Infective endocarditis is a severe infection arising in the lining of the chambers of the heart with a high mortality rate.
Many dental procedures cause bacteraemia and it was believed that this may lead to bacterial endocarditis (BE) in a few people. Guidelines in many countries have recommended that prior to invasive dental procedures antibiotics are administered to people at high risk of endocarditis. However, recent guidance by the National Institute for Health and Care Excellence (NICE) in England and Wales has recommended that antibiotics are not required.
To determine whether prophylactic antibiotic administration, compared to no such administration or placebo, before invasive dental procedures in people at risk or at high risk of bacterial endocarditis influences mortality, serious illness or the incidence of endocarditis.
The following electronic databases were searched: the Cochrane Oral Health Group's Trials Register (to 21 January 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12), MEDLINE via OVID (1946 to 21 January 2013) and EMBASE via OVID (1980 to 21 January 2013). We searched for ongoing trials in the US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the metaRegister of Controlled Trials (http://www.controlled-trials.com/mrct/). No restrictions were placed on the language or date of publication when searching the electronic databases.
Due to the low incidence of BE it was anticipated that few if any trials would be located. For this reason, cohort and case-control studies were included where suitably matched control or comparison groups had been studied. The intervention was the administration of antibiotic, compared to no such administration, before a dental procedure in people with an increased risk of BE. Cohort studies would need to follow those individuals at increased risk and assess outcomes following any invasive dental procedures, grouping by whether prophylaxis was received or not. Included case-control studies would need to match people who had developed endocarditis (and who were known to be at increased risk before undergoing an invasive dental procedure preceding the onset of endocarditis) with those at similar risk but who had not developed endocarditis. Outcomes of interest were mortality or serious adverse events requiring hospital admission; development of endocarditis following any dental procedure in a defined time period; development of endocarditis due to other non-dental causes; any recorded adverse events to the antibiotics; and cost implications of the antibiotic provision for the care of those patients who developed endocarditis.
Data collection and analysis
Two review authors independently selected studies for inclusion then assessed risk of bias and extracted data from the included study.
No randomised controlled trials (RCTs), controlled clinical trials (CCTs) or cohort studies were included. One case-control study met the inclusion criteria. It collected all the cases of endocarditis in the Netherlands over two years, finding a total of 24 people who developed endocarditis within 180 days of an invasive dental procedure, definitely requiring prophylaxis according to current guidelines, and who were at increased risk of endocarditis due to a pre-existing cardiac problem. This study included participants who died because of the endocarditis (using proxies). Controls attended local cardiology outpatient clinics for similar cardiac problems, had undergone an invasive dental procedure within the past 180 days, and were matched by age with the cases. No significant effect of penicillin prophylaxis on the incidence of endocarditis could be seen. No data were found on other outcomes.
There remains no evidence about whether antibiotic prophylaxis is effective or ineffective against bacterial endocarditis in people at risk who are about to undergo an invasive dental procedure. It is not clear whether the potential harms and costs of antibiotic administration outweigh any beneficial effect. Ethically, practitioners need to discuss the potential benefits and harms of antibiotic prophylaxis with their patients before a decision is made about administration.
Antibiotik untuk pencegahan endokarditis bakteria dalam bidang pergigian.
Jangkitan endokarditis adalah satu jangkitan teruk yang berlaku di lapisan jantung dan mempunyai kadar kematian yang tinggi.
Banyak prosedur pergigian menyebabkan bakteremia yang dipercayai membawa kepada endokarditis bakteria (EB) dalam sesetengah orang. Garispanduan di kebanyakan negara mengesyorkan pemberian antibiotik kepada orang berisiko endokarditis sebelum prosedur pergigian invasif. Namun garispanduan Institut untuk Kecemerlangan Penjagaan dan Kesihatan Kebangsaan (NICE - National Institute for Health and Care Excellence) England dan Wales telah mengesyorkan bahawa antibiotik adalah tidak perlu.
Untuk menentukan sama ada pemberian antibiotik pencegahan berbanding dengan tiada antibiotik atau plasebo sebelum prosedur pergigian invasif dalam kalangan orang yang berisiko atau berisiko tinggi untuk EB mempengaruhi tingkat kematian, penyakit yang serius atau insidens endokarditis.
Pencarian dilakukan dalam Pangkalan data berikut: Daftar Kajian Klinikal Kumpulan Kesihatan Oral Cochrane (hingga 21 Januari 2013), Daftar Pusat Kajian Klinikal Terkawal Cochrane (CENTRAL) ( Perpustakaan Cochrane 2012, Isu 12), MEDLINE melalui OVID (1946 hingga 21 Januari 2013) dan EMBASE melalui OVID (1980 hingga 21 Januari 2013). Kami juga membuat carian kajian klinikal yang sedang berterusan di Daftar Kajian Klinikal Kesihatan di Institut Kebangsaan Amerika Syarikat (http://clinicaltrials.gov) dan metaDaftar Kajian Klinikal Kontrol (http://www.controlled-trials,com/mrct/). Daftar Kajian Klinikal Rawak Terkawal (http://www.controlled-trials,com/mrct/). Tiada sebarang sekatan bahasa atau tarikh penerbitan dalam membuat carian di pangkalan data elektronik.
Oleh kerana insiden EB rendah, kami menjangkakan hanya sedikit kajian klinikal dapat dikesan. Dengan itu, kajian kohort dan kes-kontrol dipilih di mana padanan kontrol atau kumpulan perbandingan yang bersesuaian telah dikaji. Intervensi adalah pemberian antibiotik berbanding dengan tiada pemberian antibiotik sebelum prosedur pergigian dalam kalangan orang yang berisiko EB. Kajian kohort perlu menyelidiki individu-individu berisiko dan menilai hasil selepas sebarang prosedur pergigian invasif, dikumpulkan berdasarkan kumpulan yang menerima pencegahan atau tidak. Kajian kes-kontrol yang terpilih perlu membuat padanan orang yang dapat EB (juga yang diketahui berisiko tambahan sebelum menjalani prosedur pergigian invasive terdahulu dari terjadinya EB) dengan orang-orang yang berisiko sama tetapi tidak menghidap endokarditis). Hasil yang hendak diketahui adalah kematian atau kesan sampingan serius yang memerlukan kemasukan hospital; pembentukan endokarditis selepas sebarang prosedur pergigian dalam jangkamasa tertentu; endokarditis atas sebab-sebab lain; sebarang kesan sampingan antibiotik; implikasi kos pemberian antibiotik untuk penjagaan pesakit yang menghidap endokarditis.
Pengumpulan Data dan Analisis
Dua penulis ulasan sistematik secara berasingan memilih kajian untuk dimasukkan dan menilai risiko bias, kemudian penggalian data dari kajian-kajian terpilih.
Tiada kajian klinikal rawak terkawal, kajian klinikal terkawal atau kajian kohort yang dimasukkan dalam ulasan sistematik ini. Satu kajian kes-kontrol memenuhi kriteria pemilihan. Kajian tersebut mengumpulkan semua kes endokartitis di Belanda sepanjang tempoh dua tahun, melibatkan 24 orang yang menghidap endokarditis dalam masa 180 hari selepas prosedur pergigian invasif yang sepatutnya menerima profilaksis mengikut garispanduan semasa, berisiko tambahan untuk endokarditis kerana masalah jantung sedia ada. Kajian ini juga menyelidiki peserta yang terkorban akibat endokarditis (menggunakan proksi). Kumpulan kawalan dalam kajian ini telah pula hadir di klinik pesakit luar kardiologi untuk masalah jantung yang sama, telah menjalani prosedur pergigian invasif dalam tempoh 180 hari yang lalu dan mereka dipadankan dengan umur kes-kes. Tiada kesan signifikan profilaksis penicillin ke atas insiden endokarditis yang dapat dilihat. Tiada maklumat juga berkaitan hasil lain.
Masih belum ada bukti sama ada profilaksis antbiotik berkesan atau tidak terhadap endokarditis bakteria dalam kalangan orang berisiko yang akan menjalani prosedur pergigian invasif. Adalah tidak jelas sama ada bahaya yang mungkin berlaku dan kos pemberian antibiotik melebihi sebarang kesan manfaat. Secara etika, pengamal perlu berbincang dengan pesakit tentang potensi manfaat dan bahaya yang mungkin berlaku akibat profilaksis antibiotik sebelum membuat keputusan.
Antibiotics for the prevention of bacterial endocarditis (severe infection or inflammation of the lining of the heart chambers) in dentistry
This review, carried out by authors of the Cochrane Oral Health Group, has been produced to determine whether people at increased risk of bacterial endocarditis, a severe infection or inflammation of the lining of the heart chambers, should routinely take antibiotics before invasive dental procedures in order to reduce the incidence of endocarditis, the number of deaths, and the amount of serious illness this group of people experiences.
Bacterial endocarditis (BE) is a rare disease, it is generally accepted that 10 out of 100,000 people will suffer from it each year. The infection often occurs on previously damaged or malformed areas of the heart. It is usually treated with antibiotics, however BE is a life-threatening condition and up to 30% of people who suffer from it die, even with antibiotic treatment.
It is thought that invasive dental procedures may cause BE in people who are at risk of developing it. It is not known how many cases of BE (if any) are directly caused this way. Many dental procedures cause bacteraemia, which is the presence of bacteria in the blood, and although it is usually dealt with quickly by the body’s immune system, it has been believed that bacteraemia may lead to BE in a few at risk people. Guidelines in many countries have recommended that before undergoing invasive dental procedures, people at high risk of BE should be given antibiotics in order to reduce the possibility of BE occurring. However, recent guidance by the National Institute for Health and Care Excellence (NICE) in England and Wales has recommended that antibiotics are not required for any interventional procedure, either dental or surgical.
Some authorities have questioned the routine use of antibiotics, arguing that overprescription has resulted in the emergence of resistance of many organisms to common antibiotics, and also that the occasional adverse effects of antibiotics (severe allergic reactions) may outweigh the potential benefits.
The evidence on which this review is based was up to date as of January 2013.
The objective was to determine whether preventive (prophylactic) use of antibiotics, compared to no antibiotics or placebo, before invasive dental procedures in people at risk or at high risk of bacterial endocarditis influences the numbers of deaths, serious illness or incidence of endocarditis.
One study was included in this review, which compared the treatment of people at high risk of endocarditis who did develop BE and a group of people at high risk of endocarditis who did not develop BE. The study was an observational case-control study based in the Netherlands which looked at information about 349 people who contracted BE over a specific two year period. These people were matched to a similar group of people who had not contracted BE. All those participating in the study had undergone an invasive medical or dental procedure. The two groups were compared with regard to who had received preventive antibiotics before these procedures and those who did not.
It is unclear whether taking antibiotics as a preventive measure before undergoing invasive dental procedures is effective or ineffective against bacterial endocarditis in people at risk.
No studies were located that assessed numbers of deaths, serious adverse events requiring hospital admission, other adverse events, or cost implications of treatment.
There is a lack of evidence to support previously published guidelines in this area. It is not clear whether the potential harms and costs of antibiotic administration outweigh any beneficial effect. Ethically, practitioners need to discuss the potential benefits and harms of preventive antibiotic treatment with their patients before a decision is made about prescribing it.
Quality of the evidence
Although external factors relating to the study, such as inclusion of relevant participants and well defined parameters, were good, overall the observational and retrospective nature of the design of the study conferred a substantial risk of bias.
Ringkasan bahasa mudah
Antibiotik untuk mencegah endokarditis bakteria (jangkitan teruk atau keradangan pada lapisan dalam ruang-ruang jantung) dalam bidang pergigian.
Kajian oleh penulis-penulis Kumpulan Kesihatan Oral Cochrane ini dihasilkan untuk menentukan sama ada orang yang berisiko untuk endocarditis bakteria, suatu jangkitan atau keradangan lapisan ruang jantung yang teruk, patut mengambil antibiotik secara rutin sebelum sebarang prosedur pergigian untuk mengurangkan insidens endokarditis, bilangan kematian, dan jumlah penyakit serius yang dialami oleh pesakit dalam kumpulan ini.
Endokarditis bakteria (EB) adalah penyakit yang jarang. Sepuluh dalam 100,000 orang boleh menghidapinya setiap tahun. Jangkitan sering berlaku kepada bahagian jantung yang cacat atau rosak. Ia dirawat dengan antibiotik. Namun keadaan ini boleh mengancam nyawa dan hampir 30% yang menghidapinya terkorban walaupun diberi rawatan antibiotik.
Ia dikatakan bahawa prosedur pergigian invasif boleh menyebabkan BE kepada orang yang berisiko mendapatkannya. Ia adalah tidak diketahui berapa banyak kes-kes BE (jika ada) adalah disebabkan secara langsung melalui cara ini. Banyak prosedur pergigian menyebabkan bakteremia yang dipercayai membawa kepada endokarditis bakteria (EB) dalam sesetengah orang. Garispanduan di kebanyakan negara mengesyorkan pemberian antibiotik kepada orang berisiko endokarditis sebelum prosedur pergigian invasif. Namun garispanduan Institut untuk Kecemerlangan Penjagaan dan Kesihatan Kebangsaan (NICE - National Institute for Health and Care Excellence) England dan Wales telah mengesyorkan bahawa antibiotik adalah tidak perlu.
Sesetengah pihak mempersoalkan penggunaan antibiotik secara rutin, dengan alasan bahawa pengambilan yang terlalu banyak akan menyebabkan kemunculan banyak ketahanan organisma kepada antibiotik biasa, dan juga bahawa kesan buruk sesekali antibiotik (reaksi alahan yang teruk) boleh melebihi potensi manfaat.
Ulasan sistematik ini berasaskan bukti-bukti penyelidikan sehingga Januari 2013.
Tujuan ulasan sistematik ini adalah untuk menentukan sama ada penggunaan antibiotik pencegahan (profilaktik) berbanding tanpa antibiotik atau plasebo sebelum prosedur pergigian invasif dalam kalangan orang yang berisiko atau berisiko tinggi untuk EB mempengaruhi jumlah kematian, penyakit serius atau insiden endokarditis.
Satu kajian yang membandingkan rawatan bagi orang yang berisiko tinggi untuk EB tetapi tidak mendapat EB disertakan dalam ulasan sistematik ini. Kajian tersebut merupakan pemerhatian kes-kontrol di Belanda yang meneliti maklumat 349 orang yang mendapat EB dalan jangkamasa spesifik dua tahun. Mereka dipadankan kepada kumpulan yang agak sama tetapi tidak menghidap EB. Kesemua yang terlibat dalam kajian ini telah menjalani prosedur pergigian atau perubatan yang invasif. Kedua-dua kumpulan ini dibandingkan dari sudut mereka yang telah menerima antibiotik pencegahan sebelum prosedur dengan mereka yang tidak menerima antibiotik.
Adalah tidak jelas sama ada pengambilan antibiotik pencegahan sebelum prosedur pergigian invasif berkesan atau tidak terhadap EB untuk orang yang berisiko.
Tiada kajian yang menilai jumlah kematian, kesan samping serius yang memerlukan kemasukan ke hospital, kesan sampingan lain atau juga implikasi kos rawatan.
Tiada bukti yang menyokong penerbitan garispanduan terdahulu di bidang ini. Adalah tidak jelas sama ada bahaya yang mungkin berlaku dan kos pemberian antibiotik melebihi kesan manfaat. Secara etika, pengamal perlu berbincang dengan pesakit tentang potensi manfaat dan bahaya yang mungkin berlaku sebelum membuat keputusan.
Walaupun faktor luaran yang berkait dengan kajian ini, misalnya pemilihan peserta yang relevan dan parameter adalah jelas, secara keseluruhan bentuk pemerhatian dan sifat retrospektif kajian memberi risiko bias yang besar.
Diterjemahkan oleh: Noorliza Mastura Ismail (Melaka-Manipal Medical College) Untuk pertanyaan tentang terjemahan ini, sila hubungi firstname.lastname@example.org.
Antibiotici za sprječavanje bakterijskog endokarditisa u dentalnoj medicini
Ovaj sustavni pregled, proveden unutar Cochrane uredničke skupine za oralno zdravlje (engl. Cochrane Oral Health Group) analizirao je dokaze iz kliničkih studija koje istražuju trebaju li ljudi izloženi povećanom riziku od bakterijskog endokarditisa, ozbiljnim infekcijama ili upalama stijenke srčanih klijetki, rutinski uzimati antibiotike prije invazivnog dentalnog zahvata da bi se smanjila pojavnost endokarditisa, broj smrtnih slučajeva i pojavnost ozbiljnih bolesti kojima je ta skupina ljudi izložena.
Bakterijski endokarditis (BE) je upala unutarnjeg dijela srca, rijetka bolest te je općeprihvaćeno da će od nje patiti 10 od 100.000 ljudi svake godine. Infekcija se često razvija na prethodno oštećenim ili deformiranim područjima srca. Obično se liječi antibioticima, iako je BE stanje opasno po život i do 30% ljudi koji od njega pate umru, čak i uz primjenu antibiotske terapije.
Smatra se da invazivni dentalni zahvat može uzrokovati BE u ljudi koji su skloni njegovom razvoju. Nije poznato koliko je slučajeva BE-a (ako je i jedan) izravno uzrokovano tim putem. Mnogo dentalnih postupaka dovodi do pojave bakterija u krvi (bakterijemija) i, premda se imunosti sustav tome brzo suprotstavlja, vjeruje se da bakterijemija može dovesti do BE u malog broja ljudi izloženih riziku. Mjere opreza preporučene su u mnogim državama da se prije izlaganja invanzivnim dentalnim zahvatima u ljudi povećanog rizika od BE provede liječenje antibioticima u svrhu smanjenja mogućnosti razvitka BE. Međutim, nedavne britanske smjernice su preporučile da antibiotici nisu potrebni u slučajevima bilo kakvog interventnog postupka, dentalnog ili operacijskog.
Neke institucije su dovele u pitanje svrhu rutinskog korištenja antibiotika, raspravljajući da je velika proširenost propisivanja antibiotika za posljedicu imala razvitak rezistencije mnogih organizama na uobičajene antibiotike te da povremeni suprotni učinci antibiotika (teške alergijske reakcije) mogu prevagnuti u odnosu na potencijalne koristi.
Dokazi na kojima se temelji ovaj pregled dolaze iz kliničkih studija objavljenih do siječnja 2013.
Cilj je bio utvrditi utječe li preventivna (profilaktička) primjena antibiotika, u odnosu na druge lijekove ili placebo, prije invazivnih stomatoloških zahvata u ljudi izloženih riziku ili visokom riziku bakterijskog endokarditisa, na broj smrtnih slučajeva, teške bolesti ili učestalost endokarditisa.
U ovaj pregled uključeno je jedno istraživanje, koje je usporedile ljude s visokim rizikom endokarditisa koji su razvili BE sa skupinom ljudi s visokim rizikom od endokarditisa koji nisu razvili BE. Studija je bila opažajna studija parova (slučajeva i kontrola) provedena u Nizozemskoj. Pregledani su podatci 349 osoba koje su razvile BE tijekom dvije analizirane godine. Ti su ljudi uspoređeni sa sličnom skupinom ljudi koja nije razvila BE-a. Svi oni koji su sudjelovali u istraživanju bili su podvrgnuti inavazivnom medicinskom ili stomatološkom postupku. Dvije skupine su uspoređene s obzirom na to koja je primila preventivne antibiotike prije tih postupaka i koja nije.
Temeljem objavljenih podataka nije jasno je li uzimanje antibiotika – kao preventivna mjera protiv BE-a prije podvrgavanja invazivnom dentalnom zahvatu – učinkovito ili nije.
Ne postoji studija koja procjenjuje broj smrtnih slučajeva, ozbiljne nuspojave koje zahtijevaju prijam u bolnicu, druge nuspojave ili trošak implikacija liječenja.
Nema dokaza koji bi bili sukladni prethodno objavljenim smjernicama u tom području. Nije jasno nadilaze li potencijalna šteta i troškovi antibiotske administracije neki koristan učinak. Zbog etičkih razloga, zdravstveni radnici trebaju s pacijentima razgovarati o potencijalnoj koristi i štetnosti preventivnog antibiotskog postupka prije nego li se donese odluka o propisivanju antibiotika.
Iako su vanjski čimbenici koji se odnose na studiju, kao što je uključivanje relevantnih sudionika i dobrih definiranih postupaka, bili dobri, vrsta studije – koja je bila retrospektivna i opservacijska – nosi značajan rizik od pristranosti i krivih zaključaka zbog čega takve studije nemaju visoku pouzdanost.
Cochrane Hrvatska Prevela: Josipa Ordulj Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: email@example.com
Antibiotic prophylaxis compared with no antibiotic prophylaxis for the prevention of bacterial endocarditis in dentistry
Patient or population: Adults or children at risk of endocarditis
Settings: Dental setting
Intervention: Antibiotic prophylaxis
Comparison: No antibiotic prophylaxis
No of participants (studies)
Quality of the evidence (GRADE)
No mortality data reported
Development of endocarditis (in those with definite indication for prophylaxis)
Very low quality
There was no difference in the number of people (with a definitive indication for prophylaxis) who developed endocarditis between those receiving prophylaxis compared with those not receiving prophylaxis (OR 1.62; 95% CI 0.57 to 4.57)
No adverse event data reported
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Description of the condition
Infective endocarditis is a rare disease caused by infected vegetations (growths), which often occur on previously damaged or congenitally malformed cardiac valves or endocardium (heart chamber lining). The infecting organisms are usually bacteria but less commonly are fungi, particularly of the Candida species, which may enter the blood via a number of portals. Bacterial endocarditis (BE) is infective endocarditis caused by bacteria which enter the blood (bacteraemia). Bacteria may enter the blood through a variety of portals but especially mucosal surfaces. The gingiva and periodontal ligament, which surrounds all teeth, are almost constantly experiencing a degree of inflammation and as such are a potential point of entry for bacteria within the blood. Indeed, it has been demonstrated that everyday activities such as toothbrushing cause bacteraemia (Lucas 2000; Roberts 1999).
There is a generally accepted incidence of BE of approximately 10 per 100,000 of the population per year. Though rare, it is a life-threatening condition with a mortality of up to 30%, even with antibiotic therapy (Delahaye 1995; Netzer 2000; Verheul 1993). In the past the majority of patients who developed endocarditis had a known pre-existing cardiac defect. More recently, however, this trend has shifted with nearly half of the cases of endocarditis having no known previous cardiac disease (Duval 2012; Hoen 2002; Hoen 2006). Common cardiac conditions that put people at risk include previous endocarditis, prosthetic heart valves, valvular stenosis, ventricular septal defect and valvular damage following rheumatic fever (Danchin 2005; Farook 2012). People with some of these conditions have a higher risk of developing endocarditis, namely those with previous endocarditis and prosthetic heart valves (Durack 1994). The above conditions either cause changes in the surface of the heart lining (endocardium) or changes in the blood flow, which damage the endocardium and enable organisms in the blood to adhere and multiply forming bacterial vegetations. This leads to a severe systemic illness as well as having direct effects on the functioning of the heart. Fragments of the vegetations may break away and become lodged elsewhere in the circulation (embolism).
The incidence of BE is low and the proportion of cases arising as a result of dental treatment is arguable, estimated to be as low as 4% (Gendron 2000; Gunneroth 1984) and as high as 64% of cases of BE (Bennis 1995). Although dental procedures are commonly implicated in the causation of endocarditis, the number of cases where the temporal relationship can be demonstrated ranges between only 4% and 7.5% of cases (Gendron 2000).
Description of the intervention
Most dental procedures cause bacteraemia and it was believed that this may lead to BE. There has previously been a well established practice of administering antibiotics, typically penicillins, to individuals who are at risk of developing BE prior to procedures during which a bacteraemia may develop. Early guidelines supported this practice (Dajani 1997; EWP 1993). The rationale for this was that a high circulating dose of antibiotic will prevent the development of an infected vegetation on damaged endocardium and thus prevent endocarditis. However, since the publication of the first version of this review in 2004, some authorities have questioned the routine use of antibiotics for endocarditis prophylaxis (Strom 1998), arguing that the adverse effects of antibiotics may outweigh the potential benefits. For example, in France, one study stated that patients receiving penicillin were five times more likely to die from an anaphylactic (allergic) reaction than from endocarditis (Bor 1984), however this study only considered people with mitral valve prolapse who are not at greatly increased risk of endocarditis. Across Europe, the US and Australia there have been radical changes to the guidelines, moving away from giving antibiotics to all at risk patients to only advising that they are given to those at high risk (Farook 2012). The definition of 'high risk' varies across American, European and Australian regulatory bodies. More recently, in England and Wales, the National Institute for Health and Care Excellence (NICE) published guidance that was more restrictive, stating that no antibiotics were required for any interventional procedure (dental or other surgical site) (NICE 2008). Despite marked reductions in antibiotic prophylaxis for BE over the past 10 years, no increase in its incidence has been shown (Duval 2012; Thornhill 2011).
Why it is important to do this review
Antibiotic prophylaxis before invasive procedures has been a key strategy for preventing BE for several decades, and remains so in many parts of the world (Thornhill 2011). Antibiotic therapy for the treatment of BE is not in question; without antibiotic therapy, infective endocarditis is fatal (Durack 1994). However, the use of antibiotic prophylaxis for the prevention of BE remains controversial.
To determine whether prophylactic antibiotic administration, compared to no such administration or placebo, before invasive dental procedures in people at risk or at high risk of bacterial endocarditis influences mortality, serious illness or the incidence of endocarditis.
To determine whether the effect of dental antibiotic prophylaxis differs in people with different cardiac conditions predisposing to raised risk of endocarditis, and in people undergoing different high risk dental procedures.
If there was no evidence from randomised controlled trials or cohort studies on whether prophylactic antibiotics affected mortality or serious illness, and there was evidence from these or case-control studies suggesting that prophylaxis with antibiotics reduced the incidence of endocarditis, then the following would have also been assessed: whether the harms of prophylaxis with single antibiotic doses such as with penicillin (amoxicillin 2 g or 3 g) before invasive dental procedures, compared with no antibiotic or placebo, in people at high risk of endocarditis did not differ from the benefits in prevention of endocarditis.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) would be included where available. Due to the low incidence of bacterial endocarditis it was anticipated that few such trials would be found. Cohort and case-control studies were included where suitably matched control or comparison groups had been studied.
Types of participants
RCTs and CCTs
Studies must have included adults or children, or both, who had any of the following pre-existing cardiac defects (that is patients known to be at risk): congenital heart defects, a history of rheumatic fever, and those at high risk with prosthetic heart valves (tissue and mechanical), or who had had endocarditis previously. People with pacemakers (and no other risk factors) were excluded.
The dental procedures which the patients may have undergone in the studies included: supragingival and subgingival scaling of teeth, extensive restorations of teeth, endodontics, and oral surgery including dental extractions. Procedures performed under local and general anaesthetic were considered.
Types of interventions
RCTs and CCTs
The prime intervention assessed was the administration of an antibiotic, compared with no such administration or placebo, before a dental procedure. Studies in which an antibiotic was administered post-operatively were included if this was part of a protocol in which the antibiotic was administered pre-operatively. The antibiotics could be administered by oral, intravenous or intramuscular routes but not topically.
Co-interventions may have included the following procedures: the use of mouthwash pre-operatively or the mechanical cleaning of teeth.
Types of outcome measures
RCTs and CCTs
The primary outcome measures were the following. (1) Mortality or serious adverse events (from any cause) requiring hospital admission. (2) The development of endocarditis following any dental procedure in a defined time period. (3) The development of endocarditis due to other non-dental causes.
The secondary outcome measures were the following. (1) Any recorded adverse events to the antibiotics. (2) Cost implications of antibiotic provision for prophylaxis compared with the cost of care of those extra patients who develop bacterial endocarditis (BE).
Assessment of harms would have included all studies where potentially serious (such as would be expected to result in hospitalisation) or fatal side effects of a single antibiotic dose had been reported or assessed. Studies included would have been any studies already included in the review, as well as randomised controlled trials, cohort studies, case-control studies, uncontrolled trials, case series and case reports.
Characteristics of included cohort studies and case-control studies
Cohort studies to be included would fulfil the following criteria. Participants were people at high risk of endocarditis (as above). Their progress was followed (no minimum time period) and invasive dental procedures carried out; use (or not) of prophylactic antibiotics at these visits and occurrence or not of BE, death or serious illness were recorded (as a minimum). It would have been possible to compare incidence of BE, and death or serious illness in those who received invasive dental procedures with and without antibiotics.
Case-control studies included fulfilled the following criteria. The groups that were compared included a group of people at high risk of endocarditis who did develop BE, and a group of people at high risk of endocarditis who did not develop BE. Information was provided on the numbers of people in each group who had undergone invasive dental procedures within a (stated) set period, and the numbers who had received antibiotic prophylaxis concomitant with that dentistry. Post hoc it was decided that studies which excluded cases when they died due to endocarditis would be excluded as up to 30% of people who contract endocarditis will die of it and these participants may be different from those who do not die.
Search methods for identification of studies
For the identification of studies to be included or considered for this review, we developed detailed search strategies for each database that was searched. These were based on the search strategy developed for MEDLINE (OVID) but were revised appropriately for each database. The search strategy used a combination of controlled vocabulary and free text terms. Details of the MEDLINE search are provided in Appendix 1. We opted not to use a study design filter as the yield from the subject search was small.
We searched the following electronic databases:
The Cochrane Oral Health Group's Trials Register (to 21 January 2013) (Appendix 2);
The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12) (Appendix 3);
MEDLINE via OVID (1946 to 21 January 2013) (Appendix 1);
EMBASE via OVID (1980 to 21 January 2013) (Appendix 4).
No restrictions on language or date of publication were applied in the searches of the electronic databases.
Searching other resources
We searched the following trials registers for ongoing studies (to January 2013):
Only handsearching done as part of the Cochrane Worldwide Handsearching Programme and uploaded to CENTRAL was included (see the Cochrane Masterlist for details of journal issues searched to date).
Data collection and analysis
Inclusion and exclusion criteria
Study titles and abstracts obtained from the search were screened for inclusion independently by two review authors. The review authors were not blinded to the authors, institution or journal. Full text papers that were retrieved were similarly screened for inclusion independently by two review authors. The inclusion criteria were as stated above. Disagreements over inclusion were resolved by discussion; if agreement could still not be reached it was intended that the paper would be taken to a third party, but this did not occur.
Data and quality information were independently extracted by two review authors onto a custom designed data collection form. Briefly, in addition to bibliographic details of the paper, the key items of data were the study design, country of origin, details of the antibiotic intervention, study population details including risk factors and type of dental procedure. The outcome data collected from RCTs and CCTs included number of deaths; number of hospital admissions; the number of serious illnesses that would be expected to result in hospital admission; the number of cases of endocarditis; any other adverse events noted; and the number of people originally randomised to each group. The outcome data collected from cohort studies would have included the same information as for RCTs plus adjusted odds ratios or risk ratios and information on which factors were adjusted for. The outcome data collected from case-control studies included the adjusted odds ratio of a person at high risk of endocarditis having had antibiotic prophylaxis before invasive dentistry before either developing endocarditis (cases) or not (controls). Authors were contacted for further details of their studies as well as to assess inclusion, where necessary.
Assessment of study quality
Included studies were to be ranked according to study design: RCT, CCT, cohort study, case-control study.
All included studies were assessed for risk of bias by two review authors using the Cochrane risk of bias assessment tool for non-randomised studies. Domains assessed for each included study are: sequence generation, allocation concealment, confounding, blinding of outcome assessment, completeness of outcome data, risk of selective outcome reporting, and risk of other potential sources of bias. For the primary outcome the following factors have been identified as important confounders; other sources of fluoride, social class; ethnicity and residential history while the use of other fluoride sources is the only confounder considered to be relevant to the secondary outcome.
A description of the risk of bias domains was tabulated for each included trial, along with a judgement of low, high or unclear risk of bias.
A summary assessment of the risk of bias for the primary outcome (across domains) across studies would have been undertaken (Higgins 2011) had data allowed. Within a study, a summary assessment of low risk of bias was given when there was a low risk of bias for all key domains, unclear risk of bias when there was an unclear risk of bias for one or more key domains, and high risk of bias when there was a high risk of bias for one or more key domains.
Where data appeared ambiguous or incomplete, the study authors would have been contacted.
It was planned that data on the number of patients with each outcome event, by allocated treatment group (RCTs) or quantile (cohort studies), would be sought. We aimed to calculate a pooled estimate of the treatment effect for each outcome (separately) across RCTs, CCTs, cohort studies and case-control studies in a random-effects meta-analysis as an odds ratio (the ratio of odds in the prophylaxis group to the odds in the no prophylaxis group), since the odds ratio is the only good measure of association that works across prospective studies and case-control studies (Fleiss 1981). Heterogeneity between trial results was to be tested for using a standard Chi2 test, and considered significant where P value < 0.1. For case-control studies it was planned that the odds of antibiotic prophylaxis before dental treatment in the previous three months for cases and controls would not be pooled with data from other types of studies. It was planned that if harm data were collected they would be tabulated according to study design, but not pooled.
For amoxicillin, if sufficient data were available, then the interventions of 2 g and 3 g amoxicillin would be considered separately. Also, if appropriate, subgrouping would be used to explore the effects of different underlying causes of at risk and high risk status for endocarditis, and of different invasive dental techniques.
It was also planned that sensitivity analysis would be carried out on any pooled analyses, removing studies where there appeared to be significant differences in risk factors for endocarditis between the groups compared and where this had not been adequately adjusted for.
Description of studies
A total of 1390 references were identified by the above search strategy. Assessment of the titles and abstracts, where available, resulted in 122 references of potential relevance; all of which were obtained in full text (Figure 1). A further 86 were rejected since they were clearly discussion papers, editorials or guidelines. A total of 36 references were assessed for inclusion, in duplicate. Of these full papers, 35 were eventually excluded (see Characteristics of excluded studies for further details). In particular, one potentially useful cohort study was identified but excluded as it was not possible to separate out those who received prophylaxis, or not, before dental treatment (Gersony 1977). Several case-control studies were identified where only some of the cases were at high risk of endocarditis before dental treatment (Strom 1998B; Strom 2000). It was evident that there were many review articles, commentaries and guidelines but few primary studies.
No randomised controlled trials (RCTs) were identified, nor were any other controlled trials (quasi-randomised, historically controlled) or cohort studies identified. Three case-control studies were initially included (Imperiale 1990; Lacassin 1995; Van der Meer 1992) however on discussion with editors of the Cochrane Oral Health Group it was decided that two of these, Imperiale 1990 and Lacassin 1995, might have been severely biased and so should be excluded. In these studies people with endocarditis (cases) who died, about 20% of potential cases in both studies, were not included. Excluding this group, whose characteristics may have been very different from those cases who survived endocarditis, from the cases but not from the controls (where appreciably fewer people were likely to have died) will have made the characteristics of the two groups very different. Thus only one case-control study was included in this review, Van der Meer 1992.
The Van der Meer 1992 study collected details of all of the 349 people who developed definite native-valve endocarditis in the Netherlands over a two-year period (first November 1986 to first November 1988). Cases were eligible if they had previously had congenital heart disease, coarctation of the aorta, rheumatic or other valvular dysfunction, or mitral valve prolapse with mitral regurgitation. They had to have undergone a medical or dental procedure that required prophylaxis within 180 days of the onset of symptoms of endocarditis. Proxy responders (spouses or general practitioners) were used where cases were too ill to be interviewed or had died.
Controls had not been diagnosed with endocarditis but had one of the cardiac conditions and were outpatients at cardiology departments of one of five hospitals. Controls were matched for age (within the same five year age category) and had undergone a medical or dental procedure within 180 days of their interview. A random sample of potential controls was drawn, and where there were at least four controls per case all were contacted. Where there were fewer than four controls a further random sample was drawn.
For both groups, all information about invasive procedures and use of prophylaxis was checked with medical or dental specialists and pharmacists.
Risk of bias in included studies
The included study used a case-control design and was therefore at risk of the usual sources of bias associated with this observational study design. The study was judged to be at risk of selection bias and outcome reporting bias (Characteristics of included studies; Figure 2). There were some concerns regarding attrition bias as cases who were very ill or who died were included in the analysis via the use of proxy responders, however this did not occur for the 53/889 controls who died. In addition, there were concerns that it was unclear how similar the groups were with regard to type of cardiac risk factor, gender, or type of dental intervention.
Overall, the observational and retrospective nature of the design conferred a high risk of bias.
In the included case-control study (Van der Meer 1992), of the 349 people with definite native-valve endocarditis 197 had previous heart disease (proxy responders were interviewed for 10 of these). Of these, 54 had undergone a medical or dental procedure with an indication for prophylaxis within the past 180 days, of whom in six a causal relationship was ruled out as it was unlikely that the agent isolated from the blood originated in the area of the procedure. Of the 48 people with endocarditis that were left, 44 had undergone a dental procedure which the paper identified as having a definite (24) or possible (20) indication for prophylaxis (none of these cases had used a proxy responder). Indications for definite prophylaxis were dental extractions and dental root work, while indications for possible prophylaxis were defined as dental scaling.
Of 889 potential controls who were sent an introductory letter, 689 were ineligible (53 had died, 29 had a prosthetic heart valve, 62 could not be located, 102 could not be contacted by phone, and 418 had not undergone an invasive dental or medical procedure within the past 180 days). The remaining 200 were interviewed by phone two to five days later; 181 of these controls had undergone a dental procedure with definite (79) or possible (102) indications for prophylaxis.
Seven of 24 cases and 16 of 79 controls had had appropriate prophylaxis for a dental procedure requiring definite prophylaxis within 180 days.
The characteristics of the cases and controls were not well described as those who had received a dental procedure (rather than a medical one) were not separated out in the publication (the separated data were provided by Professor Van der Meer). The median time between a dental procedure requiring definite prophylaxis and onset of endocarditis was 10 days in the cases, and the median time between a dental procedure requiring definite prophylaxis and interview was 71 days in the controls (data missing for 12 controls). The procedure was apical surgery in one case (4%) and one control (1%), dental avulsion in one case (4%) and 12 controls (15%), dental extraction in nine cases (38%) and 15 controls (19%), dental abscess in one case (4%) and one control (1%), removal of subgingival calculus in three cases (13%) and eight controls (33%), removal of calculus plus polishing of teeth in six cases (25%) and 34 controls (43%), and root canal therapy in three cases (13%) and eight controls (10%).
Including the cases and controls undergoing either definite or possible indication for prophylaxis, and including the four cases and 19 controls who underwent a non-dental indication, 69% of cases were male and 55% of controls. The median age of this larger group was 41 years for cases and 40 for controls (the controls were age-matched).
Seven of 21 cases and 9 of 46 controls had had appropriate prophylaxis for a dental procedure requiring definite prophylaxis within 90 days. Seven of 44 cases and 17 of 181 controls had had appropriate prophylaxis for a dental procedure requiring definite or possible prophylaxis within 180 days. Seven of 32 cases and 9 of 100 controls had had appropriate prophylaxis for a dental procedure requiring definite or possible prophylaxis within 90 days. No information was presented on the adjunctive use of mouthwash.
In each of these ways of assessing the data the proportion of those receiving prophylaxis was greater in the cases than in the controls. Translating the data so that we assessed the odds of developing endocarditis in those receiving prophylaxis compared with those not receiving prophylaxis we find an odds ratio (OR) which was not significantly different from the OR for any of the groupings (OR 1.62, 95% confidence interval (CI) 0.57 to 4.57 for those with a definite indication for prophylaxis over 180 days).
Only four cases developed endocarditis following non-dental medical interventions (within the past 180 days and with pre-existing cardiac indications for the use of prophylaxis), so assessment of the effects of prophylaxis in these cases was not possible.
It was unclear whether antibiotic prophylaxis was effective or ineffective against bacterial endocarditis in people at risk who were about to undergo an invasive dental procedure.
No studies were located that assessed mortality, serious adverse events requiring hospital admission, other adverse events or cost implications of treatment.
Because no significant protective effect of antibiotic prophylaxis was seen against endocarditis, we did not do a wide ranging search to pool information on the potential harmful effects of antibiotic prophylaxis as pre-specified in the protocol.
Summary of main results
This review update has identified no further studies meeting the review's inclusion criteria.
The one included case-control study, which included all of the people in the Netherlands who developed endocarditis following an invasive dental procedure while at known cardiac risk over a two-year period (24 individuals who underwent a procedure definitely requiring prophylaxis, and a further 20 that may possibly have required prophylaxis), provides no conclusive evidence about whether antibiotic prophylaxis is effective or ineffective against bacterial endocarditis in high risk individuals about to undergo an invasive dental procedure.
A non-statistically significant difference for the development of endocarditis over 180 days in those receiving prophylaxis compared with those not receiving prophylaxis was shown for those individuals with a definite indication for prophylaxis (OR 1.62, 95% CI 0.57 to 4.57). If we include data from the two excluded case-control studies (Imperiale 1990; Lacassin 1995) (excluded due to inappropriate comparisons, see Characteristics of excluded studies) a total of 59 participants developed endocarditis of the 67 people receiving appropriate prophylaxis and 148 people not receiving prophylaxis across all three studies (random-effects OR 0.56, 95% CI 0.15 to 2.15).
There are currently insufficient primary data to know whether antibiotic prophylaxis before invasive dental procedures in people at high risk of endocarditis does actually prevent endocarditis, deaths or other serious illness.
For the original version of this review we canvassed opinion among some healthcare workers with an interest in evidence based care and a separate group of dentists who had attended an evidence based practice course. Those healthcare workers and dentists who were blinded to the details of the intervention and condition, but shown the level of evidence and the non-significant odds ratio, stated that in this circumstance they would attempt to seek out further evidence (randomised controlled trials (RCTs), cohort studies etc) or involve their patients in the decision about whether to use the intervention, or both. However, those dentists who were not blinded, who were told that the topic was endocarditis prophylaxis using penicillin, stated that they would use prophylaxis despite the paucity of evidence and cited medico-legal reasons for this decision. It will be interesting how the National Institute for Health and Care Excellence (NICE) guideline (NICE 2008) is adhered to not just by dentists but other healthcare professionals to which it applies. A recent study examined the legal situation of claimants who had contracted endocarditis against the dentists who had recently treated them (Martin 2007). The authors concluded that as long as dentists adhere to current published guidelines there is little course for redress and it is eminently defensible in a court of law.
Overall completeness and applicability of evidence
As the usefulness of prophylaxis could not be established, we have not examined in detail the harms of antibiotic administration; this would be a systematic review in itself. Such a review would, however, be extremely valuable and could potentially be used by a wide spectrum of research workers and other systematic reviews. In the absence of a systematic review on the harms of penicillins, the most authoritative source is Meyler's Side Effects of Drugs (Aronson 2006). The range of potential side effects from the administration of antibiotics is vast, largely with a hypersensitive aetiology, but some direct toxic effects may also occur.
The effects of the NICE guidance on the incidence of endocarditis in the UK are going to be monitored using the Hospital Episode Statistics (HES). Tracked over a number of years and compared with the pre-NICE guideline era the incidence of endocarditis might be one method to answer this conundrum, albeit in a rather crude fashion.
Another under explored area is the cost of prophylaxis, both in terms of finance and health. The financial cost to health services of providing large quantities of prophylactic antibiotics must be weighed against the cost of treating patients who develop endocarditis, which, although significant, occurs in appreciably fewer patients than those potentially at risk. The health costs need considering, particularly the potential harms of the administration of antibiotics compared to the development of endocarditis. The involvement of health economists would be beneficial. This was explored in depth in the recent NICE guidance (NICE 2008).
Despite the varying guidelines produced over the years and the recent significant change recommended by NICE, it is important for medical and dental practitioners to remember that patients remain at risk of developing endocarditis. Many patients will develop endocarditis with organisms that have originated from the oral cavity. Whilst there is no evidence that dental treatment is directly related to the development of the disease or not, nor that prophylactic antibiotics can prevent the development of the disease or not, it would appear logical to recommend that the highest level of oral health should be achieved and maintained in at risk patients.
Quality of the evidence
The overall quality of the evidence is low, coming from a single study at high risk of bias. It would be useful to have evidence about the effectiveness of antibiotic prophylaxis of endocarditis in dentistry from higher levels of evidence. As the incidence of endocarditis is so low, a randomised controlled trial run over two years would require approximately 60,000 patients with a cardiac risk factor for endocarditis to be included (a cohort study over 10 years would require approximately 18,000 patients). Such a trial would require an intense international effort.
A larger, well conducted case-control study might be more feasible but would still require a large effort and multicentre participation. If including every endocarditis case in the Netherlands for two years produces only 24 appropriate cases then the area or time span covered will be very large indeed. Selection of appropriate controls is probably the most challenging aspect; ideally, as in Van der Meer's study, they would have had dental treatment in a predefined time and be matched very closely for sex, age and type of cardiac risk factor. Additionally, neither cases nor controls should be excluded for death or serious illness (use of proxy respondents would be ideal and this would require retrospective identification of controls as well as ongoing prospective identification of cases) and dental records would be available and be explicit about the use (or not) of prophylaxis. Full details would be collected on other factors which may compound the risk such as general well being, coexisting medical problems, socio-economic status and oral health status.
Agreements and disagreements with other studies or reviews
There is general agreement that there is little scientific evidence to support the effectiveness of antibiotic prophylaxis for the prevention of bacterial endocarditis (Duval 2012; Farook 2012; Thornhill 2011). This lack of evidence has led to variations in guideline recommendations with regard to who should or should not be prescribed antibiotic prophylaxis and who is or is not considered high risk for bacterial endocarditis. However, one area where most guidelines are in agreement is with regard to the need for regular dental surveillance to promote good oral hygiene, thus reducing the need for invasive dental procedures and subsequently reducing the risk of bacterial endocarditis (Chambers 2012).
Implications for practice
There remains no evidence that antibiotic prophylaxis is either effective or ineffective against bacterial endocarditis in people considered at risk who are about to undergo an invasive dental procedure. It is not clear whether the potential harms and costs of penicillin administration outweigh any beneficial effect.
Implications for research
A randomised controlled trial (RCT) would only be feasible in extensive areas of very centralised and organised health care, due to the large numbers of participants with risk factors for endocarditis required. A well designed multicentre cohort or case-control study is possible but would still require a very large and co-ordinated effort, and a great deal of attention would need to be paid to recruiting suitable control participants. These would be most feasible to perform in an area where registers exist so that it is possible to identify all people with current risk factors for endocarditis, and would randomise them or follow their dental histories in detail and identify outcomes completely and accurately.
A systematic review of the harms and costs associated with antibiotic use is needed, and such a review may be useful to assess the harms for systematic reviews of a number of different interventions. It would be important to assess the effects of type of antibiotic, route of administration, dose, previous history of reaction and duration of use on the side effects and adverse events experienced by people on antibiotic therapy.
Our gratitude goes to Dr Van der Meer (Academic Medical Center, University of Amsterdam) for splitting his data into people who had or had not had a relevant dental intervention, and to Dr Imperiale (Yale University School of Medicine) for his helpful information on his study. Thanks also to the Cochrane Non-Randomised Methods Group, and the Harms subgroup, for support, discussion and ideas about the review. We are grateful to Luisa Fernandez Mauleffinch of the Cochrane Oral Health Group for excellent support, Anne Littlewood (Cochrane Oral Health Group), Margaret Burke (Cochrane Heart Group) and Vittoria Lutje (Cochrane Infectious Diseases Group) for kindly searching their trials registers for us, and Marco Esposito, Helen Worthington, Sylvia Bickley, Jan Clarkson, Paul Coulthard, Jayne Harrison, David Rickard, Robin Richardson, Jan van der Meer, Robin Seymour and Jeremy Bagg for constructive comments on the manuscript.
1. exp Endocarditis/ 2. endocarditis.tw. 3. (endocardium adj5 (inflamm$ or infect$)).tw. 4. (ABE or SABE).ti,ab. 5. or/1-4 6. exp Dental prophylaxis/ 7. exp Dentistry, operative/ 8. exp Endodontics/ 9. exp Oral surgical procedures/ 10. ((oral or tooth or teeth) adj5 (surg$ or extract$ or restor$ or invas$ or scale or scaling or polish$ or endodontic$ or "root canal" or apicectom$ or apicoectom$)).tw. 11. (dental or dentist$).tw. 12. or/6-11 13. Antibiotic prophylaxis/ 14. (antibiotic$ or anti-biotic$ or antimicrobial$ or anti-microbial$).tw. 15. Anti-bacterial agents/ 16. exp Penicillins/ 17. (amoxicillin$ or amoxycillin$ or amoxil or actimoxi or clamoxyl or hydroxyampicillin or penamox or trimox or wymox).tw. 18. ("penicillin v$" or apocillin or beromycin or betapen or fenoxymethylpenicillin or "Pen VK" or phenoxymethylpenicillin or "V-Cillin K" or vegacillin).tw. 19. Clindamycin/ 20. (clindamycin or chlolincocin or cleocin or "Dalacin C").tw. 21. Cephalexin/ 22. (cephalexin or cefalexin$ or ceporexine or Palitrex or cephahexin$).tw. 23. Azithromycin/ 24. (azithromycin or azadose or azitrocin or azythromycin or gozal or sumamed or toraseptol or ultreon or vinzam or zentavion or zithromax or zitromax).tw. 25. Clarithromycin/ 26. (clarithromycin or biaxin).tw. 27. Cefazolin/ 28. (cefazolin or ancef or cefamedin or cefamezine or cephamezine or cephazolin or gramaxin or kefzol or totacef).tw. 29. Ceftriaxone/ 30. (ceftriaxone or benaxona or cefatriaxone or cefaxona or ceftrex or ceftriaxon$ or lendacin or longacef or longaceph or rocefalin or rocefin or rocephin$ or tacex or terbac).tw. 31. or/13-30 32. 5 and 12 and 31
Appendix 2. Cochrane Oral Health Group's Trials Register search strategy
#1 (endocarditis) AND (INREGISTER) #2 ((endocardium and (inflamm* or infect*)):ti,ab) AND (INREGISTER) #3 ((ABE or SABE):ti,ab) AND (INREGISTER) #4 (#1 or #2 or #3) AND (INREGISTER) #5 ((antibiotic* or anti-biotic* or antimicrobial* or anti-microbial*):ti,ab) AND (INREGISTER) #6 ((antibacterial* or anti-bacterial*):ti,ab) AND (INREGISTER) #7 ((penicillin* or amoxicillin* or amoxycillin* or amoxil or actimoxi or clamoxyl or hydroxyampicillin or penamox or trimox or wymox):ti,ab) AND (INREGISTER) #8 ((apocillin or beromycin or betapen or fenoxymethylpenicillin or "Pen VK" or phenoxymethylpenicillin or "V-Cillin K" or vegacillin):ti,ab) AND (INREGISTER) #9 ((clindamycin or chlolincocin or cleocin or "Dalacin C"):ti,ab) AND (INREGISTER) #10 ((cephalexin or cefalexin* or ceporexine or Palitrex or cephahexin*):ti,ab) AND (INREGISTER) #11 ((azithromycin or azadose or azitrocin or azythromycin or gozal or sumamed or toraseptol or ultreon or vinzam or zentavion or zithromax or zitromax):ti,ab) AND (INREGISTER) #12 ((clarithromycin or biaxin):ti,ab) AND (INREGISTER) #13 ((cefazolin or ancef or cefamedin or cefamezine or cephamezine or cephazolin or gramaxin or kefzol or totacef):ti,ab) AND (INREGISTER) #14 ((ceftriaxone or benaxona or cefatriaxone or cefaxona or ceftrex or ceftriaxon* or lendacin or longacef or longaceph or rocefalin or rocefin or rocephin* or tacex or terbac):ti,ab) AND (INREGISTER) #15 (#5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14) AND (INREGISTER) #16 (#4 and #15) AND (INREGISTER)
Appendix 3. Cochrane Central Register of Controlled Trials search strategy
#1 [mh Endocarditis] #2 endocarditis #3 (endocardium near/5 (inflamm* or infect*)) #4 (ABE or SABE):ti,ab #5 #1 or #2 or #3 or #4 #6 [mh "Dental prophylaxis"] #7 [mh ^"Dentistry, operative"] #8 [mh Endodontics] #9 [mh "Oral surgical procedures"] #10 ((oral or tooth or teeth) near/5 (surg* or extract* or restor* or invas* or scale or scaling or polish* or endodontic* or "root canal" or apicectom* or apicoectom*)) #11 (dental or dentist*) #12 #6 or #7 or #8 or #9 or #10 or #11 #13 [mh ^"Antibiotic prophylaxis"] #14 (antibiotic* or anti-biotic* or antimicrobial* or anti-microbial*) #15 [mh ^"Anti-bacterial agents"] #16 [mh Penicillins] #17 (amoxicillin* or amoxycillin* or amoxil or actimoxi or clamoxyl or hydroxyampicillin or penamox or trimox or wymox) #18 ("penicillin v*" or apocillin or beromycin or betapen or fenoxymethylpenicillin or "Pen VK" or phenoxymethylpenicillin or "V-Cillin K" or vegacillin) #19 (clindamycin or chlolincocin or cleocin or "Dalacin C") #20 (azithromycin or azadose or azitrocin or azythromycin or gozal or sumamed or toraseptol or ultreon or vinzam or zentavion or zithromax or zitromax) #21 (clarithromycin or biaxin) #22 (cefazolin or ancef or cefamedin or cefamezine or cephamezine or cephazolin or gramaxin or kefzol or totacef) #23 (ceftriaxone or benaxona or cefatriaxone or cefaxona or ceftrex or ceftriaxon* or lendacin or longacef or longaceph or rocefalin or rocefin or rocephin$ or tacex or terbac) #24 (cephalexin or cefalexin* or ceporexine or Palitrex or cephahexin*) #25 #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 #26 #5 and #12 and #25
Appendix 4. EMBASE (OVID) search strategy
1. exp Endocarditis/ 2. endocarditis.tw. 3. (endocardium adj5 (inflamm$ or infect$)).tw. 4. (ABE or SABE).ti,ab. 5. or/1-4 6. exp Dental surgery/ 7. exp Endodontics/ 8. exp Oral surgery/ 9. ((oral or tooth or teeth) adj5 (surg$ or extract$ or restor$ or invas$ or scale or scaling or polish$ or endodontic$ or "root canal" or apicectom$ or apicoectom$)).tw. 10. (dental or dentist$).tw. 11. or/6-10 12. Antibiotic prophylaxis/ 13. (antibiotic$ or anti-biotic$ or antimicrobial$ or anti-microbial$).tw. 14. Antiinfective agent/ 15. exp Penicillin derivative/ 16. (amoxicillin$ or amoxycillin$ or amoxil or actimoxi or clamoxyl or hydroxyampicillin or penamox or trimox or wymox).tw. 17. ("penicillin v$" or apocillin or beromycin or betapen or fenoxymethylpenicillin or "Pen VK" or phenoxymethylpenicillin or "V-Cillin K" or vegacillin).tw. 18. Clindamycin/ 19. (clindamycin or chlolincocin or cleocin or "Dalacin C").tw. 20. Cefalexin/ 21. (cephalexin or cefalexin$ or ceporexine or Palitrex or cephahexin$).tw. 22. Azithromycin/ 23. (azithromycin or azadose or azitrocin or azythromycin or gozal or sumamed or toraseptol or ultreon or vinzam or zentavion or zithromax or zitromax).tw. 24. Clarithromycin/ 25. (clarithromycin or biaxin).tw. 26. Cefazolin/ 27. (cefazolin or ancef or cefamedin or cefamezine or cephamezine or cephazolin or gramaxin or kefzol or totacef).tw. 28. Ceftriaxone/ 29. (ceftriaxone or benaxona or cefatriaxone or cefaxona or ceftrex or ceftriaxon$ or lendacin or longacef or longaceph or rocefalin or rocefin or rocephin$ or tacex or terbac).tw. 30. or/12-29 31. 5 and 11 and 30
Appendix 5. US National Institutes of Health Trials Register search strategy
endocarditis AND dental AND prophylaxis endocarditis AND dental AND prophylaxis
Appendix 6. metaRegister of Controlled Trials search strategy
endocarditis AND dental AND prophylaxis endocarditis AND dental AND prophylaxis
31 July 2013
New citation required but conclusions have not changed
The background and discussion have been updated to reflect recent literature in this area. 'Risk of bias' and 'Summary of findings' tables have been added. Change in authors.
12 July 2013
New search has been performed
Search updated to January 2013.
Protocol first published: Issue 3, 2002 Review first published: Issue 2, 2004
24 July 2008
New citation required but conclusions have not changed
Review updated and scope expanded to include all antibiotics and not just penicillins. Change in authors.
24 July 2008
New search has been performed
Search updated to June 2008.
24 June 2008
Converted to new review format.
Contributions of authors
Anne-Marie Glenny: led the review update, screened update search results, amended background and discussion to reflect recent literature, added risk of bias tables and summary of findings table. Richard Oliver: initiated the review, involved with the design and writing of the protocol, searching, duplication of assessment of titles and abstracts, inclusion and exclusion of full text papers, data extraction and quality assessment of included studies, data analysis and interpretation. Lee Hooper: Lee was involved in the design of the first published version of the review, writing of the protocol, searching, duplication of assessment of titles and abstracts, inclusion and exclusion of full text papers, data extraction and quality assessment of included studies, data analysis and interpretation. Graham J Roberts: provided background information for the protocol and review. Helen Worthington: provided methodological and statistical support; screened update search results.
Declarations of interest
Anne-Marie Glenny: no interests to declare. Richard Oliver: no interests to declare. Graham J Roberts: no interests to declare. Lee Hooper: no interests to declare. Helen V Worthington: no interests to declare.
Sources of support
Central Manchester and Manchester Children's University Hospitals NHS Trust, UK.
The University of Manchester, UK.
Eastman Dental Institute, UK.
Manchester Academic Health Sciences Centre (MAHSC), UK.
The Cochrane Oral Health Group is supported by MAHSC and the NIHR Manchester Biomedical Research Centre
Department of Health Cochrane Review Incentive Scheme 2007, UK.
Cochrane Oral Health Group Global Alliance, UK.
All reviews in the Cochrane Oral Health Group are supported by Global Alliance member organisations (British Orthodontic Society, UK; British Society of Paediatric Dentistry, UK; British Society of Periodontology, UK; Canadian Dental Hygienists Association, Canada; National Center for Dental Hygiene Research & Practice, USA; New York University College of Dentistry, USA; and Royal College of Surgeons of Edinburgh, UK) providing funding for the editorial process (http://ohg.cochrane.org/)
National Institute for Health Research (NIHR), UK.
CRG funding acknowledgement: The NIHR is the largest single funder of the Cochrane Oral Health Group
Disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Van der Meer 1992
All of the 349 people who developed definite native-valve endocarditis in the Netherlands over a 2-year period (1st November 1986 to 1st November 1988) were collected. Cases (n = 48) were eligible if they had previously had congenital heart disease, coarctation of the aorta, rheumatic or other valvular dysfunction, or mitral valve prolapse with mitral regurgitation. Proxy responders (spouses or general practitioners) were used where cases were too ill to be interviewed or had died. Controls (n = 200) had not been diagnosed with endocarditis but had 1 of the cardiac conditions and were outpatients at cardiology departments of 1 of 5 hospitals. Controls were matched for age (within the same 5-year age category). A random sample of potential controls was drawn, and where there were at least 4 controls per case all were contacted. Where there were fewer than 4 controls a further random sample was drawn.
Cases and controls had to have undergone a medical or dental procedure that required prophylaxis within 180 days of the onset of symptoms of endocarditis (cases) or of their interview (controls). 6 of 24 (25%) cases and 34 of 79 (43%) controls undergoing a dental procedure with definite indication for prophylaxis had removal of calculus plus polishing of teeth, 9 of 24 (38%) cases and 15 of 79 (19%) controls had a dental extraction, 1 case and 1 control had apical surgery, 1 case and 1 control had dental extraction, 1 (4%) case and 12 (15%) controls had dental avulsion, 3 (13%) cases and 8 (10%) controls had removal of subgingival calculus, 3 (13%) cases and 8 (10%) controls had root canal therapy. Median time from dental procedure to onset of endocarditis in cases was 10 days, range 0 to 175 days (and for the 7 who received antibiotics median time to onset was 18 days, range 7 to 60). Median time from dental procedure to interview in controls was 71 days, range 0 to 179 (12 missing values ignored), and for the controls who received antibiotics a median of 83 days, range 5 to 151 (1 missing value ignored). For both groups all information about invasive procedures and use of prophylaxis was checked with medical or dental specialists and pharmacists.
Of 349 people with definite native-valve endocarditis, 197 had previous heart disease (10 proxy responders). Of these, 54 had undergone a medical or dental procedure with an indication for prophylaxis within the past 180 days, of whom in 6 a causal relationship was ruled out as it was unlikely that the agent isolated from the blood originated in the area of the procedure. Of the 48 people with endocarditis left, 44 had undergone dental procedure with a definite (24) or possible (20) indication for prophylaxis (none of these cases had used a proxy responder).
Of 889 potential controls who were sent an introductory letter 689 were ineligible (53 had died, 29 had a prosthetic heart valve, 62 could not be located, 102 could not be contacted by phone and 418 had not undergone an invasive dental or medical procedure within the past 180 days), the remaining 200 were interviewed by phone 2 to 5 days later. 181 of these controls had undergone a dental procedure with definite (79) or possible (102) indication for prophylaxis.
Endocarditis was defined by the diagnostic criteria of Von Reyn 1981, and it was checked that controls had not developed endocarditis. Appropriateness of antibiotic prophylaxis was checked with medical, dental and pharmacy staff, and assessed against the Netherlands Heart Foundation recommendations.
7 of 24 cases and 16 of 79 controls had had appropriate prophylaxis for a dental procedure requiring definite prophylaxis within 180 days.
The published paper provides data on participants who had both medical and dental invasive procedures. The author kindly separated out those who had had invasive dental interventions.
Risk of bias
Support for judgement
Random sequence generation (selection bias)
Not undertaken (case-control study). It is possible that as the dentist is deciding whether to give prophylaxis or not on the basis of the information held about the patient in front of him or her that those patients appearing frailer may have been more likely to receive prophylaxis.
Allocation concealment (selection bias)
Not undertaken (case-control study).
Blinding of outcome assessment (detection bias) All outcomes
Incomplete outcome data (attrition bias) All outcomes
Cases who were very ill or who died were included via use of proxy responders, however this did not occur for the 53/889 controls who died.
Selective reporting (reporting bias)
Expected outcomes and exposure reported.
Type of cardiac risk factor, sex not described for the subgroup who had had a dental procedure, and type of dental intervention appears different in the cases and controls, but cases and controls matched for age. Both groups were required to have undergone invasive dental techniques within 180 days of onset of symptoms/interview and data are split by time period for both groups.
Characteristics of excluded studies [ordered by study ID]
Retrospective analysis of cumulative exposure to bacteraemia following various dental procedures in children with severe congenital heart disease but no cases of endocarditis.
Economic analysis of the cost-effectiveness of using prophylactic antibiotics using same data as Bonhomme 1992.
2 case studies of high risk patients developing endocarditis after dental treatment with antibiotic prophylaxis.
Not all cases at risk and no controls.
No control group.
Retrospective analysis of 28 cases of endocarditis, no controls.
Economic analysis of the cost-effectiveness of using prophylactic antibiotics based on published data.
No control group.
Assessment of the effect of mitral valve prolapse on risk of endocarditis (rather than assessment of the effect of prophylaxis), case-control design.
Participants not at high risk of endocarditis.
Cohort study but it was not stated how many patients had preceding dental treatment, only two cases with preceding dental treatment and no prophylaxis.
Case report (German).
All children with cardiac disease received antibiotic prophylaxis before dental extraction, no controls.
Retrospective study of a group of people at high risk of endocarditis who had had appropriate prophylaxis for medical and dental interventions, and a group of people at similar risk who did not have appropriate prophylaxis for such interventions. It is not possible to ascertain how many of the cases or controls had had dental interventions, and the source of the 2 groups is unclear.
Case-control study: people with endocarditis (cases) who died were excluded, although the mortality rate in the cases was much higher (20%) than was likely in the control group, thus making the 2 groups incomparable.
CCT, but participants not at high risk of endocarditis and no relevant outcomes measured.
Case-control study: people with endocarditis (cases) who died were excluded, although the mortality rate in the cases was much higher (20%) than was likely in the control group, thus making the 2 groups incomparable.
Cohort study of patients having dental extractions but all patients received antibiotics.
Letter on failures of prophylaxis on a case by case basis, not RCT, CCT, cohort or case-control design.
Retrospective study of cases of endocarditis but no controls.
Serological study of bacteraemia following penicillin V administration and tooth extraction.
Not an assessment of penicillin prophylaxis (concerned with adjunctive use of antiseptic solution).
No at risk patients. Examined serum levels of amoxicillin in healthy volunteers.
Case-control study based in the USA of 273 hospital patients with endocarditis. Not all the cases (38%) or controls (6%) had a previously known risk of endocarditis.
Case-control study of same patient group as Strom 1998B. Not all the cases or controls were at known risk of endocarditis.
No dental interventions, and participants not at high risk of endocarditis.
Same group of patients as Tzukert 1986.
High risk participants undergoing dental procedures all received a regimen that included antibiotic prophylaxis, no control group.
Van der Meer 1992a
Epidemiological study of endocarditis in the Netherlands, no controls.
Basic science research paper.
Cohort study of 17 patients undergoing dental extractions but all received antibiotics.