralfors calculated that if a mouthrinse were able to kill 75 percent of the oral flora, the original numbers would be present within one hour. This kill value is about the level which some antibacterial mouthrinses report concerning the decrease in salivary bacterial counts. Even here, the level of salivary reduction is misleading, as the salivary flora bears little resemblance to the supra- or subgingival plaque flora. Thus the reductions in the salivary flora achieved with some mouthrinses may be obtained against a group of organisms which have never been associated with caries or periodontal disease. These considerations make all the more remarkable the antiplaque and antigingivitis action of chlorhexidine and the anticaries action of fluoride when delivered in mouthrinses. Since this beneficial result is most likely dependent on the substantivity of these agents on the tooth surfaces, it may be concluded that only agents with similar substantivity can be effective when delivered in a mouthrinse.



漱口水

以漱口水作為牙菌班抗菌藥物的給予效率不高，因為1分鐘或更多的漱口時間對藥物穿透深層牙齦下牙菌斑、咬合面溝隙、牙齦溝、牙周囊袋及鄰接面空間，還有殺死細菌是不夠的，Stralfors計算，如果漱口水要能殺死75%的口腔微生物，原始數目必須存在一小時內，這能夠殺死細菌的值，約是一些抗菌漱口水考慮到降低唾液細菌數目所提出的量，甚至，因為當唾液中微生物很少與牙齦上或牙齦下牙菌斑微生物是相似的，唾液減少量是令人誤解的。所以，在一些漱口水中達到唾液微生物的降低，可能只能得到對抗一群與蛀牙及牙周並無關的微生物，這些考量，使得當以漱口水型式給予，chlorhexidine有更顯著的抗牙菌斑及抗牙周炎作用，且氟的抗蛀牙作用更明顯。所以這有利的結果，是歸功於這些藥物在牙齒表面上的substantivity，結論是只有有相似substantivity的藥物，當以漱口水給予會較有效率。



Frequent usage, such as every three to four hours, may be an effective treatment schedule for mouthrinses containing antimicrobial agents with rapid killing action and low or no substantivity. This regimen could be maintained for one to two weeks with patient cooperation, if used for treatment of a diagnosed infection. However, if used prophylactically on an open-ended schedule, the cooperation of most subjects would be difficult to obtain.



時常使用，例如每3-4小時使用一次，在含抗菌藥物的漱口水可能是有效的治療，他有快速的殺死細菌作用，且其substantivity是很低或沒有的，如果診斷為有感染情況下，這種療法可以在患者合作下維持1-2周，然而，如果預防性的沒有期限下使用，多數個體要維持合作度將是困難的。



Applicator Trays. The applicator tray is a device which fits over the coronal surfaces of the teeth. It can be individually fabricated out of plastic from a model of the teeth or can be purchased in standard sizes from certain dental suppliers. With some trays, a sponge insert can be placed in the trays so as to occlude the space between tray and tooth. The applicator is an effective way of delivering a chemotherapeutic agent to the tooth surfaces. The agent is not diluted by the saliva and has little contact with the soft tissue and tongue, thereby minimizing mucosal irritations. Applicator trays are not convenient for continuous daily usage, as would be indicated under the NSPH, and have been generally neglected by the dental profession, except as a means of giving six-month or yearly topical fluoride treatments. However, they hold great promise as a delivery system for antimicrobial agents used under the rationale of the SPH (See "Cheektowaga Study" in Chap. 18).



牙托

牙托是一個能吻合牙齒冠狀面的裝置，他可以由牙齒模型個別製造成塑膠形式，或是從某些牙材供應商得到固定尺寸的牙托，某些牙托，有海綿裝在牙托上使其佔據牙托與牙齒中間的空間，這種方式對給予牙齒表面化學治療藥物是相當有效率的方法，藥物不會被唾液稀釋，且很少與口腔軟組織和舌頭接觸，所以降低黏膜的刺激，連續性每天使用牙托是不方便的，在NSPH指示下，除了當作每半年或一年局部塗氟治療的工具，牙托一般被牙科專業人士忽略。然而，在SPH的基礎下，牙托作為抗菌藥物的傳遞媒介系統有很高的承諾?(查閱第十八章"cheektowaga研究")。



Chewing Gums, Tablets, Adherent Paste and Lozenges. Chewing gums, tablets, adherent pastes and lozenges could serve as slow-release devices that would permit the presence of an antimicrobial agent in the oral cavity for periods of five minutes or more. If the agent had an affinity for the dental surfaces, such as fluoride and chlorhexidine have, then this delivery system could be effective.




口香糖、藥片、黏著牙膏和錠劑

口香糖、藥片、黏著牙膏和錠劑可做為慢速釋放的工具，使得抗菌藥物在口腔中停留五分鐘或更久，如果藥物對牙齒表面有親合力，如同氟及chlorhexidine，則此傳遞系統將會是有效的。



Depot Devices. A more convenient and efficacious method of drug delivery would be to place the drug in a receptacle or device which can be anchored to the tooth surface. If the drug could be embedded in a matrix which is slowly solubilized in the saliva, then continuous antimicrobial levels could be maintained in the saliva for days or weeks after the insertion of the device. The receptacle would have to be small and within the physiological tolerance of the dental structures. The acceptance of orthodontic therapy would indicate that patients will tolerate a small device secured to one or more teeth. The kinetics of drug release would have to be predetermined to assure drug levels above the MIC (minimal inhibitory concentration) levels of various plaque organisms. The devices could be attached to newly erupted teeth in individuals who have a history of above-average caries experience or who have elevated levels of S. mutans of lactobacilli in their saliva. In the case of periodontal disease, the device could be placed directly into the pocket and need not be attached to the tooth.



儲存裝置

藥物傳遞更方便且有效率的方法是，將藥物放在一個可固定連結到牙齒表面容器或裝置中，如果藥物可以被包埋在一個在唾液中慢速溶解的模型，然後抗菌藥物可以在投入此裝置後，在唾液中持續維持一定濃度達幾天到幾周。此容器必須要小且在牙齒結構的生理耐受度內，根據對矯正牙齒治療的接受度指出，患者能夠接受固定一或數顆牙齒的小裝置，必須事先決定藥物動力學的釋放，來確保藥物濃度高於多種牙菌斑為生物的MIC(最低抑制濃度)，這裝置可以連結到有高於平均蛀牙率歷史，或唾液中有較高S. mutans和lactobacilli濃度的個體，其新萌發的牙齒，在牙周病中，此裝置可被放置與牙周囊袋直接接觸，且不需要接觸到牙齒。



The depot preparations represent a logical development in topical delivery systems for use in the oral cavity. Considerable clinical testing will be necessary before optimal drug levels can be determined. This development should come about cautiously and within the framework of the SPH.



此儲藏裝置準備代表使用在口腔中局部傳遞系統的合理發展，在最理想的藥物濃度確定前，必須有相當多的臨床測試，此產物必須謹慎的發展且須在SPH的框架中。



Dosages and Treatment Schedules



Topical antimicrobial agents should be delivered to the dentogingival surfaces in dosages that are adequate to yield a therapeutic result. But how do you measure a therapeutic result in the case of dental caries, when six to 24 months are necessary to determine whether the caries incidence has been reduced or stopped? Is there some clinical-pathological parameter that can be quickly changed by an effective agent(s) that is properly delivered to the caries-prone sites on the teeth? Many investigators have used plaque reduction as such an indicator. However, the plaque that is assessed is from the noncaries-prone sites at the dentogingival margin and most likely does not resemble the microbial composition found on caries-prone fissures and approximal sites. With the demonstration of the involvement of S. mutans and lactobacilli in dental caries, it became possible to use the levels of these organisms in saliva and their proportions in the plaque as a means of measuring treatment efficacy.



劑量與使用時間表

局部抗菌藥物必須以足夠達到治療結果的劑量，傳遞到牙齒牙齦表面，但是當需要6-24個月來確定是否蛀牙率有降低或停止時，要如何去測量一個蛀牙案例的治療結果呢?是否有一些被適當給予到牙齒容易蛀牙部位的藥物，可以迅速改變臨床病理變數?很多研究者使用牙菌斑減少當做指標，然而，確定評估從牙齒牙齦邊緣非高蛀牙率部位，及最高蛀牙率的溝隙和鄰接面的牙菌斑，在蛀牙中包含S. mutans和lactobacilli的證明，這證實使用這些唾液中微生物的量和他們在牙菌斑的組成，可當做測量治療效用的依據。



When S. mutans is found in levels greater than 100,000/ml saliva, active caries or a high DMFS score is usually present. When S. mutans is found in levels less than 1,000/ml saliva, active caries is usually absent. This last value could then serve as a therapeutic goal for treatment. Thus if usage of an antimicrobial agent suppressed S. mutans to levels below 1,000/ml of saliva, this treatment could be considered to be effective. In fact, such a treatment endpoint could possibly jeopardize S. mutans' survival on the teeth, as this salivary level is near the colonization threshold of S. mutans for fissures and below its colonization threshold, i.e., 10,000 CFU/ml for smooth surfaces (See "S. mutans Colonization" in Chap. 6). Accordingly, treatment which suppresses S. mutans to below 1000 CFU/ml of saliva could so reduce the chances for S. mutans to recolonize the teeth, that it could take months for S. mutans to reestablish itself in numbers that would constitute a cariogenic challenge to the teeth.



當在唾液中發現S. mutans的量大於100,000/ml時，通常可發現有活躍性的蛀牙或高DMFS分數，當唾液中S. mutans的量小於1,000/ml時，通常沒有活躍性的蛀牙，這最後的數值可當做治療的目標，所以如果使用一個抗菌藥物可以抑制S. mutans到在唾液中小於1,000/ml的量，則此治療可被視為有效的，事實上，這種治療的終點可能危及S. mutans在牙齒的存活，因為此唾液量是接近S. mutans在溝隙中形成菌落的閾值，且低於他形成菌落的閾值，例如在平滑面試10,000 CFU/ml (查閱第六章"S. mutans的菌落")，因此，抑制S. mutans到唾液中低於1000 CFU/ml的治療可以降低S. mutans在牙齒上重新形成菌落的機會，這對S. mutans來說會需要幾個月的時間重新建立足夠數目，來組成對牙齒產生威脅的量。



This ecological information was not available at the time of the initiation of the clinical trials that will be discussed in this chapter. In the absence of such a well-defined bacteriological endpoint, these clinical studies sought to determine whether various agents given in a variety of treatment schedules could simply reduce the salivary and/or plaque levels of S. mutans and/or lactobacilli. In certain studies the bacteriological findings were correlated with the subsequent caries experience of the patients.



這個生態學的資料在此章節討論的臨床連續實驗開始時還未可得，在缺少此清楚定義的細菌學終點時，這些臨床研究尋求，決定是否以不同治療時間表給予不同的藥物可以單純的降低唾液或牙菌斑中，S. mutans或lactobacilli的量，在一些研究中，細菌學的發現與患者隨後的蛀牙經驗有關。



Three treatment schedules were evident in these studies. One schedule required the patients to use the agent daily or almost daily. The only reason why these studies would not be considered as treatment according to the NSPH was the diagnosis in the patients, by clinical and/or bacteriological criteria, of a high caries risk. The second schedule also was derived from the NSPH, as it required the patients to use the medication repeatedly at regular intervals. Only the third schedule was unique to the SPH, as it involved a single short-term, intensive application of the agent.



在這些研究中，證實了三種治療時間表，第一種時間表需要患者每天或幾乎每天使用藥物，根據NSPH，為什麼這些研究不被考慮為治療的原因是，這些病患在臨床或細菌學標準的診斷是屬於高蛀牙率的，第二種時間表是源於NSPH，需要患者重複在一定的期間使用藥物，只有第三種時間表對SPH來說是獨特的，單次短暫密集的給予藥物。



CLINICAL STUDIES



Clinical studies involving a complex and chronic infection such as dental caries are fraught with operational difficulties. The studies to be described have in common that the treated patients were diagnosed as being at risk to caries. The chemical agents used, with the exception of chlorhexidine, are antimicrobials that were existent prior to the 1962 amendment to the Federal Drug Act.



臨床研究

臨床研究包括複雜且慢性的感染，例如住牙是伴隨著處理困難性的，討論到的研究，診斷有蛀牙風險來治療的患者是有相關性的，除了chlorhexidine以外，在1962年聯邦藥物管理局修正以前，使用化學藥物來抗菌就已存在。



Topical Fluorides



Anti-S. mutans Studies. Fluoride in low concentrations, especially in an acidic environment has a strong antimicrobial action mediated primarily against enolase (See Fig. 18-2). This antimicrobial effect of fluoride would occur any time a topical fluoride treatment was given.



局部塗氟

抗S. mutans研究

氟化物以低濃度，特別是在酸性環境有很強的抗菌作用，來傳達初步抗enolase (查閱圖18-2)，這個氟的抗菌作用會在局部塗氟治療中任何間點發生。



A specific effect of fluoride in vivo on S. mutans in humans was first demonstrated by Woods. He selected patients who had S. mutans in their plaques (a bacteriological diagnosis) and treated them with a dental polishing, using pastes with and without fluoride. One week later a significant decrease in the proportions of S. mutans was found in plaques taken from individuals who had been treated with fluoride. We have confirmed this result and have shown that the reduction in proportions of S. mutans can persist for up to 12 weeks after fluoride treatment. In these studies, teenage boys, living in a rehabilitation center, were randomly assigned to fluoride (1.23 percent acidulated phosphate fluoride (APF) gel) or placebo groups. Prior to getting treatment, the average values for percent S. mutans and percent S. sanguis were comparable in each group. Ten five-minute applications of either APF or placebo gels in applicator trays were given under supervision for two consecutive school weeks. No prior dental polishing was given. The proportions of S. mutans in the single approximal plaque was reduced by 50 to 70 percent in the APF group, compared to pretreatment values at each sampling period (Table 19-4). In the placebo group the proportions of S. mutans increased at each sampling period.



在人體研究氟化物在S. mutans的特別作用首先被Woods證明，他選擇在牙菌斑中有S. mutans的患者(細菌學診斷)，且使用含氟或不含氟的膏狀物來打亮牙齒治療，一個星期後，牙菌斑中發現使用氟化物治療的個體，其S. mutans有顯著的減少，我們肯定了這個結果，且顯示了在S. mutans比例的降低可以維持到氟化物治療後12周，在這些研究中，居住在一個復健中心的青少年男孩，隨機的分配到氟化物組(1.23% APF氟膠)，或安慰劑組別。在治療前，比較不同組別的S. mutans和S. sanguis平均百分比值，在學期中的連續兩個星期，在指導下，使用APF或安慰劑膠放入牙托中五分鐘重複十次，治療前沒有打滑牙齒， 在APF組別，在每個樣本時間點，與治療前數值的比較 (表19-4)，單一鄰接面牙菌斑的S. mutans比例下降了50-70%，在安慰劑組別，S. mutans比例則是在每個樣本時間點都增加。



The effect on S. mutans appeared to be selective in that the proportions of S. sanguis in the same plaque samples were not affected by the PAF treatments. In vitro testing showed S. mutans, S. sanguis and S. mitis to be equally sensitive to fluoride inhibition. This meant that the source of the specificity was not due, at least in vitro, to S. mutans having a lower tolerance to fluoride. The explanation was found by a consideration of the ecology of S. mutans and S. sanguis in the oral cavity. S. sanguis has a greater affinity than S. mutans for the tooth surfaces, owing to its ability to recognize surface receptors in the acquired enamel pellicle. S. sanguis is also present in higher numbers than S. mutans in the saliva, which is probably a reflection of its having more oral surface reservoirs which can shed into the saliva. Thus if a tooth surface has been either mechanically cleaned and/or disinfected with an antimicrobial agent, the odds are more favorable for S. sanguis to recolonize than S. mutans.



在S. mutans的作用顯然在相同牙菌斑樣本的S. sanguis比例是有選擇性的，且不被PAF治療影響?，體外測試顯示，S.mutans、S. sanguis和S. mitis對氟化物的抑制的敏感性是相同的，這表示，獨特性的來源，至少在體外，不是因為S. mutans對氟有較低的耐受性，考慮到在口腔中S. mutans和S. sanguis的生態而發現了解釋方法，S. sanguis比S. mutans與牙齒表面有較高的親合力，由於他辯認在必須的牙釉質黏體acquired enamel pellicle表面受體的能力，S. sanguis在唾液中也比S. mutans的量更多，這可能是他有更多口腔表面儲存的反應，使其能隱藏在唾液中，所以如果一個牙齒表面不是機械性清潔或用抗菌藥物消毒，S. sanguis重新形成菌落的優勢是高於S. mutans的。



This recolonization scheme could explain the beneficial results of any antimicrobial agent which is delivered to the tooth surfaces in a high enough concentration and for a time period sufficient to either disinfect or sterilize the plaque. The S. mutans to S. sanguis ratio could then be a sensitive and reliable measurement of the adequacy of treatment. In the data shown in Table 19-4, the S. mutans-S. sanguis ratio was about one prior to treatment and stayed about that value in the placebo group for the 12 weeks after the treatment period. However, in the fluoride subjects, the value decreased to 0.25 and stayed at that reduced value for at least 12 weeks. Thus by considering the directional movement of both the undesired species, such as S. mutans, and the desired species, such as S. sanguis, in a single index, a more accurate assessment of the efficacy of an antimicrobial agent, such as fluoride, can be made.



這重新形成菌落的系統可以解釋，任何抗菌藥物以夠高的濃度被帶到牙齒表面，且停留一定的時間來抗菌或消毒牙菌斑的有益結果。S. mutans和S. sanguis比例可以是一個治療適當的敏感且可靠的測量法。在表19-4顯示的數據，S. mutans-S. sanguis比例在治療前約是1，且在治療期間後，安慰劑組維持這個數值達12周，然而，在氟化物組別的個體，此數值降低到0.25且維持在此數值至少12周，所以考慮到不受歡迎的菌種，像是S. mutans，及受歡迎的菌種，像是S. sanguis的方向性移動，抗菌藥物像是氟，可更確定的評估其效用。



Anti-caries Studies. The ability of fluoride to decrease caries incidence in high-caries-active children was demonstrated by Koch. He separated nine to 11-year-old children into high and low caries groups on the basis of the number of decayed and filled surfaces (DFS). Those children with a DFS above 15 were divided into two groups, one of which received weekly oral hygiene instructions during the school year and brushed with a 0.22 percent NaF dentifrice. After one year these treated children had 60 percent less new decay than the untreated high-caries-active children and 30 percent less decay than untreated low-caries-active children (Table 19-5). Note that the benefits obtained on the occlusal surfaces were less than on the other surfaces, indicating that the fissures constitute a special situation that will require different treatment considerations. The treatment design was such that this improvement could be attributed to the combination of fluoride and oral hygiene instructions. However, other investigators have found oral hygiene per se to be of little value in curbing new caries incidence in children (See Chap. 15) or in radiation xerostomia patients (See Table 19-6). Thus the results obtained most likely were due to the high fluoride-containing dentifrice.



抗蛀牙研究

Koch證實氟化物在高蛀牙率孩童中會降低蛀牙率，他根據蛀牙及填補牙面的數目(DFS)，將9-11歲孩童分為高與低蛀牙率兩組，DFS值高於12的孩童被分成兩組，一組在學期的一年中接受口腔衛教，且使用0.22% NaF牙膏刷牙，在一年後，這些治療的孩童與其他未治療高蛀牙率的孩童比較，新蛀牙降低60%，且與未治療低蛀牙率的孩童比較，新蛀牙降低30% (表19-5)。注意到所得到的益處在咬合面小於其他面，表示溝隙構成一個特別的狀況，需要不同的治療考量，治療的設計進步可以歸功於氟化物與口腔衛教的組合。然而，其他研究者發現口腔衛生本身而言，在孩童(查閱第15章)，或放射線治療的口乾症患者中(查閱表19-6)，抑制新蛀牙的產生價值不高，所以獲得此結果多半是歸功於高濃度含氟牙膏。



An even more impressive demonstration of the ability of fluoride to suppress caries development was observed in radiation xerostomia patients. These individuals, as a result of their salivary shutdown, developed rampant caries associated with significant increases of S. mutans and lactobacilli in their plaques and salivas (See Tables 11-6 and 12-5). Driezen, Brown and their colleagues sought to prevent caries development in these individuals by the application of intensive prophylactic treatments involving oral hygiene, fluoride gels and sucrose restriction.



更令人印象深刻的是，證明氟化物在放射線治療的口乾症患者觀察到其抑制蛀牙發展的能力，這些患者，由於他們唾液腺的功能降低，發展出猛爆性蛀牙，與他們的牙菌斑及唾液中，S. mutans和lactobacilli的顯著增加有關(查閱表11-6與12-3)，Driezen、Brown及其同事尋找出在這些個體中，預防蛀牙發展是經由，加強口腔衛教、氟膠與食物中限制蔗糖量來達到的。



Fifteen patients were randomly distributed to a regimen which included the daily application to the teeth for five minutes of a gel containing a red plaque disclosing dye. Each patient was instructed and shown how to remove all dye-disclosed plaque by brushing and flossing. A second group of 15 patients received the same gel, which now contained one percent neutral NaF and were given the same instructions. A third group received both the fluoride gel and the oral hygiene instructions and in addition, had dietary sucrose restricted. These latter patients were given a list of high-sugar-containing foods and were advised not to eat these foods. During their stay in the hospital these foods were deleted from their diets and presumably there usage would remain reduced following the patients' discharge from the hospital.



15個患者被隨機分配到，包括每天給予五分鐘含紅色染色的牙菌斑顯示劑的療法，教導每個患者使用且顯示如何使用刷牙牙線移除被染色的牙菌斑，第二組的15個患者使用相同的膠包含1%中性NaF，以相同的指示進行，第三組給予氟膠及口腔衛教，另外，限制食物上蔗糖的攝取，最後一群患者給予一張含高蔗糖的食物的列表，且建議他們不要食用這些食物，在他們待在醫院的期間，他們的飲食中排除這些食物，推測在這些患者出院後，使用這些食物會保持降低的狀況。



The oral hygiene regimen was completely without benefit. Nine months into treatment these patients had 11 DMF teeth and 22.2 DMF surfaces. This contrasted markedly with the 95 percent reduction in caries experience of the patients who had received the fluoride gels with or without sucrose restriction (Table 19-6). Sucrose restriction contributed little to the caries suppression above that observed with the fluoride alone. This did not necessarily mean that the sucrose restriction was without effect, as the therapeutic efficacy of the fluoride treatment was so great, that it may have overwhelmed any other treatment effects. Nine of the 14 patients in the oral hygiene group were placed on the fluoride gel regimen and their monthly caries score was reduced to 0.05 DMFT and 0.15 DMFS (Table 19-6). The clinical results of this study are so dramatic that it is possible to state that daily fluoride gels used in this manner are curative for dental caries. A fluoride regimen of this magnitude is indicated when the risk to caries is as predictable as it is in these xerostomia patients. What is needed next is to determine whether similar results can be achieved with a less demanding treatment schedule.



口腔衛生療法完全沒有益處，九個月的治療後，這些患者有11個DMF的牙齒及22.2個DMF的牙面，這些氟化物治療的患者不管有或沒有食物中蔗糖量的限制，其對照蛀牙率有顯著95%的降低(表19-6)，蔗糖限制對蛀牙抑制貢獻不高，但高於只有氟化物治療的組別?，這不是代表蔗糖抑制是沒用的，因為氟化物治療的效用太高，所以掩蓋了其他治療效果。在口腔衛教組中，14個患者內9個併入氟膠療法，他們每個月的蛀牙分數降低到0.05 DMFT和0.15DFMS (表19-6)，此研究的臨床結果是非常卓越的，顯示每天氟膠在此方式下使用，對蛀牙有顯著的治療效用，當像在口乾症患者蛀牙的風險是可預測的時候，顯示出氟化物療法的重要性， 下一個必須達到的是決定，是否相似的結果可在較不那麼要求的治療時間表下重現。



The means by which this cure was achieved were investigated from a bacteriological perspective. The patients in the oral hygiene group exhibited an accelerated increase in plaque proportions of S. mutans so that by three months after radiation, they had significantly more S. mutans than the other patients (Table 19-7). Thereafter the proportions of S. mutans declined coincident with an increase in the proportions of lactobacilli. When these patients were switched to the fluoride gels, no further changes in the proportions of these organisms occurred. In the fluoride group the proportions of S. mutans increased during the radiation treatment to about six percent, and remained at that level until the nine-month sampling period, when they increased to 16 percent (Table 19-7). These persistent high proportions of S. mutans were not associated with caries development, although comparable proportions had been in the oral hygiene group. This anomalous situation was partially clarified by the demonstration that at least some of these S. mutans were resistant to fluoride, and the observation by others that fluoride resistance is associated with decreased acid production (See "Fluoride Resistance in S. mutans" in this chapter). Thus, these S. mutans may not have been capable of producing sufficient acid to demineralize the tooth surface. In the fluoride-sucrose restriction group, the S. mutans proportions decreased during the period of radiation therapy. This was in contrast to the other groups and suggested that the sucrose restriction was responsible, as this was the time period in which the dietary control was strictly enforced. The plaque proportions of S. mutans and lactobacilli in this group did not attain the values observed in the other groups, further indicating an effect of the sucrose restriction.



達到此治癒的方法是從細菌學觀點研究來的，在口腔衛教組別的患者顯現出在牙菌斑中S. mutans比例加速的增加，所以在放射線治療後三個月，他們較其他患者口中S. mutans有顯著的增加(表19-7)，之後，S. mutans的比例降低與lactobacilli的比例增高同時發生，當這些患者被轉到氟膠組別，這些微生物比例的轉換沒有繼續發生，在氟化物組別，S. mutans在放射線治療其間增加約6%，之後停留在這個高度直到9個月的取得樣本期間，會增加到16% (表19-7)，這個持續的高S. mutans比例與蛀牙的發展沒有關係，雖然比的上的比例也在口腔衛教組發現?。這個異常的情況，部分被以至少有一些S. mutans是對氟有抵抗性的證明來澄清，其他觀察到對氟的抵抗性是與產酸的減少有關 (查閱本章"S. mutans對氟化物的抵抗性)，所以，這些S. mutans也許無法產生足夠的酸來將牙齒表面去礦化，在氟化物合併限制蔗糖攝取的組別，在放射線治療期間S. mutans的比例降低，這與其他組別是極度對比的，且暗示了限制蔗糖的攝取是有效的，因為這個期間飲食控制是嚴格被加強的，在這個組別中，牙菌斑中的S. mutans及lactobacilli的比例並沒有達到與其他組別所觀察到的程度，進而顯示出限制蔗糖攝取的效用。



These bacteriological findings are consistent with the fluoride exerting an antimicrobial effect on the flora. However, the ability of the fluoride to remineralize the tooth surfaces and possibly to kill bacteria in situ in the white spot lesions (See "Whit Spot Hypothesis" in this chapter) would also contribute to the clinical success.



這些細菌學的發現與氟對口腔微生物發揮抗菌作用是一致的，然而，氟對牙齒表面再礦化的能力，及可能在白斑病變原位殺死細菌的能力(查閱此章"白斑假說")，也會促成臨床上的成功。



Vancomycin



Vancomycin is a polypeptide, nonabsorbable antibiotic with a gram positive spectrum of activity. The drug is relatively tasteless, is stable in nonaqueous solutions, but has a shelflife of only a few weeks when added to aqueous vehicles. Englander and Keyes reported that the topical application of vancomycin to the teeth of hamsters fed a sucrose diet, eliminated S. mutans and inhibited dental caries. This finding, plus the relatively minimal medical usage of vancomycin, led Jordan, DePaola and their colleagues to extensively evaluate vancomycin in school children or young adults infected with S. mutans. Particular care was taken to select for individuals in whom S. mutans was either prominent in the plaque or continuously present during the pretreatment period.



萬古黴素

萬古黴素是一個與格蘭氏陽性菌活動有關，聚胺基不可吸收的抗生素，這個藥物相對是無味，在非水性的溶液是穩定的，但其耐儲時間在水狀傳播媒介中只有幾周。Englander和Keyes報告局部給予倉鼠牙齒萬古黴素，餵食蔗糖飲食可以抑制S. mutans且限制牙齒蛀牙，這個發現加上相對少量萬古黴素的使用，使得Jordan、DePaola和他們的同事深入的評估萬古黴素在受到S. mutans感染的學童及年輕的成人的影響，特別用心來選擇在牙菌斑中S. mutans是顯著的或S. mutans持續在治療前存在的個體。



A series of trials were conducted in which the vancomycin was delivered via custom-fitted applicator trays, but in which the dosage and treatment schedules varied. One, three and 15 percent vancomycin gels or paste significantly suppressed S. mutans in the period immediately following treatment, but thereafter S. mutans returned. A dose-response relationship was evident, as when 15 percent vancomycin was used, S. mutans could not be detected in any patient for eight days after treatment and remained undetectable in about 60 percent of the 13 patients during the eight-week post treatment observation period. S. sanguis was observed to increase in the plaque as a result of treatment in a manner analogous to that observed with topical fluoride (Table 19-4).



一連串的連續研究以個人訂做的牙托傳遞萬古黴素來實行，但是劑量與治療時間表不同，1, 3, 15%的萬古黴素膠或膏狀物可能顯著的立即在治療時間後抑制S. mutans，但之後S. mutans又會重現。一個劑量反應的關係是明顯的，因為當使用15%的萬古黴素，在治療後八天後沒有任何患者能測到有S. mutans，在治療後八周的觀察期間內，13個患者有約60%維持無法偵測到S. mutans，與使用局部氟化物觀察到的一樣，牙菌斑中也觀察到S. sanguis有增加。



These findings demonstrated that vancomycin could suppress S. mutans for a finite period of time. In order to eliminate and/or continuously suppress S. mutans, the gel treatment would either have to remove all reservoirs of S. mutans that existed in the incipient and established carious lesions, or the gel would have to be given continuously. Jordan and DePaola chose the latter approach and conducted a trial in which a one percent gel was given daily under supervision during one school year. Under these conditions the plaque levels of S. mutans remained low during the entire treatment period and a significant reduction of caries compared to a no-treatment group was observed.



這些發現證實了萬古黴素可以在有限的一段時間內抑制S. mutans，為了抑制或持續阻止S. mutans，膠狀物治療會移除所有起初就存在或已經形成的蛀牙病灶中S. mutans的儲藏室，或是被持續的給予。Jordan和DePaola選擇後者的介入且實行一個連續的研究，1%的膠狀物在一年的學期中每天經指導下給予，在此狀況下，S. mutans的牙菌斑程度在整個治療期間中保持低下，且與沒有治療的組別比較，觀察到顯著地蛀牙減少。



These vancomycin studies fulfilled the criteria of treatment according to the SPH (See Table 14-1) in that children with a diagnosed S. mutans infection were treated so as to control that infection, and as a result, their caries levels decreased. Conceptually these investigations were more focused than the Karlstad, Ypsilanti or Cheektowaga studies. However, any treatment that requires daily supervision and yields only a reduction of about one DMF surface compared to children who received no such treatment, has to be considered cost inefficient. What is needed is not a better theory nor selection criteria, but possibly more effective agents and more cost-efficient treatment schedules.



這些萬古黴素的研究符合了根據SPH治療的標準(查閱表14-1)，治療在診斷出有S. mutans感染的孩童，結果使蛀牙程度減低，概念上，這些調查較Karlstad、Ypsilanti或Cheektowaga的研究更被重視，然而，任何需要每天指導且結果只達到與沒有接受任何治療的孩童比較，約1個DMF牙面的降低，此治療被認為其花費是沒效率的。需要的不是一個更好的理論或選擇的標準，而可能是更有效率的藥物，及花費有效率的治療時間表。



Furadroxyl



Furadroxyl appears to be such an agent, as it was associated with an impressive 75 percent reduction in the incremental DMFS rate when compared to a placebo group (Table 19-8). Dreizen and Spies selected patients with high caries activity, evidenced by a DMFS score of greater than 20 and the presence of at least five decayed surfaces. These patients were separated into furadroxyl, placebo and non-treatment groups. The furadroxyl and placebo groups were given chewing gums that differed only in the presence of 7.5 mg of furadroxyl in the treatment group. Both groups were instructed to chew one stick of gum for at least ten minutes after each meal. The no-treatment group was of similar age and caries experience but received no gums. Each subject was seen at least once every three weeks for dental examinations and for the distribution of gums to the respective groups. No attempt was made to change the dietary or oral hygiene habits of the participants.



Furadroxyl

Furadroxyl是一種可以達到與安慰劑組別比較下，其增加的DMFS率有高達75%的降低 (表19-8)，Dreizen與Spies選擇有高蛀牙活動力的患者，其DMFS分數證實有高於20且至少有五個蛀牙面，這些患者被分成Furadroxyl、安慰劑和未治療三組。Furadroxyl與安慰劑組都給予口香糖，其差別只在治療的組別含有7.5mg的Furadroxyl，兩組都被指示在每餐過後都要嚼一片口香糖至少十分鐘，未治療組患者的年齡與蛀牙率都與治療組差不多，但未治療組沒有給予口香糖，每個患者至少每三周會做牙齒檢查一次，且分配口香糖給這些患者，沒有試圖去改變這些參與者的飲食或口腔衛生習慣。



After one year the furadroxyl group averaged 0.9 new decayed surfaces, whereas the placebo group had 3.3 and the no-treatment group, 4.2 decayed surfaces (Table 19-9). Sixty percent of the furadroxyl patients had no new caries, whereas only 28 percent and eight percent, respectively, of the control groups had no new caries. When one considers that the treatment was unsupervised and there was no other intervention, save the chewing gums, the findings are remarkable and are extremely cost efficient. What then was so unique about furadroxyl, in that 30 minutes daily exposure to about 22 mg of agent could achieve this magnitude of caries reduction?



經過一年後，Furadroxyl組平均產生0.9個新蛀牙面，安慰劑組則產生3.3個，未治療組產生4.2個 (表19-9)。Furadroxyl組別的患者中有60%沒有新蛀牙的產生，分別地，在對照組各自只有28%及8%沒有新蛀牙產生。當考慮到若治療是不在指導下進行，也沒有其他介入，沒有口香糖，這個結果是很顯著且在花費上是極度有效率的。對Furadroxyl來說最特殊的是，一天30分鐘約22mg藥物的暴露可以達到蛀牙降低的重要性？



Furadroxyl is a nitrofuran derivative with the chemical formula 5-nitro-2-furaldehyde-2-semicarbazone. The nitrofurans as a group are broad-spectrum antibacterial agents that currently are used systemically for the management of urinary tract infections and topically for the treatment of skin, mucous membrane and wound infections. The compounds act as electron acceptors and inhibit enzymatic reactions in which NADH and thiamine pyrophosphate act as cofacters, thereby interfering with carbohydrate metabolism. Dreizen and Speis were aware of the Stephen curve (Figure 10-3), which demonstrated that acid production by the plaque continues for some 30 to 60 minutes following carbohydrate ingestion. Therefore, they timed the taking of the furadroxyl to coincide with those time periods in which carbohydrate metabolism in the plaque would be greatest, i.e., minutes after the ingestion of a meal, so as to achieve maximal inhibition. This solid theory was rewarded with the dramatic reductions in caries described in Table 19-8.



Furadroxyl是一個帶有化學分子式5-nitro-2-furaldehyde-2-semicarbazone的nitrofuran衍生物，nitrofuran是一群廣泛性抗菌藥物，目前以系統性使用來治療泌尿道感染，或是局部使用治療皮膚、黏膜或傷口的感染。此複合物以電子接收器來作用，且抑制NADH與thiamine pyrophophate當作協同因子的酵素作用，進而影響碳水化合物的代謝，Dreizen與Speis查覺到Stephen curve史帝芬曲線 (圖10-3)，證實了牙菌斑的酸產物會在碳水化合物消化後30-60分鐘後出現，所以，他們計算符合在牙菌斑中碳水化合物代謝最多最大的時間區間，來服用Furadroxyl，例如一餐消化後幾分鐘，已達到最高的抑制效果，這完整的理論在表19-8，以卓越的蛀牙降低被賞識。



And yet this study, reported in 1951, stands as an isolated event, without a confirming investigation. The pharmaceutical company involved was unable to obtain FDA approval for development of this agent "because a drug to be used daily as it would be in chewing gum, should be harmless under all conditions of use and misuse. The nitrofurans are too toxic for use in chewing gum." Apparently the prescription usage of this agent only in patients with high caries activity was never considered because at that time the evidence in support of the SPH was not yet in place. Because of the absence of confirmatory studies, the clinical results achieved with furadroxyl, by such a minimal intervention as the introduction of a chewing gum, constitutes a tantalizing success story but nothing more.



這個研究在1951年發表，沒有一個肯定的調查以獨立事件存在，有關的製藥廠商無法取得這種藥物發展的FDA認可，因為每天使用一種存在口香糖中的藥物，必須是在使用或誤用的任何情況下，都是無害的，nitrofuran使用在口香糖中毒性太高，顯然的，只在高蛀牙率的患者開此藥物的使用處方簽是從未被考慮的，因為當時支持SPH理論的證據還不足，因缺乏確定的研究，furadroxyl達到的臨床結果，藉由以口香糖採用很微量的介入，構成誘人的成功故事，但僅止於此。



Iodine



Various iodine preparations have long been used as disinfectants in oral and periodontal surgery and in endodontics, but they have not been employed to combat cariogenic infections. Gibbons et al. showed that an iodine solution (two percent iodine and two percent potassium iodide) applied for one to two minutes to discrete approximal surfaces was able to reduce S. mutans counts to undetectable levels in 28 of the 44 treated sites. The majority of these 28 sites did not become recolonized with S. mutans over a period of two months' observation. This finding indicated that if a caries-free smooth tooth surface can be disinfected, that the organisms which recolonize this surface most likely will not include S. mutans.



碘

各種不同碘的配置長久以來被使用來作為口腔及牙周手術還有牙髓病科的消毒劑，但是它們沒有被作為抵抗蛀牙感染的功用。Gibbons及其同事提出碘劑 (2%碘及2%碘化鉀)塗抹在分離的鄰接面上1-2分鐘可以降低S. mutans的量，在44個治療的位置有28個達到無法測出的降低量。在觀察兩個月的期間，這28個位置多數沒有成為S. mutans重新形成菌落的地方，這個發現指出如果沒有蛀牙的平滑牙面可以不被感染，則重新在此牙面形成菌落的微生物很可能不會包括S. mutans。



The situation with a fissure or incipient lesion may be different, as in these locations organisms that are within the depths of the fissure or lesion may escape the antimicrobial action of the agent and may even be selected for in the recolonization procedure (See "White Spot Hypothesis" in this chapter). The refractory nature of S. mutans in occlusal fissures was demonstrated in a second study involving topical application of iodine. In this study five subjects with salivary levels of S. mutans greater than 10,000 per ml were given a dental prophylaxis plus three treatments with topical iodine applied immediately after the prophylaxis and three and five days later. This treatment significantly reduced the occlusal proportions and salivary levels of S. mutans for four to six weeks (Table 19-9). But this same regimen significantly reduced the approximal levels of S. mutans for the entire 24-week period of observation.



溝隙或是起初的蛀牙病灶情況可能是不一樣的，因為在這些位置的微生物在溝隙的深處，或是病灶可能逃離抗菌藥物能達到的作用位置，甚至可能被選擇為重新形成菌落過程內?(查閱本章"白斑假說")，在咬合面溝隙的S. mutans，其有抵抗力的特色在包括局部塗抹碘的第二個研究中被證實。在這個研究，五個唾液中S. mutans的量大於每毫升10,000的個體，給予牙科潔牙加上潔牙後三天和五天後立即三次局部碘治療，這個治療在4-6星期後，顯著地降低咬合面S. mutans的分布，及唾液中S. mutans的量(表19-9)，但這個相同的療法在全部24周觀察期間，顯著的降低了S. mutans的鄰接量。



The reappearance of S. mutans in the occlusal plaques could represent either an outgrowth of organisms from the fissure depths which were never exposed to the iodine solution, or a new colonization by S. mutans present in the saliva. This latter possibility existed because one week after the iodine treatment the salivary levels of S. mutans averaged about 2000 organisms per ml of saliva (Table 19-9). Svanberg and Loesche had shown that sterile artificial fissures placed in the mouths of humans became infected with S. mutans provided that the salivary concentrations of this organism were 1000 per ml or higher (See Table 6-11). Thus, salivary levels of S. mutans capable of colonizing fissures were present in all subjects within a few weeks after the iodine applications. But as these salivary levels are a function of the shed rate of S. mutans from the tooth surfaces, this ascendancy of S. mutans in the saliva reflected the reemergence of S. mutans from buried reservoirs, such as the fissures, and only secondarily could these levels contribute to recolonization of uninfected fissures.



在咬合面牙菌斑中，S. mutans的再出現表示，從溝隙深處從未與碘劑接觸的微生物產生，或是存在在唾液中S. mutans新的菌落，這可能是因為在碘治療一周後，唾液中S. mutans平均每毫升約有2000個微生物 (表19-9)，Svanberg和Loesche提出將消毒過後的人工溝隙放入人類口腔中數個月，會被唾液中每毫升1000個或更多的S. mutans感染 (查閱表6-11)，所以，唾液中S. mutans量，在所有個體中碘治療後數周，是可能在溝隙中形成菌落。但是，因為這些唾液量是從牙齒表面S. mutans散佈率的函數?，這唾液中S. mutans的優勢反應了從隱藏儲藏地重新出現的S. mutans，例如溝隙中，和只有間接在未被感染的溝隙中重新形成菌落的貢獻?。



Kanamycin



The cited studies show that S. mutans cannot be easily eliminated from occlusal fissures, presumably because these fissures harbor S. mutans within their depths. If this is so, then the treatment strategy under the SPH has to include some means of gaining access to these buried reservoirs of S. mutans. One tactic would be to combine the antimicrobial regimen with the mechanical debridement of carious lesions. Results obtained when short-term usage of kanamycin was integrated with caries debridement provided further insights into the nature of the tooth surface reservoirs of S. mutans.



Kanamycin

被篩選出的研究顯示出，S.mutans無法輕易的從咬合面溝隙中被消滅，主要因為這些溝隙將S. mutans庇護在它們的深溝中，如果是這樣，則根據SPH的治療策略必須包括一些能到達這些S. mutans包埋在內的儲藏地。一個策略是包含在蛀牙病灶的機械性清創抗菌療法，結果包括短期使用kanamycin合併提供牙齒表面S. mutans儲藏地的蛀牙清創。



Children with rampant caries, as defined by having ten or more carious surfaces, were treated with either a five percent kanamycin gel or a placebo gel. The patients were instructed in how to apply the gels in applicator trays to the dentogingival surfaces twice a day for one week prior to the placement of all necessary dental restorations and again for one week after the placement of the restorations. The gel treatment was unsupervised and performed at home by the patients. Kanamycin was chosen because it has no objectionable taste, is stable and had been shown in a previous gingivitis study to inhibit plaque streptococci. The plaque was cultured from the most distal, occlusal fissure and interproximal site in each quadrant and pooled so as to give occlusal and approximal samples. These plaque samples, as well as saliva, were collected before and after each gel treatment and at the three-month recall visits.



有10個或以上的蛀牙面定義為有猛爆性蛀牙的孩童，，使用5%kanamycin膠或安慰劑膠治療，指導患者如何使用牙托放置膠在牙齒及牙齦表面，在填補所有必須填補的蛀牙前一星期，一天兩次，膠狀物治療是在沒有被指導下在家裡由患者自行使用，選擇kanamycin是因為沒有令人討厭的異味，是穩定的且在先前牙齦炎研究中能夠抑制牙菌斑中的鏈球菌，從每個象限中大部分遠心側、咬合面溝隙及鄰接面取得牙菌斑培養，且共同培養來提供咬合面及鄰接面樣本。這些牙菌斑樣本及唾液，在每次膠狀物治療之前之後及三個月的回診中被取得。



The kanamycin gel treatment given while the open carious lesions were present in the teeth lowered the levels but not the proportions of S. mutans in the plaque (Table 19-10). The placement of the dental restorations caused the proportions of S. mutans to decrease in both groups. The kanamycin was taken for a second one-week period and again while the plaque levels of S. mutans decreased, the proportions continued to increase. In fact, the proportions of S. mutans in the approximal plaques were now significantly higher in the kanamycin group than in the placebo group (Table 19-10). Closer inspection revealed that while most of the approximal samples in the kanamycin group had now proportions of S. mutans, a few samples had more than 20 percent S. mutans. This indicated that while the kanamycin reduced the plaque levels of S. mutans in most subjects, it also was capable of selecting for S. mutans in certain mouths. The biological import of this phenomenon soon became apparent in the caries scores observed at the recall visits.



在蛀牙病灶還未治療前給予kanamycin膠治療顯示降低S. mutans的量但沒有降低其在牙菌斑中的分佈 (表19-10)，牙科填補物置入後在兩個組別中都會降低S. mutans分佈，使用第二個一星期的kanamycin治療，且再次的當牙菌斑中S. mutans量會降低，但其分佈卻持續增高。事實上，在鄰接面牙菌斑S. mutans的分佈在kanamycin組別比安慰劑組別顯著的較高 (表19-10)，更仔細的檢查透露出，當在kanamycin組別多數鄰接面的樣本，其S. mutans的分佈較高，少數的樣本有高於20%的S. mutans，這顯示，當kanamycin在多數個體中降低了牙菌斑的S. mutans，但同時也能夠在幾個月中選擇出S. mutans，這個現象生物學的含意很快的在回診的蛀牙分數觀察中，變成是顯而易見的。



The number of new carious lesions was greater in the kanamycin-treated patients in the first eight to ten months after treatment (Table 19-11). This caused us to stop the entry of new patients into the study and to closely monitor the caries experience of the existing patients. Over the next one to two years, the kanamycin patients developed few new lesions, whereas the placebo patients continued to develop new lesions. When the data were eventually summarized, the kanamycin treatment was associated with a net caries reduction of about 45 percent compared to the placebo treatment. This left the need to explain how the kanamycin caused an acceleration in decay and then a burnout or quiet period, during which time the placebo group caught up to and surpassed the kanamycin group in terms of new decayed surfaces. This was done by postulating that an additional reservoir for S. mutans existed that was not accessible to either the kanamycin or the caries debriding procedures. This reservoir could either be cracks in the tooth surface and/or the white spot (incipient) lesion.



新蛀牙的病灶數目在kanamycin治療後八到十個月的患者身上較高 (表19-11)，這使得我們停止納入新患者到此研究，且密集的監測現有患者的蛀牙率，在接下來的一到兩年，kanamycin組的患者形成一些新蛀牙。當平均地總結這些資料顯示，kanamycin治療與相關的淨蛀牙降低量，與安慰劑治療比較約是45%，這留下解釋kanamycin如何造成蛀牙加速，然後一個殆盡或靜止期的需要，在同時，依據新產生的蛀牙面，安慰劑組別趕上且優於kanamycin組別，假定存在S. mutans多餘的儲藏地，kanamycin或蛀牙清創步驟無法達到此處，而達到此結果，這個儲藏地可以是牙面中的裂縫或白斑(起初的)蛀牙。



The White Spot Hypothesis. The white spot hypothesis is conceivable only in the context of bacterial specificity in the caries process. It states that the primary, or white spot, lesion represents a focal infection of S. mutans or some other organism(s), which is specifically involved in the caries process. The white spot hypothesis assumes that S. mutans or the other cariogens have already invaded the enamel and are within the depths of the white spot. When an antimicrobial agent is delivered to the tooth surface, if the agent cannot penetrate the white spot, either because of ionic charge or occlusion of the channels within the white spot by bacterial cells, those organisms within the white spot will survive. When the treatment ceases, the survivors within the white spot are able to grow out from the lesion and become dominant in the newly-forming plaque flora. If these surviving organisms include a cariogen, such as S. mutans, then the caries process is accelerated.



白斑假說

可理解的，白斑假說只在蛀牙形成中細菌特定性的背景中存在，他指出，起初或白斑的病灶，表示一個S. mutans或一些其他特定與蛀牙形成相關的微生物的病灶感染，白斑假說採用S. mutans或其他致蛀牙因子已經侵犯牙釉質，且存在在白斑的深處，當抗菌藥物被帶到牙齒表面，如果藥物因為帶電離子或在白斑被細菌細胞閉塞通道，無法穿透白斑，這些在白斑中的微生物會存活下來，當治療停止，在白斑中存活下來的微生物能夠從病灶中生長出來，且在新形成的牙菌斑菌落中占優勢，如果這些存活下來的微生物包含致蛀牙因子，像是S. mutans，則將促進蛀牙形成。



This white spot hypothesis can explain how the kanamycin treatment accelerated the rate of caries development on some surfaces while preventing the development of caries on other surfaces. In this model (Fig. 19-1), the tooth surface has three situations relative to health or disease l) the caries-free surface; 2) the primary or white spot lesion; 3) the secondary lesion of obvious cavitation. Each of these situations will respond differently to an effectively-delivered antimicrobial agent. On the caries-free surfaces, the active agent will reduce the total number of bacteria, possibly eliminating S. mutans, as is shown in Figure 19-1. This agrees with the general reduction in viable count and S. mutans seen following both periods of kanamycin therapy (Table 19-10). In the primary lesion if the agent does not penetrate into the demineralized zones, a nidus of bacteria will survive. In the reformation of the plaque these organisms will grow out of the lesion and comprise a higher proportion of the returning plaque flora. An increase in S. mutans was found in certain approximal samples after the completion of the kanamycin treatment but was not observed with the placebo treatment. This selection for S. mutans could account for the accelerated caries rate observed at the nine-month recall period in the kanamycin patients (Table 19-11). In the kanamycin group, the caries-free surfaces may be rid of a S. mutans infection and stay that way during the recall period (Fig. 19-1). In the placebo group the caries-free surfaces may remain infected with S. mutans and some will go on to become carious during the recall period. The amount of caries that develops on these initially caries-free surfaces actually determines the net caries difference between the two treatment groups.



白斑假說可以解釋kanamycin治療如何在某些牙面促進蛀牙發展率的同時，預防其他牙面蛀牙的發生，在此模型中 (圖19-1)，牙面健康或有病灶有三種情形；1)沒有蛀牙的牙面；2)初期或白斑病灶；3)明顯蛀牙窩洞的次級病灶。每個情況會對有效傳遞的抗菌藥物有不同的反應，在沒有蛀牙的牙面，活躍有效的藥物會降低整體細菌的量，可能會抑制S. mutans，如同顯示在圖19-1，這同意了可發展量整體的降低，且兩段kanamycin治療後的S. mutans的降低 (表19-10)，在初期病灶，如果藥物無法穿透進入去礦化區域，細菌在發源窩能夠存活。在重新形成的牙菌斑中，這些微生物會從病灶中發展，且構成重回的牙菌斑菌落更高的分佈，在完成kanamycin治療後的一些鄰接面樣本，其S. mutans會增加，但在安慰劑治療中並沒有發現，這個S. mutans的篩選可算是促進kanamycin患者中，在九個月回診期間的蛀牙率 (表19-11)，在kanamycin組，未蛀牙的牙面可能是沒有S. mutans感染，且在觀察回診期間維持此狀況 (圖19-1)，在安慰劑組，未蛀牙牙面可能維持被S. mutans感染且有些會在觀察期間發展成蛀牙，初期未蛀牙牙面發展成蛀牙的數量，事實上決定了兩個治療組別間的淨蛀牙差異。



The model indicates that antimicrobial treatment prior to the placement of dental restorations, or in the presence of primary and secondary lesions will be counterproductive, as such treatments will select for organisms buried within the lesions. If these organisms have cariogenic potential, such as S. mutans, then an accelerated caries attack rate might ensue. The model predicts that an antimicrobial agent that is capable of penetrating the white spot will prevent decay from being accelerated in these lesions. The failure of kanamycin to penetrate would not appear to be due to its molecular weight, since it is a relatively small molecule. But as with chlorhexidine, it has a net positive charge, which could cause it to bind at the tooth surface. Fluoride, which is known to penetrate the enamel and to be elevated in arrested lesions, has a net negative charge. Fluoride, according to the model, would penetrate the lesion, kill the bacteria in situ and should not lead to a selection for S. mutans in the newly-formed plaque nor to an accelerated caries rate.



此模型指出，在填補蛀牙後的抗菌治療，或是在初期或次級病灶發生時，會產生不良結果，因為此治療會挑選埋藏在病灶中的微生物，如果這些微生物有致蛀牙傾向，例如S. mutans，則促進蛀牙攻擊的比例會接踵而來，此模型預測，能夠深入白斑的抗菌藥物，會在這些病灶中預防窩洞形成，kanamycin無法深入病灶不是因為他的分子量，因為他相對是小分子，但是chlorhexidine，他有帶靜正電，能夠使其連結到牙齒表面，氟，已知能穿透牙釉質且在受威脅的病灶中被提高，有帶靜負電，氟，根據此模型，能夠穿透病灶，殺死在原處的細菌，且不該導致在新形成的牙菌斑中的S. mutans的選擇，也不會導致蛀牙率的加劇。



Morphological verification of bacteria in the white spot lesions was provided by Brannstrom and his colleagues. Their electron microscopic examination of white spot lesions led them to conclude that: "The presence of bacteria in small lacunae in the enamel prism, as well as deep in the enamel under white spot lesions, together with pores in the enamel surface, would seem to indicate that bacteria may penetrate the enamel at an early stage." The presence of bacteria with a coccal morphology is clearly seen in their electron photomicrographs (Fig. 19-2).



Brannstrom與他的同事提供了細菌在白斑病灶中型態學的確認，他們在電子顯微鏡下檢查白斑做出以下結論：〝細菌形成在牙釉質晶柱中小髓腔，同樣在牙釉質白斑病灶深度，與牙釉質表面孔洞，同時指出，細菌可能在初期穿透牙釉質〞，在電子顯微鏡下清楚的看見有球狀型態的細菌出現 (圖19-2)。



Testing of the White Spot Hypothesis. The white spot hypothesis was tested in rampant caries children using fluoride as the antimicrobial agent. Children five to six years of age, who had ten or more carious surfaces in the primary dentition and no erupted permanent molars, were treated with 1.23 percent neutral sodium fluoride or placebo gels. This level of fluoride was chosen because it had been shown previously to reduce the proportions of S. mutans in the plaque (Table 19-4). Neutral sodium fluoride was used because it has a less objectionable taste than either acidulated phosphate fluoride or stannous fluoride. This was important in terms of compliance, as the gels were to be taken unsupervised, at home, in applicator trays twice a day for one-week periods prior to and after the placement of the necessary dental restorations. Unlike the kanamycin protocol, the gels were readministered at about six- to eight-month intervals during the years that the patients remained in the study. These children were chosen as patients because of their high caries experience, i.e., they averaged about 22 decayed surfaces and because their first permanent molars, when they erupted, would provide a sensitive indicator of caries protection afforded by the fluoride regimen. In this manner we hoped to treat an infection in the primary dentition so as to minimize or prevent its spread to the permanent dentition.



測試白斑假說

在使用氟化物當作抗菌藥物的猛爆性蛀牙的孩童中，測試白斑假說，5-6歲的孩童，在乳牙齒列有10個或以上的蛀牙面，且沒有萌發中的恆牙，使用1.23%中性氟化鈉或安慰劑治療，選擇此氟化物濃度是因為之前顯示出，其能夠降低牙菌斑中S. mutans的分佈 (表19-4)，中性氟化鈉因為與APF或氟化亞錫比較，有較少令人討厭的異味而被選擇，這對孩童的合作度相當重要，因為氟膠是在填補蛀牙前後一周，一天兩次在沒有指導下使用牙托在家中進行，不同於kanamycin的規則，這些膠會在研究期間六到八個月後重新被給予，這些孩童因為其高蛀牙率被選取，例如平均蛀牙面約22，且因為在他們的第一大臼齒即將要萌發期間，會提供氟化物療法給予其蛀牙保護敏感的指標，在此情況下，我們希望在乳牙齒列中治療此感染，進而減低或預防其擴散到恆牙齒列。



The protocol was partially successful in that there was no selection for S. mutans by the fluoride and in fact, the fluoride-treated children had lower levels of S. mutans. More importantly, there was no accelerated caries rate in the fluoride group relative to the placebo group as there had been with kanamycin. Instead, the fluoride children exhibited one less decayed surface in the first year following treatment than did the placebo children (Table 19-12). This difference of one decayed surface per year was maintained during the second and third years of the study, so that the cumulative difference between the two groups was 3.2 surfaces (Table 19-12).



此協議草案是局部成功的，因為沒有氟化物對S. mutans的選取，且事實上，氟化物治療的孩童，有較低的S. mutans量，更重要的是，在氟治療組別，與安慰劑組別比較，沒有加劇的蛀牙率，但在kanamycin研究中是有的，反而，氟化物治療的孩童顯示在治療後第一年，與安慰劑組別比較減少一個蛀牙面 (表19-12)，這個每年一個蛀牙面的降低，在此研究的第二及第三年期間會繼續維持，所以兩組間累積降低差異達到3.2的牙面 (表19-12)。