Antibiotic treatment for Clostridium difficile-associated diarrhea in adults

  • Review
  • Intervention

Authors


Abstract

Background

Clostridium difficile is recognized as a frequent cause of antibiotic-associated diarrhea and colitis.

Objectives

The aim of this review is to investigate the efficacy of antibiotic therapy for C. difficile-associated diarrhea (CDAD).

Search methods

MEDLINE (1966 to March 24, 2010), EMBASE (1980 to March 24, 2010), Cochrane Central Register of Controlled Trials and the Cochrane IBD/FBD Review Group Specialized Trials Register were searched using the following search terms: "pseudomembranous colitis and randomized trial"; "Clostridium difficile and randomized trial"; "antibiotic associated diarrhea and randomized trial".

Selection criteria

Only randomized, controlled trials assessing antibiotic treatment for CDAD were included in the review. The following outcomes were sought: initial resolution of diarrhea; initial conversion of stool to cytotoxin and/or culture negative; recurrence of diarrhea; recurrence of fecal evidence of CDAD; patient response to cessation of prior antibiotic therapy; emergent surgery; and death.

Data collection and analysis

Three authors independently assessed abstracts and full text articles for inclusion. The risk of bias was independently rated by two authors. For dichotomous outcomes, relative risks (RR) and 95% confidence intervals (CI) were derived from each study and summary statistics obtained when appropriate, using a fixed effects model, except where significant heterogeneity was detected, at which time a random effects model was used.

Main results

Fifteen studies (total of 1152 participants) with CDAD were included. Nine different antibiotics were investigated: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin, bacitracin and fidaxomicin (OPT-80). Most of the studies were active comparator studies comparing vancomycin with other antibiotics. The risk of bias was rated as high for 12 of 15 included studies. Patients with severe CDAD were often excluded from the included studies. In the only placebo-controlled trial vancomycin was found to be superior to placebo for treatment of CDAD for initial symptomatic cure. Initial symptomatic cure was achieved in 41% of vancomycin patients compared to 4% of placebo patients (1 study; 44 patients; RR 9.00; 95% CI 1.24 to 65.16). Vancomycin was significantly superior to placebo for initial bacteriologic response. Initial bacteriologic response was achieved in 45% of vancomycin patients compared to 4% of placebo patients (1 study; 44 patients; RR 10.00; 95% CI 1.40 to 71.62). The results of this study should be interpreted with caution due to the small number of patients and high risk of bias. No statistically significant differences in efficacy were found between vancomycin and metronidazole, vancomycin and fusidic acid, vancomycin and nitazoxanide, or vancomycin and rifaximin. No statistically significant differences in efficacy were found between metronidazole and nitazoxanide or metronidazole and fusidic acid. Vancomycin was significantly superior to bacitracin for initial bacteriologic response. Initial bacteriologic response was achieved in 48% of vancomycin patients compared to 25% of bacitracin patients (2 studies; 104 patients; RR 0.52; 95% CI 0.31 to 0.86). Teicoplanin, an antibiotic of limited availability and great cost, was significantly superior to vancomycin for initial bacteriologic response and cure. Initial bacteriologic response was achieved in 62% of vancomycin patients compared to 87% of teicoplanin patients (2 studies; 110 patients; RR 1.43; 95% CI 1.14 to 1.81). Bacteriologic cure was achieved in 45% of vancomycin patients compared to 82% of teicoplanin patients (2 studies; 110 patients; RR 1.82; 95% CI 1.19 to 2.78). These results should be interpreted with caution due to the small number of patients and the high risk of bias in the two studies in the pooled analysis. Teicoplanin was significantly superior to metronidazole for initial bacteriologic response. Initial bacteriologic response was achieved in 71% of metronidazole patients compared to 93% of teicoplanin patients (1 study; 59 patients; RR 0.76; 95% CI 0.60 to 0.98). This result should be interpreted with caution due to the small number of patients and high risk of bias in the study. Only one study investigated synergistic antibiotic combination, metronidazole and rifampin, and no advantage was demonstrated for the drug combination. This result should be interpreted with caution due to the small number of patients and high risk of bias in the study. Adverse events including surgery and death occurred infrequently in the included studies. There was a total of 18 deaths among 1152 patients in this systematic review. Among the studies that commented on the cause of mortality the deaths were attributed to underlying disease rather than CDAD or antibiotic treatment. One study reported a partial colectomy after failed CDAD treatment.

Authors' conclusions

Current evidence leads to uncertainty whether mild CDAD needs to be treated. The studies provide little evidence for antibiotic treatment of severe CDAD as many studies excluded these patients. Considering the two goals of therapy: improvement of the patient's clinical condition and prevention of spread of C. difficile infection to other patients, one should choose the antibiotic that brings both symptomatic cure and bacteriologic cure. A recommendation to achieve these goals cannot be made because of the small numbers of patients in the included studies and the high risk of bias in these studies, especially related to dropouts. Most of the active comparator studies found no statistically significant difference in efficacy between vancomycin and other antibiotics including metronidazole, fusidic acid, nitazoxanide or rifaximin. Teicoplanin may be an attractive choice but for its limited availability (Teicoplanin is not available in the USA) and great cost relative to the other options. More research of antibiotic treatment and other treatment modalities of CDAD is required.

摘要

與難治梭狀芽胞桿菌(Clostridium difficile)相關之成人腹瀉的抗生素治療

背景

難治梭狀芽胞桿菌(Clostridium difficile)為與抗生素相關之腹瀉與大腸炎的常見肇因。

目的

本文獻回顧旨在探討抗生素療法對C. difficile相關性腹瀉(C. difficile-associated diarrhea, CDAD)的療效。

搜尋策略

我們使用下列搜尋關鍵用語對MEDLINE (1966年至2010年3月24日)、EMBASE (1980年至2010年3月24日)、Cochrane Central Register of Controlled Trials與Cochrane IBD/FBD Review Group Specialized Trials Register進行搜尋:「偽膜性大腸炎與隨機分組試驗」(“pseudomembranous colitis and randomized trial”)、「Clostridium difficile與隨機分組試驗」(“Clostridium difficile and randomized trial”)與抗生素相關性腹瀉與隨機分組試驗(“antibiotic associated diarrhea and randomized trial”)。

選擇標準

本文獻回顧僅納入評估C. difficile相關性腹瀉(CDAD)之抗生素療效的隨機分組對照試驗。對以下評估指標事件進行搜尋:腹瀉的初步紓解;糞便開始轉為細胞毒素及/或培養陰性;腹瀉復發;重新出現CDAD的糞便證據;病患對停用先前的抗生素治療有反應;緊急手術;以及死亡。

資料收集與分析

三位作者分別獨立針對摘要及全文文獻評估是否符合納入條件,偏差風險則由兩位作者分別獨立進行評量。對於二分法量值評估指標,使用固定效應模型(fixed effects model),從每項試驗計算相對風險(RR)與95%信賴區間,並取得總結統計值(若可行),除非偵測到顯著的異質性(此時則使用隨機效應模型[random effects model])。

主要結果

總共納入15項針對CDAD進行的試驗(總計有1152名受試者)。所研究的抗生素有9種:vancomycin、metronidazole、fusidic acid、nitazoxanide、teicoplanin、rifampin、rifaximin、bacitracin與fidaxomicin (OPT-80)。大部分的試驗皆為有活性比較劑的試驗,針對vancomycin與其他抗生素進行比較。所納入的15項試驗中有12項被評為具有高偏差風險。所納入的試驗多數皆排除重度CDAD患者。在唯一以安慰劑對照的試驗中,就初步症狀痊癒(initial symptomatic cure)而言,vancomycin對CDAD的療效優於安慰劑。Vancomycin組受試者有41%獲致初步症狀痊癒,安慰劑組則僅4%(1項試驗;44名受試者;RR 9.00;95%信賴區間:1.24至65.16)。就初步細菌學反應(initial bacteriologic response)而言,vancomycin的功效顯著優於安慰劑。Vancomycin組有45%受試者獲致初步細菌學反應,安慰劑組則僅4%(1項試驗;44名受試者;RR 10.00;95%信賴區間:1.40至71.62)。由於受試者人數少且具有高偏差風險,因此這項試驗結果的解讀必須謹慎。Vancomycin與metronidazole、vancomycin與fusidic acid、vancomycin與nitazoxanide、或vancomycin與rifaximin之間的療效無具統計顯著性的差異存在。Metronidazole與nitazoxanide或metronidazole與fusidic acid之間的療效無具統計顯著性的差異存在。在初步細菌學反應方面,vancomycin的功效顯著優於bacitracin。Vancomycin組有48%受試者獲致初步細菌學反應,bacitracin組則為25%(2項試驗;104名受試者;RR 0.52;95%信賴區間:0.31 至0.86)。Teicoplanin是較難取得且費用極高的抗生素,其就初步細菌學反應與痊癒而言的療效皆顯著優於vancomycin。Vancomycin組有62%受試者獲致初步細菌學反應,teicoplanin組則為87%(2項試驗;110名受試者;RR 1.43;95%信賴區間:1.14至1.81)。Vancomycin組有45%受試者獲致細菌學痊癒,teicoplanin組則為82%(2項試驗;110名受試者;RR 1.82;95%信賴區間:1.19至2.78)。因為這項綜合分析中的兩項試驗受試者人數少且具有高偏差風險,因此這些結果的解讀必須謹慎。Teicoplanin在初步細菌學反應方面的功效顯著優於metronidazole。Metronidazole組有71%受試者獲致初步細菌學反應,teicoplanin組則為93%(1項試驗;59名受試者;RR 0.76;95%信賴區間:0.60至0.98)。由於此項試驗受試者人數少且具有高偏差風險,因此其結果的解讀必須謹慎。僅有一項試驗針對具有協同作用的抗生素合併療法(metronidazole+rifampin)進行研究,且發現此合併療法並不具優勢。由於此項試驗受試者人數少且具有高偏差風險,因此其結果的解讀必須謹慎。所納入的試驗中所發生的不良事件包括手術與死亡,但皆極少發生。在本系統性文獻回顧中的1152名受試者中總共有18個死亡病例。在有針對死亡原因進行說明的試驗中,死亡事件皆可歸因於病患原有的疾病,而非CDAD或抗生素治療所致。有一項試驗報告一例在CDAD治療無效後進行大腸部分切除術(partial colectomy)的病例。

作者結論

無法依據目前的證據確定輕度CDAD是否需要加以治療。在以抗生素治療重度CDAD病患上,這些試驗所提供的證據極少,因為許多試驗皆不納入這些病患。為了達成兩項治療目標(改善病患的臨床狀況與防止C. difficile感染症傳播給其他病患),我們必須選擇能夠提供症狀痊癒與細菌學痊癒的抗生素。由於這些試驗所納入的受試者人數少且具有高偏差風險(尤其與退出試驗有關者),因此無法針對如何達成這些目標提出任何建議。使用活性比較劑的試驗大多發現vancomycin與其它抗生素(metronidazole、fusidic acid、nitazoxanide或rifaximin)之間無具統計顯著性的差異存在。若非取得不易(teicoplanin尚未在美國上市),且價格高於其他療法,teicoplanin應為極具吸引力的選擇。我們需要更多針對CDAD之抗生素療法與其它療法的研究。

Résumé scientifique

Antibiothérapie pour le traitement de la diarrhée associée à Clostridium difficile chez l'adulte

Contexte

Il est admis que Clostridium difficile est une cause fréquente de diarrhée et de colite associées aux antibiotiques.

Objectifs

L'objectif de cette revue est d'examiner l'efficacité de l'antibiothérapie dans la diarrhée associée à C. difficile (DACD).

Stratégie de recherche documentaire

MEDLINE (1966 au 24 mars 2010), EMBASE (1980 au 24 mars 2010), le registre Cochrane central des essais contrôlés et le registre spécialisé des essais du groupe de revue Cochrane sur les MII/TFI ont été consultés en utilisant les termes de recherche suivants : Colite pseudomembraneuse et essai randomisé ; Clostridium difficile et essai randomisé ; Diarrhée associée aux antibiotiques et essai randomisé.

Critères de sélection

Seuls les essais contrôlés randomisés évaluant une antibiothérapie dans la DACD ont été inclus dans la revue. Les critères de jugement suivants ont été recherchés : résolution initiale de la diarrhée ; conversion initiale des selles à la cytotoxine et/ou culture négative ; récurrence de la diarrhée ; récurrence des preuves de DACD dans les selles ; réponse du patient à l'arrêt de l'antibiothérapie initiale ; chirurgie urgente ; et décès.

Recueil et analyse des données

Trois auteurs ont évalué les résumés et le texte intégral des articles éligibles de manière indépendante. Le risque de biais a été évalué par deux auteurs de manière indépendante. Pour les résultats dichotomiques, les risques relatifs (RR) et les intervalles de confiance (IC) à 95 % ont été dérivés de chaque étude, et les statistiques de synthèse ont été obtenues, le cas échéant, à l'aide d'un modèle à effets fixes. En cas d'hétérogénéité significative, un modèle à effets aléatoires a été utilisé.

Résultats principaux

Quinze études portant sur la DACD ont été incluses (1 152 participants au total). Neuf antibiotiques étaient évalués : vancomycine, métronidazole, acide fusidique, nitazoxanide, teicoplanine, rifampicine, rifaximine, bacitracine et fidaxomicine (OPT-80). La plupart des études comparaient de la vancomycine à d'autres antibiotiques (comparateurs actifs). Le risque de biais était élevé dans 12 des 15 études incluses. Les patients atteints de DACD sévère étaient souvent exclus des études. Dans le seul essai contrôlé par placebo, la vancomycine s'avérait supérieure au placebo en termes de guérison symptomatique initiale dans le traitement de la DACD. Une guérison symptomatique initiale était obtenue chez 41 % des patients sous vancomycine, contre 4 % des patients sous placebo (1 étude ; 44 patients ; RR = 9,00 ; IC à 95%, entre 1,24 et 65,16). La vancomycine était significativement supérieure au placebo en termes de réponse bactériologique initiale. Une réponse bactériologique initiale était obtenue chez 45 % des patients sous vancomycine, contre 4 % des patients sous placebo (1 étude ; 44 patients ; RR = 10,00 ; IC à 95 %, entre 1,40 et 71,62). Les résultats de cette étude devraient être interprétés avec précaution en raison de son effectif réduit et de son risque de biais élevé. Aucune différence statistiquement significative n'était observée en termes d'efficacité entre la vancomycine et le métronidazole, la vancomycine et l'acide fusidique, la vancomycine et la nitazoxanide ou la vancomycine et la rifaximine. Aucune différence statistiquement significative n'était observée entre le métronidazole et la nitazoxanide ou le métronidazole et l'acide fusidique en termes d'efficacité. La vancomycine était significativement supérieure à la bacitracine en termes de réponse bactériologique initiale. Une réponse bactériologique initiale était obtenue chez 48 % des patients sous vancomycine, contre 25 % des patients sous bacitracine (2 études ; 104 patients ; RR = 0,52 ; IC à 95 %, entre 0,31 et 0,86). La teicoplanine, un antibiotique associé à une disponibilité limitée et un coût très élevé, était significativement supérieure à la vancomycine en termes de réponse bactériologique initiale et de guérison bactériologique. Une réponse bactériologique initiale était obtenue chez 62 % des patients sous vancomycine, contre 87 % des patients sous teicoplanine (2 études ; 110 patients ; RR = 1,43 ; IC à 95 %, entre 1,14 et 1,81). Une guérison bactériologique était obtenue chez 45 % des patients sous vancomycine, contre 82 % des patients sous teicoplanine (2 études ; 110 patients ; RR = 1,82 ; IC à 95 %, entre 1,19 et 2,78). Ces résultats devraient être interprétés avec précaution en raison de l'effectif réduit et du risque de biais élevé des deux études utilisées dans l'analyse combinée. La teicoplanine était significativement supérieure au métronidazole en termes de réponse bactériologique initiale. Une réponse bactériologique initiale était obtenue chez 71 % des patients sous métronidazole, contre 93 % des patients sous teicoplanine (1 étude ; 59 patients ; RR = 0,76 ; IC à 95 %, entre 0,60 et 0,98). Ces résultats devraient être interprétés avec précaution en raison de l'effectif réduit et du risque de biais élevé de cette étude. Une seule étude examinait une combinaison synergique d'antibiotiques, du métronidazole et de la rifampicine, et ne démontrait aucun avantage associé au traitement combiné. Ces résultats devraient être interprétés avec précaution en raison de l'effectif réduit et du risque de biais élevé de cette étude. Des effets secondaires, y compris une chirurgie et un décès, se produisaient peu fréquemment dans les études incluses. Au total, 18 décès pour 1 152 patients ont été identifiés dans cette revue systématique. Dans les études qui documentaient la cause de la mortalité, les décès étaient imputés à la maladie sous-jacente plutôt qu'à la DACD ou à l'antibiothérapie. Une étude documentait une colectomie partielle après l'échec du traitement de la DACD.

Conclusions des auteurs

Les preuves actuelles permettent de se demander si la DACD légère doit réellement être traitée. Les études apportent peu de preuves de l'efficacité de l'antibiothérapie dans la DACD sévère car beaucoup excluaient ce groupe de patients. Compte tenu des deux objectifs du traitement (amélioration de l'état clinique du patient et prévention de la propagation de l'infection à C. difficile à d'autres patients), il est conseillé de choisir l'antibiotique permettant une guérison à la fois symptomatique et bactériologique. Nous ne sommes pas en mesure de présenter de recommandations dans ce domaine en raison de l'effectif réduit des études incluses et de leur risque de biais élevé, notamment en ce qui concerne les sorties d’étude. La plupart des études utilisant un comparateur actif ne rapportaient aucune différence statistiquement significative en termes d'efficacité entre la vancomycine et les autres antibiotiques, y compris le métronidazole, l'acide fusidique, la nitazoxanide ou la rifaximine. La teicoplanine pourrait être un choix intéressant, mais sa disponibilité est limitée (la teicoplanine n'est pas disponible aux États-Unis) et son coût est très élevé par rapport aux autres options. D'autres recherches sont nécessaires concernant l'antibiothérapie et les autres modalités de traitement de la DACD.

Resumo

Antibioticoterapia para adultos com diarreia causada por Clostridium difficile (DCD)

Introdução

Clostridium difficile é uma causa frequente de diarreia e colite associada ao uso de antibiótico.

Objetivos

O objetivo desta revisão foi avaliar a eficácia da antibioticoterapia para a diarreia porClostridium difficile(CD).

Métodos de busca

A busca foi realizada nas seguintes bases de dados: MEDLINE (1966 a 24 de março de 2010), EMBASE (1980 a 24 de março de 2010), Cochrane Central Register of Controlled Trials e Cochrane IBD/FBD Review Group Specialized Trials Register. A estratégia utilizou os seguintes termos: "pseudomembranous colitis and randomized trial"; "Clostridium difficile and randomized trial"; "antibiotic associated diarrhea and randomized trial".

Critério de seleção

Foram incluídos na revisão somente ensaios clínicos randomizados que avaliaram o tratamento de diarreia por CD com antibióticos. Os desfechos foram: resolução inicial da diarreia, negativação inicial de citotoxina ou cultura nas fezes, recorrência da diarreia; evidência de recorrência de diarreia por CD; resposta do paciente à suspensão da antibioticoterapia inicial; cirurgia e óbito.

Coleta dos dados e análises

Três autores avaliaram de forma independente os resumos e os textos completos dos estudos para inclusão. Dois autores avaliaram de forma independente o risco de viés dos estudos. Para os desfechos dicotômicos, foram calculados os riscos relativos (RR) e intervalos de confiança (CI) de 95% Nas metanálises com baixa heterogeneidade, foi usado o modelo de efeito fixo. Nas metanálises com alta heterogeneidade, foi utilizado o modelo de efeito randômico.

Principais resultados

A revisão incluiu 15 estudos (total de 1.152 participantes) que testaram 9 antibióticos diferentes para o tratamento da diarreia por CD: vancomicina, metronidazol, ácido fusídico, nitazoxanida, teicoplanina, rifampicina, rifaximina, bacitracina e fidaxomicina (OPT-80). A maioria dos estudos comparou vancomicina com outros antibióticos. O risco de viés foi avaliado como alto em 12 dos 15 estudos incluídos. Pacientes com diarreia grave por CD eram frequentemente excluídos dos estudos incluídos nesta revisão. O único estudo placebo-controlado mostrou que a vancomicina foi superior ao placebo para a cura inicial dos sintomas. A cura inicial dos sintomas foi obtida em 41% dos pacientes tratados com vancomicina comparada a 4% no grupo placebo (1 estudo, 44 pacientes; RR 9,00, 95% CI 1,24 a 65,16). A vancomicina foi significativamente superior ao placebo para a resposta bacteriológica inicial. A resposta bacteriológica foi alcançada em 45% dos pacientes do grupo vancomicina comparada a 4% do grupo placebo (1 estudo, 44 pacientes; RR 10,00, 95% CI 1,40 a 71,62). Os resultados desse estudo devem ser interpretados com cautela devido ao número pequeno de pacientes e ao alto risco de viés. Não houve diferença estatisticamente significante na eficácia entre vancomicina versus metronidazol, vancomicina versus ácido fusídico, vancomicina versus nitazoxanida ou vancomicina versus rifaximina. Não houve diferença estatisticamente significante na eficácia do metronidazol versus nitazoxanida ou metronidazol versus ácido fusídico. A vancomicina foi significativamente superior à bacitracina para a resposta bacteriológica inicial: 48% nos pacientes do grupo vancomicina versus 25% nos que usaram a bacitracina (2 estudos, 104 pacientes; RR 0,52; 95% CI 0,31 a -0,86). A teicoplanina, que é um antibiótico de pouco disponível e alto custo, foi significativamente superior à vancomicina para a resposta bacteriológica e cura inicial. Houve resposta bacteriológica inicial de 87% no grupo tratado com teicoplanina versus 62% no grupo tratado com vancomicina (2 estudos, 110 pacientes, RR 1,43; 95% CI 1,14 - 1,81). A cura bacteriológica foi alcançada em 45% dos pacientes tratados com vancomicina comparados aos 82% no grupo da teicoplanina (2 estudos; 110 pacientes; RR 1,82; 95% CI 1,19 - 278). Esses resultados devem ser interpretados com cautela devido ao número pequeno de pacientes e ao alto risco de viés nos dois estudos incluídos na metanálise. A teicoplanina foi significativamente superior ao metronidazol para uma resposta bacteriológica inicial. Essa resposta foi encontrada em 93% dos pacientes tratados com a teicoplanina comparada com os 71% do metronidazol (1 estudo; 59 pacientes; RR 0,76; 95% CI 0,60 a 0,98). Esse resultado deve ser interpretado com cautela devido ao número pequeno de pacientes e ao alto risco de viés do estudo. Apenas um estudo avaliou a combinação sinérgica entre o metronidazol e a rifampicina, e não foi demonstrada vantagem para essa combinação de antibióticos. Esse resultado deve ser interpretado com cautela devido ao número pequeno de pacientes e alto risco de viés do estudo. Os eventos adversos, incluindo cirurgia e óbito, foram pouco frequentes nos estudos incluídos nesta revisão. Ocorreram 18 óbitos entre os 1.152 pacientes incluídos nessa revisão sistemática. Nos estudos que descreveram as causas dos óbitos, elas foram atribuídas às doenças de base e não à diarreia por CD ou ao tratamento com antibióticos. Um estudo relatou a realização de uma colectomia parcial após falha de tratamento da DCD.

Conclusão dos autores

As evidências atuais indicam que há incerteza sobre a necessidade de tratar pacientes com a forma leve de diarreia por CD. Os estudos fornecem pouca evidência sobre o tratamento da diarreia por CD grave com antibióticos, uma vez que muitos dos estudos excluíram esses pacientes. Ao considerar os dois objetivos da terapia, melhora da condição clínica do paciente e prevenção da disseminação da infecção por C. difficile a outros pacientes, deve-se escolher o antibiótico que oferece tanto a cura sintomática quanto a cura bacteriológica. Não é possível fazer uma recomendação para alcançar esses objetivos, devido ao pequeno número de pacientes incluídos nos estudos e ao alto risco de viés desses estudos, especialmente relacionado à taxa de abandono dos participantes. A maioria dos estudos que comparou a eficácia de diferentes antibióticos entre si não encontrou diferença estatisticamente significativa entre a vancomicina e os outros antibióticos, incluindo metronidazol, ácido fusídico, nitazoxanida ou rifaximina. A teicoplanina pode ser uma escolha interessante, porém é uma medicação com disponibilidade limitada e de alto custo. Novos estudos com antibióticos e outras formas de tratamento para diarreia por CD são necessários.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Katia Senna). Contato: tradutores@centrocochranedobrasil.org.br

Plain language summary

Antibiotic therapy for Clostridium difficile-associated diarrhea in adults

Diarrhea may be a side effect of many commonly used antibiotics, and in some cases may be due to overgrowth of a bacterium called Clostridium difficile (C. difficile) in the colon after other bacteria have been killed. The seriousness of C. difficile-associated diarrhea (CDAD) can range from being a nuisance, to a life threatening or even fatal disease. The treatment of CDAD is usually cessation of the initiating antibiotic and immediate administration of a different antibiotic. However each of these steps, cessation of the original antibiotic, immediate retreatment, and the choice of a new antibiotic are poorly supported by currently available evidence. Fifteen studies (total 1152 participants) of antibiotic treatment of CDAD were included in this review. Nine different antibiotics were investigated: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin, bacitracin and fidaxomicin (OPT-80). Most of the studies were compared vancomycin with other antibiotics. Vancomycin was found to be superior to placebo (fake medicine) for improvement of the symptoms of CDAD including resolution of diarrhea. Most of the studies found no statistically significant difference in effectiveness between vancomycin and other antibiotics including metronidazole, fusidic acid, nitazoxanide or rifaximin. Teicoplanin was found to be superior to vancomycin for curing the C. difficile infection. Teicoplanin may be an attractive choice for the treatment of CDAD. However, it is expensive compared to the other antibiotics and is of limited availability. Side effects including surgery and death occurred infrequently in the included studies. There was a total of 18 deaths among 1152 patients in this systematic review. These deaths were attributed to underlying disease rather than CDAD or antibiotic treatment. One study reported a partial colectomy (removal of the diseased part of the colon) after failed CDAD treatment. It is questionable whether mild CDAD needs to be treated. The included studies provide little evidence for antibiotic treatment of severe CDAD as many studies attempted to exclude these patients. Considering the goals of CDAD therapy: improvement of the patient's clinical condition and prevention of spread of C. difficile infection to other patients, one should choose the antibiotic that brings both symptomatic cure and bacteriologic cure. A recommendation to achieve these goals cannot be made because of the small numbers of patients in the included studies and the poor methodological quality of these studies. Over time there have been emerging therapies for the treatment of clostridium difficile such as resins, new biological compounds and probiotics as alternatives to antibiotics. These interventions along with antibiotic therapy for Clostridium difficile-associated diarrhea need further investigation. 

淺顯易懂的口語結論

與難治梭狀芽胞桿菌(Clostridium difficile)相關之成人腹瀉的抗生素治療

腹瀉為許多常用抗生素的副作用,在某些病例,可能為其他腸道細菌被消滅後,腸道中一種稱為難治梭狀芽胞桿菌 (C. difficile)的細菌過度生長所導致。與C. difficile-相關之腹瀉(C. difficile-associated diarrhea, CDAD)的嚴重程度從只是惱人至可能致命性、甚至致命不等。CDAD的治療方法通常為停用原來的抗生素,並立即使用不同的抗生素。 不過,對於停用原來的抗生素、並立即重新治療與選擇新的抗生素等步驟的採行,現有證據的證據力皆不足。本文獻回顧總共納入15項以抗生素治療CDAD的試驗(共1152名受試者),總共研究9種不同的抗生素:vancomycin、metronidazole、fusidic acid、nitazoxanide、teicoplanin、rifampin、rifaximin、bacitracin與fidaxomicin (OPT-80)。 大部分的試驗皆是針對vancomycin與其它抗生素進行比較。研究發現,vancomycin對於CDAD症狀的改善(包括腹瀉的紓解)功效優於安慰劑(虛擬藥物)。大部分的試驗皆未發現vancomycin的療效與其它抗生素(包括metronidazole、fusidic acid、nitazoxanide或rifaximin)存在具統計顯著性的差異。研究發現,teicoplanin對於C. difficile 感染症的治癒功效優於vancomycin。teicoplanin對於C. difficile感染症的治癒功效優於vancomycin。 Teicoplanin可能為極具吸引力的CDAD治療選擇,但其價格高於其他抗生素,而且較不易取得。所納入的試驗中報告的副作用包括手術與死亡,但發生率皆低。在本文獻回顧的1152名受試者中,總共有18個死亡病例。這些死亡事件皆可歸因於病患原有的疾病,而非CDAD或抗生素治療所致。有一項試驗報告一例在CDAD治療無效之後進行大腸部分切除術(將罹病的大腸部分切除)的病例。輕度CDAD是否需要治療仍有爭議。在以抗生素治療重度CDAD患者上,所納入的試驗中提供的證據極少,因為有許多試驗皆有意排除這些病患。為了達成兩項治療目標(改善病患的臨床狀況與防止C. difficile感染症傳播給其他病患),我們必須選擇能夠提供症狀痊癒與細菌學痊癒的抗生素。由於所納入的試驗受試者人數少且所納入之試驗的方法品質不佳,因此無法針對如何達成這些目標提出任何建議。這些年來已經有一些clostridium difficile的新療法(例如樹脂[resins]、新的生物製劑與益生菌[probiotics])出現,可作為抗生素的替代療法。對於這些治療與Clostridium difficile關之腹瀉的介入措施與抗生素療法,我們仍須詳加研究。

譯註

翻譯: East Asian Cochrane Alliance
翻譯補助: 台灣衛生福利部/台北醫學大學實證醫學研究中心

Résumé simplifié

Administration d'antibiotiques pour le traitement de la diarrhée associée à Clostridium difficile chez l'adulte

La diarrhée peut être un effet secondaire de nombreux antibiotiques couramment utilisés, et est parfois due à la prolifération excessive dans le côlon d'une bactérie connue sous le nom de Clostridium difficile (C. difficile) après l'élimination d'autres bactéries. La diarrhée associée à C. difficile (DACD) peut se caractériser par une simple gêne, mais peut également engager le pronostic vital ou entraîner le décès du patient. Le traitement de la DACD consiste généralement à arrêter l'antibiotique initialement utilisé et à administrer immédiatement un autre antibiotique. Néanmoins, ces différentes étapes (arrêt de l'antibiotique initial, nouveau traitement immédiat et choix du nouvel antibiotique) ne sont pas suffisamment étayées par les preuves actuellement disponibles. Quinze études (1 152 participants au total) examinant une antibiothérapie dans la DACD ont été incluses dans cette revue. Neuf antibiotiques étaient évalués : vancomycine, métronidazole, acide fusidique, nitazoxanide, teicoplanine, rifampicine, rifaximine, bacitracine et fidaxomicine (OPT-80). La plupart des études comparaient de la vancomycine à d'autres antibiotiques. La vancomycine s'avérait supérieure au placebo (médicament inactif) pour améliorer les symptômes de DACD, y compris la résolution de la diarrhée. La plupart des études ne rapportaient aucune différence statistiquement significative en termes d'efficacité entre la vancomycine et les autres antibiotiques, y compris le métronidazole, l'acide fusidique, la nitazoxanide ou la rifaximine. La teicoplanine s'avérait supérieure à la vancomycine pour guérir l'infection à C. difficile. La teicoplanine pourrait constituer une option de traitement intéressante dans la DACD. Néanmoins, ce médicament est cher par rapport à d'autres antibiotiques, et sa disponibilité est limitée. Des effets secondaires, y compris une chirurgie et un décès, se produisaient peu fréquemment dans les études incluses. Au total, 18 décès pour 1 152 patients ont été identifiés dans cette revue systématique. Ces décès étaient attribués à la maladie sous-jacente plutôt qu'à la DACD ou à l'antibiothérapie. Une étude documentait une colectomie partielle (ablation de la partie affectée du côlon) après l'échec du traitement de la DACD. On peut légitimement se demander si la DACD légère doit réellement être traitée. Les études incluses apportent peu de preuves de l'efficacité de l'antibiothérapie dans la DACD sévère car beaucoup d'études tentaient d'exclure ces patients. Compte tenu des objectifs du traitement de la DACD (amélioration de l'état clinique du patient et prévention de la propagation de l'infection à C. difficile à d'autres patients), il est conseillé de choisir l'antibiotique permettant une guérison à la fois symptomatique et bactériologique. Néanmoins, nous ne sommes pas en mesure de présenter de recommandations dans ce domaine en raison de l'effectif réduit des études incluses et de leur faible qualité méthodologique. Au fil du temps, des traitements alternatifs aux antibiotiques ont été développés pour combattre Clostridium difficile, notamment des résines, de nouveaux composés biologiques et des probiotiques. Ces interventions, de même que l'antibiothérapie, exigent des recherches plus approfondies dans le traitement de la diarrhée associée à Clostridium difficile.

Notes de traduction

Traduit par: French Cochrane Centre 1st June, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Resumo para leigos

Antibiótico para tratar diarreia porClostridium difficile em adultos

A diarreia pode ser um efeito secundário muito comum ao uso de muitos antibióticos. Em alguns casos, essa diarreia pode ocorrer devido ao crescimento excessivo da bactéria “Clostridium difficile”(C. difficile) no cólon depois de outras bactérias terem sido eliminadas. A gravidade da diarreia porC. difficile (CD) pode variar de um simples incômodo até uma ameaça à vida ou mesmo levar a morte. O tratamento da diarreia por CD geralmente consiste em parar de usar o antibiótico que vinha sendo usado e substituí-lo por outro antibiótico. Entretanto, existem poucas evidências atualmente disponíveis para embasar cada uma dessas etapas (a interrupção do antibiótico original, o imediato reinício do tratamento com outro antibiótico e a escolha do novo antibiótico). Esta revisão incluiu 15 estudos (com 1.152 participantes ao todo)que testaram 9 antibióticos diferentes para adultos com diarreia por CD: vancomicina, metronidazol, ácido fusídico, nitazoxanida, teicoplanina, rifampicina, rifaximina, bacitracina e fidaxomicin (OPT-80). A maior parte dos estudos comparou a vancomicina com outros antibióticos. A vancomicina mostrou ser superior ao placebo (falso medicamento) para a melhora dos sintomas da doença, incluindo a resolução da diarreia. A maioria dos estudos não encontrou diferença estatisticamente significativa na efetividade da vancomicina comparada a outros antibióticos, incluindo metronidazol, ácido fusidico, nitazoxanida ou rifaximina. A teicoplanina mostrou ser superior à vancomicina para a curada infecção porC. difficile.Esse antibiótico pode ser uma escolha interessante para o tratamento da diarreia por CD.Entretanto, esse medicamento custa muito mais do que os outros antibióticos e é pouco disponível.Houve poucos casos de eventos adversos, como cirurgia e óbito nos estudos incluídos.Ocorreram 18 óbitos entre os 1.152 pacientes incluídos nesta revisão.Essas mortes foram atribuídas à doenças de base e não à diarreia por CD ou ao tratamento com o antibiótico.Um dos estudos relatou que um paciente precisou fazer uma colectomia parcial (retirada da parte doente do intestino) devido à falha do tratamento.É questionável se seria necessário tratar os casos leves de diarreia por CD.Como muitos estudos excluíram os pacientes que tinham diarreia grave por CD, existem poucas evidências sobre o tratamento com antibiótico para esses casos.A finalidade do tratamento da diarreia por CD é melhorar a condição clínica do paciente e prevenir a disseminação da infecção por C. difficile para outros pacientes. Considerando esses dois objetivos, o médico deve optar pelo antibiótico que traga tanto a cura sintomática como a cura bacteriológica.Não é possível fazer uma recomendação para alcançar esses dois objetivos devido ao pequeno número de pacientes incluídos nos estudos existentes e a sua baixa qualidade metodológica.Ao longo dos últimos anos, surgiram outros tipos de tratamentos (além dos antibióticos) para os pacientes com infecção por CD, como resinas, novos compostos biológicos e também probióticos.São necessárias mais pesquisas com os antibióticos e com essas novas intervenções para o tratamento dos pacientes com diarreia porClostridium difficile.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Katia Senna). Contato: tradutores@centrocochranedobrasil.org.br

Summary of findings(Explanation)

Summary of findings for the main comparison. Metronidazole versus Vancomycin for Clostridium difficile-associated diarrhea in adults
  1. 1 Sparse data
    2 The Wenisch 1996 study was not blinded
    3 Both the Teasley 1983 and Wenisch 1996 studies did not exclude other pathogens in stool as causes of diarrhea

Metronidazole versus Vancomycin for Clostridium difficile-associated diarrhea in adults
Patient or population: patients with Clostridium difficile-associated diarrhea in adults
Settings:
Intervention: Metronidazole versus Vancomycin
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlMetronidazole versus Vancomycin
Symptomatic Cure minus recurrences including Zar with all exclusions treated as failuresStudy populationRR 0.91
(0.81 to 1.03)
335
(3 studies)
⊕⊝⊝⊝
very low 1,2,3
 
782 per 1000712 per 1000
(626 to 805)
Medium risk population
781 per 1000711 per 1000
(625 to 804)
*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% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; 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.

Summary of findings 2 Teicoplanin versus Vancomycin for Clostridium difficile-associated diarrhea in adults

Summary of findings 2. Teicoplanin versus Vancomycin for Clostridium difficile-associated diarrhea in adults
  1. 1 Sparse data

    2 The Wenisch 1996 and de Lalla 1992 studies were not blinded

    3 The Wenisch 1996 study did not exclude other pathogens in stool as causes of diarrhea

Teicoplanin versus Vancomycin for Clostridium difficile-associated diarrhea in adults
Patient or population: patients with Clostridium difficile-associated diarrhea in adults
Settings:
Intervention: Teicoplanin versus Vancomycin
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlTeicoplanin versus Vancomycin
Symptomatic CureStudy populationRR 1.21
(1.00 to 1.46)
110
(2 studies)
⊕⊝⊝⊝
very low 1
 
714 per 1000843 per 1000
(693 to 1000)
Medium risk population
708 per 1000835 per 1000
(687 to 1000)
*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% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; 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.

Summary of findings 3 Metronidazole versus Teicoplanin for Clostridium difficile-associated diarrhea in adults

Summary of findings 3. Metronidazole versus Teicoplanin for Clostridium difficile-associated diarrhea in adults
  1. 1 Sparse data

    2 The Wenisch 1996 study was not blinded

    3 The Wenisch 1996 study did not exclude other pathogens in stool as causes of diarrhea

Metronidazole versus Teicoplanin for Clostridium difficile-associated diarrhea in adults
Patient or population: patients with Clostridium difficile-associated diarrhea in adults
Settings:
Intervention: Metronidazole versus Teicoplanin
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlMetronidazole versus Teicoplanin
Symptomatic CureStudy populationRR 0.87
(0.69 to 1.09)
59
(1 study)
⊕⊕⊝⊝
low 1
 
833 per 1000750 per 1000
(583 to 966)
Medium risk population
833 per 1000750 per 1000
(583 to 966)
*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% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; 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.

Background

The administration of antibiotics is known to be associated with the development of diarrhea in patients. Erythromycin and the clavulanate in amoxicillin-clavulanate cause diarrhea by accelerating gastrointestinal motility (Bartlett 2002). Still other antibiotics are thought to cause diarrhea by reducing the number of fecal anaerobes, thereby decreasing carbohydrate digestion and absorption, leading to an osmotic diarrhea (Bartlett 2002). Nearly 15% of hospitalized patients receiving beta-lactam antibiotics develop diarrhea (McFarland 1995). Clostridium difficile (C. difficile) infection of the colon is another cause of antibiotic-associated diarrhea that is thought to be caused by an overgrowth of native or newly acquired C. difficile (Fekety 1993). C. difficile is implicated in 20 to 30% of patients with antibiotic-associated diarrhea, in 50 to 70% of those with antibiotic-associated colitis and in more than 90% of those with antibiotic-associated pseudomembranous colitis (Bartlett 1980; Bartlett 1990; George 1982; Kelly 1994). Approximately 5% of healthy adults asymptomatically carry low concentrations of C. difficile in their colon, and the growth of these bacteria has been shown in vitro to be held in check by normal gut flora (Fekety 1993). The exact mechanism by which C. difficile overgrowth occurs is still unclear, but it can occur with the administration of oral, parenteral or topical antibiotics (Fekety 1993, Thomas 2003). The incidence of C. difficile-associated diarrhea (CDAD) ranges from 1 in 100 to 1 in 1,000 hospital discharges depending on the antibiotic prescribing habits of the hospital (Ho 1996; Lai 1997; Manian 1995). Additionally, the incidence may change over time at the same hospital as it did in one study from approximately 1 in 300 to 1 in 100 hospital discharges (Olson 1994).

The consequences of CDAD can be severe. Seventy nine deaths due to CDAD were reported in Quebec, Canada in 2003 (Pindera 2004). At one academic medical center over a three-year period, 21 of 710 cases (3%) of C. difficile colitis required intensive care unit admission or died as a result of their infection (Rubin 1995). These deaths were associated with co-morbid conditions such as malignancy, COPD or renal failure and therapies such as immunosuppressive drugs, antiperistaltic medications or the prior administration of clindamycin (McFarland 1995). At another university hospital the morbidity of C. difficile infection was higher, and 24 of 157 patients (15.3%) with C. difficile colitis died from their infection (Morris 2002). The economic consequences of C. difficile infection can also be severe, with one report finding a mean cost of $10,970 (US$) per patient for the treatment of the infection and its complications (McFarland 1999). The reports from Quebec are the most worrisome, and subsequent reports of mortality rates in that province are much higher than previous reports (Pepin 2005). This is related to the appearance of a new variant of C. difficile, which is capable of secreting much higher amounts of toxin A & B and is more resistant to standard antibiotic therapy (Louie 2005). This new variant results in a higher incidence of CDAD among hospitalized patients (McDonald 2005), a greater need for urgent colectomy for toxic colitis and a high mortality rate (e.g. 37%; Pepin 2005). This variant, ribotype 027, has been reported in Quebec, the USA, and Europe (Louie 2005; Laurence 2006). The emergence of this highly virulent bacterium adds urgency to the identification of effective therapy.

It is important to explain the terms used in conjunction with C. difficile infection, as the studies analyzed in this review involve various descriptions of C. difficile disease. CDAD occurs in a patient with diarrhea that has tested positive for C. difficile toxin and/or positive stool culture of C. difficile. C. difficile colitis involves a stool test positive for the organism and signs of mucosal inflammation seen on endoscopy. Pseudomembranous colitis refers to the actual presence of pseudomembranes seen on endoscopy. These terms are extensively overlapping, but not necessarily synonymous, as many patients with antibiotic-associated diarrhea do not undergo the endoscopy and biopsy necessary for the diagnosis of colitis or the endoscopy and visualization of pseudomembranes. This systematic review will use the term CDAD for all forms of symptomatic C. difficile infection for its analysis.

Objectives

The aim of this review was to investigate the efficacy of antibiotic therapy for CDAD, to identify the most effective antibiotic treatment for CDAD in adults and to determine the need for stopping the causative antibiotic during therapy.

Methods

Criteria for considering studies for this review

Types of studies

Randomized, controlled trials assessing antibiotic treatment for CDAD.

Types of participants

The types of participants included:
(i) patients with diarrhea: various definitions exist usually describing the consistency of stool, number of bowel movements per day, duration of symptoms, and rarely stool volume;
(ii) patients with C. difficile in stool identified by stool culture positive for C. difficile and or by stool positive for C. difficile cytotoxin;
(iii) patients who had received prior antibiotic therapy for an infection other than C. difficile; and
(iv) patients 18 years of age of older.

Patients were excluded if they did not have diarrhea or if there was no evidence of C. difficile infection.

Types of interventions

Only studies involving antibiotic therapy for C. difficile-associated diarrhea were included. These studies may include comparisons among different antibiotics, between different doses of the same antibiotic, or between antibiotic therapy and placebo.

Studies were excluded if they compared antibiotic to non-antibiotic therapy (such as resins, vaccines, probiotics or biologicals) or if even in the face of antibiotic treatment, the intervention being tested was of a non-antibiotic such as those listed above. In addition interventions used for the prevention of CDAD are not included in this review.

Types of outcome measures

The following outcomes were sought:
a. initial resolution of diarrhea;
b. initial conversion of stool to C. difficile cytotoxin and/or stool culture negative;
c. recurrence of diarrhea;
d. recurrence of fecal C. difficile cytotoxin and/or positive stool culture;
e. patient response to cessation of prior antibiotic therapy;
f. emergent surgery: fecal diversion or colectomy; and
g. death.

Search methods for identification of studies

MEDLINE (1966 through March 24, 2010), EMBASE (1980 - March 24, 2010), the Cochrane Central Database of Controlled Trials and the Cochrane IBD Review Group Specialized Trials Register were searched using the following text search terms: "pseudomembranous colitis and randomized trial"; "Clostridium difficile and randomized trial"; "antibiotic associated diarrhea and randomized trial". These search terms were chosen for their general applicability to our study, so as not to miss any possible relevant trials given the variety of names given to C. difficile disease. Studies published only as abstracts were not explicitly excluded.

Data collection and analysis

Trial Selection
At least three (or more in this update: 3 for each study) authors examined all the citations and abstracts derived from the electronic search strategy and independently selected trials to be included. Full reports of potentially relevant trials were retrieved to assess eligibility. Reviewers were not blind to the names of trials' authors, institutions or journals. Any disagreements about trial inclusion were resolved by group discussion.

Quality Assessment
The methodological quality of eligible trials in the initial review was assessed independently by two reviewers in terms of method of random allocation, allocation concealment, number of withdrawals and dropouts, whether data were analyzed on an intention-to-treat basis, and whether the participants and the outcome assessors were blind to the treatment provided. Since the quality of allocation concealment may particularly affect the results of studies, each of the two authors determined whether the quality of allocation concealment and the blinding of assessor and participants were adequate, inadequate or unclear. Where the method of allocation concealment was not clearly reported, attempts were made to contact the trials' authors for clarification. All disagreements were resolved by group discussion. For the current update the ten authors assessed study quality using the above criteria and the Cochrane Risk of Bias tool (Higgins 2008). Studies were excluded if they were not randomized controlled trials or if they made comparisons other than those specified. These studies are listed in the Characteristics of excluded studies table.

Data Extraction
Data extraction was performed independently by at least two authors. Results were compared between reviewers and all studies were presented for group discussion. Where data may have been collected but not reported, further information was sought from the individual trials' authors.

Data Analysis
Data were analyzed using Review Manager 5. For dichotomous outcomes, relative risks (RR) and 95% confidence intervals (CI) were derived from each study. When appropriate, the results of included studies were combined for each outcome. For dichotomous outcomes, pooled RR and 95% CI were calculated using a fixed effect model, except where significant heterogeneity was detected, at which time the random effects model was used. Data heterogeneity was assessed using a chi square test with significance set at P < 0.10. For the current update, the denominators were the total number of patients randomized and missing values were considered to be treatment failures.

Risk of Bias Tables were generated in Revman (Figure 1, Figure 2) and Summary of Findings Tables in GradePro and imported to Revman for selected outcomes.

Figure 1.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Results

Description of studies

In all twenty one studies were identified, by the search strategy, and six were subsequently excluded because patients were stool positive for C. difficile, but did not have diarrhea (Johnson 1992), duplicate publication (Noren 2006), a non-antibiotic arm (Louie 2006; Lowy 2010; Mattila 2008), or because the study was not a randomized controlled trial (McFarland 2002). McFarland 2002 is an uncontrolled observation of treatment failures from randomized, probiotic studies. The search strategy did not identify any studies published solely as abstracts. In the original review there were nine included studies. The first update included three additional studies (Lagrotteria 2006; Musher 2006; Wullt 2004). The current update includes three additional studies (Louie 2009; Musher 2009; Zar 2007).

Of particular interest is one of the excluded studies (Johnson 1992). Johnson 1992 is a randomized, placebo-controlled, non-blinded trial of oral vancomycin 125 mg four times a day for 10 days versus oral metronidazole 500 mg two times a day for 10 days versus placebo for the treatment of asymptomatic carriers of C. difficile. Asymptomatic C. difficile excretors were identified by rectal swab during infection control surveillance of medical and surgical inpatients at a US Veterans Affairs hospital. Patients were included if they did not have diarrhea or abdominal symptoms and were not allergic to vancomycin or metronidazole. C. difficile infection was identified by stool culture and cytotoxin assay. The main outcome was presence or absence of C. difficile in the stool during treatment and two months after treatment. A total of 30 patients were equally divided into the three treatment arms. C. difficile organisms were not detected during and immediately after treatment in 9/10 patients treated with vancomycin compared with 3/10 patients treated with metronidazole and 2/10 patients in the placebo group. In contrast, by the end of follow-up-ranging from 40 to over 90 days C. difficile organisms were not detected in 3/10 patients treated with vancomycin compared with 7/10 patients treated with metronidazole and 8/10 patients in the placebo group. The authors concluded that asymptomatic fecal excretion of C. difficile was transient in most patients and treatment with metronidazole was not effective in eliminating C. difficile from stool. Although treatment with vancomycin was temporarily effective, it was associated with a significantly higher rate of C. difficile carriage two months after treatment and therefore was not recommended for asymptomatic carriers of C. difficile. The results of this small study should be interpreted with caution. Athough these results are not statistically significant, they are of concern and should stimulate further investigation of strategies to prevent the long term carrier state of C. difficile, especially in hospitalized patients.

The fifteen included studies involve patients with diarrhea who have recently received antibiotics for an infection other than C. difficile. The definition of diarrhea ranged from at least two loose stools per day with an associated symptom such as rectal temperature > 38 ºC (Anonymous 1994), to at least six loose stools in 36 hours (Teasley 1983; Louie 2009). All of the studies included a "loose" or "liquid" description of the stool in their definitions of diarrhea. In terms of exclusion criteria, patients with HIV were only explicitly excluded from one study (Anonymous 1994). Pregnant women were excluded from two studies (Anonymous 1994 and Zar 2007). The other studies had varying and vague exclusion criteria ranging from "other obvious cause of diarrhea" (Teasley 1983) to "anatomic abnormality" (Young 1985). Both Louie 2009 and Musher 2009 excluded patients deemed clinically unstable and ''not expected to survive the study period''. Zar 2007 excluded patients with suspected or proven life-threatening intra-abdominal complications.

The studies used different methods for detecting C. difficile infection. Teasley 1983 defined C. difficile disease as stool being positive for C. difficile by culture or cytotoxin assay, or by the presence of pseudomembranes on endoscopy. Stool was tested for other enteric pathogens, but the authors did not comment on the presence or absence of these pathogens. Young 1985 and Zar 2007 defined C. difficile disease in the same manner as Teasley 1983. Young 1985 tested for the presence of other enteric pathogens and excluded patients if their stool tested positive for any other pathogen. Dudley 1986 and Fekety 1989 and Louie 2009 defined C. difficile disease by both culture or cytotoxin assay. Dudley 1986 and Fekety 1989 did not test for the presence of other enteric pathogens. de Lalla 1992 defined C. difficile disease as stool being positive for cytotoxin, culture and evidence of colitis on endoscopy. de Lalla 1992 excluded patients if their stool tested positive for any other pathogen. Wenisch 1996 defined C. difficile disease as stool positive for cytotoxin or endoscopic evidence of colitis and fecal leukocytes. Wenisch 1996 did not perform stool culture on any of the study patients. The Swedish CDAD study defined C. difficile disease as being positive for cytotoxin and/or culture and excluded patients if their stool tested positive for any other pathogen (Anonymous 1994). Keighley 1978 defined C. difficile disease as being positive for culture or positive for culture and cytotoxin. Keighley 1978 did not test stool for other enteric pathogens. Boero 1990 tested stool for cytotoxin only. Four studies used toxin assay and symptomatic diarrhea to define C. difficile disease (Lagrotteria 2006; Musher 2006; Musher 2009; Wullt 2004).

Ten of the fifteen included studies compared different antibiotics for the treatment of C. difficile-associated diarrhea. Teasley 1983 compared oral vancomycin 500 mg four times a day for 10 days with oral metronidazole 250 mg four times a day for 10 days. Young 1985 compared oral vancomycin 125 mg four times a day for 7 days with oral bacitracin 20,000 units four times a day for 7 days. Dudley 1986 compared oral vancomycin 500 mg four times a day for 10 days with oral bacitracin 25,000 units four times a day for 10 days. de Lalla 1992 compared oral vancomycin 500 mg four times a day for 10 days with oral teicoplanin 100 mg two times a day for 10 days. Wenisch 1996 compared four antibiotics: oral vancomycin 500 mg three times a day for 10 days with oral metronidazole 500 mg three times a day for 10 days with oral fusidic acid 500 mg three times a day for 10 days with oral teicoplanin 400 mg two times a day for 10 days. Boero 1990 compared vancomycin 500 mg two times a day for 10 days with oral rifaximin 200 mg three times a day for 10 days. Wullt 2004 compared 250 mg of fusidic acid three times per day to 400 mg of metronidazole three times per day for 7 days each. Musher 2006 compared 250 mg of metronidazole four times per day for 10 days to 500 mg of nitazoxanide twice a day given for either 7 or 10 days. Musher 2009 compared 125mg of vancomycin four times per day for 10 days to 500 mg of nitazoxanide twice a day for 10 days. Zar 2007 compared 125 mg of vancomycin four times per day with 250 mg of metronidazole four times per day for 10 days.

The Swedish CDAD study was a dose finding study which compared oral teicoplanin 100 mg twice a day for 7 days with oral teicoplanin 50 mg twice a day for 3 days followed by 100 mg twice a day for 4 days (Anonymous 1994). Fekety 1989 performed a dosage-finding study for oral vancomycin by comparing 125 mg four times a day with 500 mg four times a day for an average of 10 days. Louie 2009 compared fidaxomicin (OPT-80) given at either 50 mg, 100 mg or 200 mg doses twice daily for ten days. Only one study was placebo controlled. Keighley 1978 compared oral vancomycin 125 mg four times a day for 5 days with placebo four times a day for 5 days.

In addition to treating CDAD with antibiotics, the above studies also dealt with the initial, offending antibiotic in different ways. Only three studies explicitly stated that all initial antibiotics were stopped (Wenisch 1996; Young 1985; Zar 2007). Three of the other studies made attempts to stop the initial antibiotics, but this antibiotic was continued if it was deemed essential to the patient's clinical treatment (Anonymous 1994; Dudley 1986; Teasley 1983). Louie 2009 excluded any patients requiring concurrent antibiotic therapy, but made no reference to the initial antibiotics used in the included participants. The remaining eight studies either stated that the initial antibiotic was either stopped or changed (Fekety 1989) or did not make any reference to the initial antibiotic at all (Boero 1990; de Lalla 1992; Keighley 1978; Lagrotteria 2006; Musher 2006; Musher 2009; Wullt 2004).

Zar 2007 defined cure as a combination of resolution of diarrhea and conversion of stool to toxin negative, whereas other authors reported these outcomes separately. Zar 2007 is the first study to stratify patients (after randomization) by disease severity when assessing the relative efficacy of metronidazole and vancomycin. This is of importance because this general concept of efficacy assessment has been adopted in one subsequent study (Musher 2009) and three major guideline publications including the UK Health Protection Agency (HPA 2008), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) (Bauer 2009) and the combined Infectious Diseases Society of America (IDSA), and the Society for Healthcare Epidemiology of America (SHEA), which is reported on the Centers for Disease Control (CDC) web site (Cohen 2010).

All included studies assessed only orally delivered antibiotics, i.e., patients unable to tolerate oral medications were excluded from each study. None of the included studies stratified the randomization of patients based on cessation or continuation of the antibiotic that caused the CDAD.

Risk of bias in included studies

The results of the risk of bias analysis are presented in Figure 1 and Figure 2. Quality concerns include unclear allocation concealment, unclear generation of the allocation sequence and blinding of researchers and participants. Only six of the 15 studies reported adequate allocation concealment (Dudley 1986; Keighley 1978; Lagrotteria 2006; Musher 2009; Wullt 2004; Zar 2007). Only six studies (Dudley 1986; Fekety 1989; Lagrotteria 2006; Wenisch 1996; Wullt 2004; Zar 2007) adequately explained the generation of the allocation sequence. Only five studies (Musher 2006; Musher 2009; Wenisch 1996; Wullt 2004; Zar 2007) clearly stated that the researchers and the subjects were both blinded. Two studies stated that patients were blinded and it was unclear if outcome assessors were blinded (Dudley 1986; Young 1985). Outcome assessors were not blinded in the Fekety 1989 study. Patients were not blinded in the Lagrotteria 2006 study. Louie 2009 was a dose finding study and was not blinded. The Wenisch 1996, de Lalla 1992 and Boero 1990 studies were not blinded. Attempts were made to contact the authors to clarify these issues and as of the submission of this review correspondence was not established.

The included studies have additional quality issues. One diagnostic concern is that 11 of the 15 included studies used C. difficile cytotoxin stool assay as the means of identifying infected patients (Anonymous 1994; Boero 1990; Dudley 1986; Musher 2009; Teasley 1983; Wenisch 1996; Young 1985; Zar 2007). Two other studies (de Lalla 1992; Fekety 1989) required stool positive for cytotoxin and growth of C. difficile on culture to establish the presence of CDAD. Keighley 1978 separated out those patients who had stool positive for cytotoxin from those with C. difficile growth on culture. However the most important quality issue encountered in this review is that no study in which there were dropouts included those dropouts in their analyses, so effectively all participants were analyzed as treated. In some studies this had a major impact, since randomization occurred before disease confirmation, and participants were eliminated after randomization when found not to have CDAD. In some cases this was as infrequent as 2% of those randomized (Musher 2009), however in several studies the dropout rate was roughly 50% due to this reason (Anonymous 1994; Dudley 1986; Keighley 1978). For all studies in this review dropouts were treated as treatment failures.

The best means of identifying C. difficile is somewhat controversial (Thomas 2003). Gerding 1995 in their position paper for the SHEA recommend either a combination of stool culture for C. difficile and cytotoxin assay or stool cytotoxin testing alone. The paper goes on to state that most strains of C. difficile produce either both toxin A and toxin B, or neither (Gerding 1995). Additionally, treatment of patients with diarrhea who are toxin negative, but culture positive is controversial in that non toxigenic strains of C. difficile are not considered pathogenic (Gerding 1995). The American College of Gastroenterology practice parameters on the diagnosis and treatment of CDAD state that C. difficile can be identified by either positive culture or toxin assay and that if both tests are negative and the diarrhea persists, then additional stool studies with the same or different tests should be ordered (Fekety 1997). In light of these two practice guidelines, papers identifying C. difficile by either culture or toxin assay were included in our analysis. The most thorough discussion of the diagnosis of CDAD is in the most recent SHEA IDSA publication (Cohen 2010).

For the initial diagnosis of CDAD, most included studies did not exclude the presence of other pathogens in the stool as the cause of diarrhea (Boero 1990; Dudley 1986; Fekety 1989; Keighley 1978; Lagrotteria 2006; Musher 2006; Musher 2009; Teasley 1983; Wenisch 1996; Wullt 2004). It is possible that a patient could be infected with both C. difficile and another pathogen. The studies do not consistently state whether the initial, offending antibiotic was stopped and if it was stopped, whether a different antibiotic was started in its place. Although Zar 2007 did screen stool samples for Shigella, Salmonella and Campylobacter, in this study all patients were negative for these microbes. Additionally, only Young 1985 controlled for patients whose diarrhea rapidly resolved on its own with the removal of the initial antibiotic by including only those patients with persistent symptoms. For these patients the diarrhea may not have been caused by C. difficile, although it was present in the stool, or the bacterium was successfully purged by the patient. Recent studies relied on positive toxin assay and diarrhea alone to make the diagnosis. Some of the older studies required endoscopic confirmation of pseudomembranes, although this was not uniformly done even within those studies. Zar 2007 did include pre-existing pseudomembrane checks, although no patients had pre-existing pseudomembranous colitis in this study.

Each specific trial also had its own unique quality issues as well. In the Teasley 1983 study which compared vancomycin to metronidazole, the offending antibiotics believed to have brought about the CDAD were said to be discontinued unless they were "essential for treatment." The authors do not indicate how many patients did not have their offending antibiotic discontinued, which may confound the interpretation of results as the original antibiotic may have caused diarrhea by a different mechanism. Dudley 1986 and Zar 2007 did not have test results for C. difficile in the stool until after randomization. As a result, all of the patients with diarrhea that were C. difficile negative (50% of the total patients that were initially randomized in (Dudley 1986)) were dropped from the study. Wenisch 1996 had a total of seven dropouts from all of the treatment arms combined. However, Wenisch 1996 did not indicate the treatment allocation of these patients, therefore precluding an accurate intention to treat analysis of the results. In the Swedish CDAD study there was an intermediate measure of cure called "improvement," but the criteria for this "improved" classification of outcome were never described (Anonymous 1994). For the purposes of this systematic review, a conservative approach was taken and the "improved" patients were not considered to have their clinical symptoms resolved. Fekety 1989 had a dropout rate of 18% and the duration of the antibiotic therapy was determined by each individual physician treating patients. The average duration of therapy was 10 days with a range of five to 15 days (Fekety 1989). Boero 1990 had an unclear definition of inclusion criteria and symptomatic cure. Patients were described as having diarrhea, but there were no quantitative measures for the number of stools per day and cure was simply described as "normalization" of stools (Boero 1990). Dropouts were 13% and 23% respectively in the Wullt 2004 and Musher 2006 studies, making an intention to treat analysis difficult. However, both studies reported dropouts by allocation group. There were no dropouts in the smaller (Lagrotteria 2006) study. Zar 2007 had a dropout rate of 12.8% (22/172), however, the study still achieved predetermined power. Zar also excluded "suspected or proven life-threatening intra-abdominal complications" as well as prescription of either vancomycin or metronidazole in the 14 days prior to enrolment. Zar 2007 retested stool for recurrence at 21 days after cure (defined as symptom-free and toxin-free stool at day 10). This protocol was not based on evidence, and it should be noted that current guidelines for management of asymptomatic carriers of C. difficile are conservative. Although Zar screened for prior antibiotic use, no data were reported on which antibiotics were used. Although Musher 2009 was a multi-centre randomized trial, 37 of 50 patients came from the principal investigator's hospital. The study excluded patients undergoing enteral tube feeding. Another exclusion criterion was use of "any drug with anti-C. difficile activity - with the exception of ≤3 oral doses of metronidazole or vancomycin - within 1 week" of entry. It should be noted that Musher 2009 had a dropout rate of 18.4% (9/49) and was terminated early due to "slower-than-expected recruitment". It also fell far short of its predetermined sample size of 350.

Louie 2009 was a phase 2a trial and was an open label study for mild to moderate C. difficile infection and excluded all patients with severe disease and those who were "not expected to survive the study period". While patients kept a symptom diary, they were only formally observed at study entry and at the end of treatment or withdrawal.

Of particular interest among the included studies is the sole placebo-controlled study by Keighley 1978. This randomized, controlled trial was performed in England in 1978. It assessed the efficacy of oral vancomycin 125 mg taken four times a day for five days (a dose lower and shorter than other studies) compared to placebo for the treatment of pseudomembranous colitis. All patients were recruited from a surgical ward and blinded during the five day treatment period. It is unclear from the study report whether the outcome assessor was blinded or not. Broad inclusion criteria were used, and any patient with postoperative diarrhea was recruited. This led to the randomization of patients with postoperative diarrhea not related to C. difficile. The only exclusion criterion was a previous history of pseudomembranous colitis. The study not only divided patients by their treatment regimen, but also divided patients into three groups by results of their stool analysis. Group one had stool that was culture positive for C. difficile and positive for C. difficile cytotoxin. Group two had stool that was culture positive for C. difficile only. Group three had stool that was culture negative and negative for cytotoxin.

Keighley 1978 reported that only 21 of 44 randomized patients had some evidence of C. difficile infection. Of these patients 16 were toxin positive and 5 were culture positive. Twelve of these patients were in the vancomycin group and nine were in the placebo group. Keighley 1978 did not specifically define cure or relapse, but defined clinical response measured by stool frequency as resolution or improvement of diarrhea. Clinical response was higher in patients who received vancomycin in groups one and two, but response was not affected by treatment in group three. Keighley 1978 describes the numbers of patients taking vancomycin or placebo in whom stool converted to negative for C. difficile strain, negative for fecal cytotoxin and negative for histological evidence of pseudomembranous colitis. There are several major quality concerns with the Keighley 1978 study. The number of patients was small, and follow-up was inadequate. During the convalescence period, there were specimens that were either not taken or mislaid. Two-thirds of the patients in the vancomycin group fell into this category. Follow-up conclusions were based on only four patients from the total of 12 patients with evidence of C difficile infection that received vancomycin (Keighley 1978).

As mentioned above, the study by (Zar 2007) has had a great influence because of its stratification in outcome assessment by disease severity. Because of this, potential quality issues bear special attention. Despite the publication date, recruitment for this study ended in 2002, before the 027 strain of C. difficile reached the Chicago area, and the severity of disease seen in this mutation had not yet been witnessed, so the severity criteria would by that standard be fairly mild. Yet, in spite of excluding the sickest patients with CDAD from the study, 8 participants died within 5 days of the onset of therapy and were excluded from further analysis rather than treated as treatment failures. Randomization also occurred before the diagnosis of C. difficile was established, and 14 randomized subjects were subsequently found to be C. difficile negative and excluded from analysis. Randomization prior to stratification may not sufficiently validate this concept of severity stratification in antibiotic choice as described by (Zar 2007). What was done is in fact a post hoc subgroup analysis by disease severity, as was also done in (Musher 2009).

Effects of interventions

See: Summary of findings for the main comparison Metronidazole versus Vancomycin for Clostridium difficile-associated diarrhea in adults; Summary of findings 2 Teicoplanin versus Vancomycin for Clostridium difficile-associated diarrhea in adults; Summary of findings 3 Metronidazole versus Teicoplanin for Clostridium difficile-associated diarrhea in adults

Symptomatic cure
In terms of symptomatic cure no statistically significant differences were found between metronidazole, bacitracin, rifaximin, nitazoxanide, fusidic acid, teicoplanin and vancomycin.

Metronidazole versus vancomycin
Symptomatic cure was achieved in 79% of patients who received vancomycin compared to 71% of patients who received metronidazole (3 studies; 335 patients; RR 0.91; 95% CI 0.81 to 1.03; P = 0.14).

Bacitracin versus vancomycin
Symptomatic cure was achieved in 46% of patients who received vancomycin compared to 27% of patients who received bacitracin (2 studies; 104 patients; RR 0.58; 95% CI 0.34 to 0.99; P = 0.05).

Rifaximin versus vancomycin
Symptomatic cure was achieved in 100% of patients who received vancomycin compared to 90% of patients who received rifaximin (1 study; 20 patients; RR 0.90; 95% CI 0.69 to 1.18; P = 0.46).

Nitazoxanide versus vancomycin
Symptomatic cure was achieved in 74% of patients who received vancomycin compared to 77% of patients who received nitazoxanide (1 study; 49 patients; RR 1.04; 95% CI 0.76 to 1.43; P = 0.79).

Fusidic acid versus vancomycin
Symptomatic cure was achieved in 77% of patients who received vancomycin compared to 66% of patients who received fusidic acid (1 study; 60 patients; RR 0.85; 95% CI 0.61 to 1.17; P = 0.31).

Teicoplanin versus vancomycin
Symptomatic cure was achieved in 73% of patients who received vancomycin compared to 87% of patients who received teicoplanin (2 studies; 110 patients; RR 1.21; 95% CI 1.00 to 1.46; P = 0.06).

In terms of initial symptomatic resolution, vancomycin was significantly more effective than placebo. Initial symptomatic resolution was achieved in 41% of vancomycin patients compared to 4% of placebo patients (1 study; 44 patients; RR 9.00; 95% CI 1.24 to 65.16). This result should be interpreted with caution because of the small number of patients for this comparison and the poor methodological quality of the trial. OPT-80 was significantly more effective when given as 200 mg twice daily (94% clinical cure rate) compared to lower doses of 100 mg or 50 mg twice daily (1 study; 48 patients; RR 0.80; 95% CI 0.65 to 0.98; P = 0.03). This result should be interpreted with caution due to the small number of patients and because there is no evidence of its efficacy compared to placebo or other antibiotics.

Bacteriologic cure
For bacteriologic cure, teicoplanin was more effective than vancomycin. Bacteriologic cure was achieved in 82% of patients who received teicoplanin compared to 45% of patients who received vancomycin (1 study, 59 patients; RR 1.82; 95% CI 1.19 to 2.78; P = 0.006). There was no statistically significant difference in bacteriologic cure between metronidazole and vancomycin. Bacteriologic cure was achieved in 45% of patients who received metronidazole compared to 53% of patients who received vancomycin (2 studies, 163 patients; RR 0.85; 95% CI 0.62 to 1.17; P = 0.33). There was no statistically significant difference in bacteriologic cure between vancomycin and fusidic acid. Bacteriologic cure was achieved in 69% of patients who received vancomycin compared to 48% of patients who received fusidic acid (1 study; 60 patients; RR 0.68 95% CI 0.44 to 1.06). For initial bacteriologic resolution, vancomycin was significantly more effective than placebo. Initial bacteriologic resolution was achieved in 45% of vancomycin patients compared to 4% of placebo patients (1 study; 44 patients; RR; 10.00 95% CI 1.40 to 71.62). Teicoplanin was significantly more effective than vancomycin for initial bacteriologic resolution. Initial bacteriologic resolution was achieved in 62% of vancomycin patients compared to 87% of teicoplanin patients (2 studies; 110 patients; RR 1.43; 95% CI 1.14 to 1.81; P = 0.002). No statistically significant difference in initial bacteriologic resolution was found between vancomycin and metronidazole (1 study; 62 patients; RR 0.96; 95% CI 0.70 to 1.30; P = 0.78). No statistically significant difference in initial bacteriologic resolution was found between vancomycin and fusidic acid (2 studies; 191 patients; RR 0.96; 95% CI 0.78 to 1.18; P = 0.68). No statistically significant difference in initial bacteriologic resolution was found between vancomycin and rifaximin (1 study; 20 patients; RR 0.90; 95% CI 0.69 to 1.18; P = 0.46). Vancomycin was significantly more effective than bacitracin for initial bacteriologic resolution (2 studies; 104 patients; RR 0.52; 95% CI 0.31 to 0.86; P = 0.01).

Risk of relapse
No statistically significant differences in relapse were found between bacitracin and vancomycin (2 studies; 104 patients; RR 1.11; 95% CI 0.50 to 2.48; P = 0.80), teicoplanin and vancomycin (2 studies; 110 patients; RR 0.44; 95% CI 0.14 to 1.36; P =0.15), fusidic acid and vancomycin (2 studies; 191 patients; RR 1.09; 95% CI 0.64 to 1.86; P = 0.76), and nitazoxanide and vancomycin (1 study; 49 patients; RR 0.61; 95% CI 0.06 to 6.33). No statistically significant difference in relapse was found between metronidazole and nitazoxanide (1 study; 142 patients; 95% CI 0.69; 95% CI 0.24 to 1.98; P = 0.49). No statistically significant difference in relapse was found between metronidazole and metronidazole plus rifampin (1 study; 39 patients; RR 0.95; 95% CI 0.33 to 2.77; P = 0.93). No statistically significant difference in relapse was found between metronidazole and teicoplanin (1 study; 59 patients; RR 2.26; 95% CI 0.48 to 10.73; P = 0.31). No statistically significant difference in relapse was found between metronidazole and fusidic acid (2 studies; 190 patients; RR 0.91; 95% CI 0.53 to 1.55; P = 0.73). No statistically significant difference in relapse was found between teicoplanin and fusidic acid (1 study; 57 patients; RR 0.26; 95% CI 0.06 to 1.11; P = 0.07).

The patients with relapse of diarrhea after treatment were re-treated in various ways. Dudley 1986 re-treated with the same antibiotic and Young 1985 re-treated with the antibiotic from the other arm of the study. de Lalla 1992 stated that the patients with relapse were re-treated, but analyzed the results in aggregate, making it impossible to compare the antibiotics for efficacy. Fekety 1989's vancomycin dose-finding study re-treated all nine relapses with vancomycin and subsequently cured these patients. Wenisch 1996 treated recurrent disease with teicoplanin with a reported a 100% cure rate. Louie 2009 re-treated with either metronidazole or vancomycin, but did not report on the success of this treatment. The remaining studies did not report on the re-treatment of relapses.

Secondary outcomes
The secondary outcomes measured in this review (surgery and death) occurred infrequently in all of the studies. Dudley 1986 reported one death and one partial colectomy after failed treatment of CDAD with bacitracin. Both patients were crossed-over to vancomycin before their adverse outcome, with the first patient improving prior to his death, and the second patient continuing to have CDAD. Fekety 1989 reported one death in each of the two vancomycin treatment arms. The Swedish CDAD study reported one death in the two times per day teicoplanin group, but the authors did not specify if it was part of the CDAD sub-section of the study or part of the general dosage-finding portion of the study (Anonymous 1994). Teasley 1983 had three deaths in the whole study, including two deaths in the vancomycin treatment arm. The authors attributed all three deaths to underlying illness and not to CDAD or the antibiotic therapy, a common claim in other studies as well, though this would seem to be a difficult judgement. de Lalla 1992 reported two deaths and Musher 2009 reported one death. Both studies did not specify the treatment group and attributed the deaths to the patients' underlying disease. Zar 2007 reported eight deaths, four in each treatment group, but did not comment on the cause of mortality. There was a total of 18 deaths among 1152 participants in this systematic review.

Two studies quantified the cost of treatment (Musher 2009; Wenisch 1996). Wenisch 1996 compared four different antibiotics. The cost data for a course of treatment were: Metronidazole, $35; Fusidic acid, $287; Vancomycin, $2030; and Teicoplanin, $3430. Musher 2009 compared two antibiotics. The cost data are as follows: Vancomycin, $618; Nitazoxanide, $316.

Discussion

The studies presented in this review are disparate in design and small in number and content. Based upon the paucity of evidence, and significant quality issues, especially in the placebo controlled trial, it remains an open question whether mild C. difficile-associated diarrhea needs to be treated with antibiotics versus simple supportive care. This represents a significant departure from current practice, so much so that several of the investigators we contacted were unwilling to undertake a placebo controlled trial. Perhaps patients with mild CDAD might resolve their symptoms as quickly without antibiotics, and with a lower recurrence rate. The Keighley 1978 study, which is the only placebo-controlled study, suggests vancomycin's superior efficacy over placebo. However, this result should be interpreted with caution, given the small numbers of patients in the trial and the poor methodological quality of the trial. The Johnson 1992 study of asymptomatic carriers suggests that placebo is better than vancomycin or metronidazole for eliminating C. difficile in stool during follow-up. A placebo controlled trial will be even more difficult to perform in light of the appearance of the highly virulent ribotype 027 toxigenic strain of C. difficile. The very high mortality rate and increasing use of surgical therapy for this disease emphasize the still inadequate development of an ideal antibiotic therapy.

If one does decide to treat, it should be with two goals: improvement of the patient's clinical condition and prevention of spread of C. difficile infection to other patients. Given these two considerations, one should choose the antibiotic that brings both symptomatic cure and bacteriologic cure. In this regard, teicoplanin may be a good choice, because it was significantly better than vancomycin for bacteriologic cure and has borderline superior effectiveness in terms of symptomatic cure. Teicoplanin is not readily available in the United States and remains expensive elsewhere, which must be taken into account (Hopkins 2009).

Cost effectiveness cannot be calculated when efficacy is still not established. Although the costs presented in this review are informative, they do not play a definitive role in antibiotic choice until efficacy is confirmed. A 10-day course of vancomycin 500 mg four times a day costs $7,358 (US$) (Mosby 2003). This regimen was used in the de Lalla 1992; Fekety 1989 and Teasley 1983 studies. If given at the lower dose of 125 mg four times a day, a ten day course of vancomycin costs $618 (Musher 2009). This regimen was used in Musher 2009 and Zar 2007. A 10 day course of metronidazole 500 mg three times a day as used in the Wenisch 1996 study costs $765 (US$) (Mosby 2003). A 10 day course of bacitracin 25,000 units four times a day as used in the Wenisch 1996 study costs $200 (US$). Teicoplanin and fusidic acid are not available in the United States; therefore, using the price listing from the British National Formulary and the exchange rate as of 1/29/04, we calculated the price of these drugs in US dollars. A 10 day course of Teicoplanin 400 mg two times a day costs $1,374 ($US) and a 10 day course of fusidic acid 500 mg three times a day costs $706 ($US) (BNF 2004). A 10 day course of Nitazoxanide 500 mg twice a day costs $316 (Musher 2009). Rifaximin has recently become available in the United States and has been available in Italy since 1988. It must be kept in mind that true costs are difficult to calculate. The numbers above are charges made for each antibiotic, as each hospital or health system negotiates different prices for medication with pharmaceutical companies.

Zar 2007 reported that vancomycin was significantly better than metronidazole for treating severe C. difficile diarrhea (P = 0.02). However 22 participants were excluded from the analysis (12.8%) and an intention to treat analysis was not reported. Bishara 2007 found no statistically significant difference in symptomatic cure between metronidazole and vancomycin in a pooled analysis of 3 studies (RR 0.93; 95% CI 0.80 to 1.09) treating exclusions, deaths and relapses as treatment failures. This result is similar to the pooled analysis reported in this review.

The severity scale designed by Zar 2007 and used in Musher 2009 is important as, for the first time, it attempts to stratify those affected by CDAD into mild versus severe disease. Such a scale would be extremely valuable, not only for the standardisation of future studies, but for use in clinical practice, particularly as the study by Johnson 1992, for example, suggests that mild disease may be successfully treated without antibiotics. Currently, the severity scale designed by Zar 2007 uses any two of the following to indicate severe disease: pyrexia (≥38.3°C), serum albumin of < 2.5 mg/dl, leukocytosis of 15,000 cells/mm3 and age (≥60 years). There is some discrepancy between studies as to the appropriate cut-off points used. For example, Louie 2009 was specifically designed to include patients with mild or moderate disease, and did not exclude patients as 'severe' unless they had a leukocytosis of ≥30,000 cells/mm.3 Zar 2007 actively excluded patients with extremely severe CDAD, thus the response to treatment in the severe arm of this study may not be representative of patients with severe CDAD. Other studies excluded patients with severe disease (Louie 2009; Musher 2009). The reluctance of researchers to include such patients means that there is still a lack of evidence about how to treat the most severely ill. Nevertheless the concept of disease severity stratification for specific therapeutic choice has been widely accepted as shown in the most recent guideline publications (See additional Table 1).

Table 1. Guidelines for Antibiotic Treatment of CDAD
  1. 1 HPA 2008; HPA 2010

    2 Bauer 2009

    3 Cohen 2010

 HPA1ESCMID2SHEA & IDSA3
MILD CDADStop inciting antibiotic and observe, or metronidazole 500 mg po tid. Alternate dosing also recommended and change to vancomycin if no better in 4 days.Stop inciting antibiotic and observe, or Metronidazole 500 mg po tidStop inciting antibiotic, or metronidazole 500 mg po tid for 10 days.
SEVERE CDADVancomycin 500 mg po qid with taperingVancomycin 125 mg po qid for 10 daysVancomycin 125 mg po qid for 10 days
SEVERE AND CANNOT TOLERATE ORAL MEDSIntravenous metronidazole and vancomycin via nasogastric tube or enemas qid.samesame
SURGERYFor toxic megacolon or lactate > 5For perforation, toxic megacolon, Ileus, lactate > 5 
RECURRENCE 

First as Primary

2nd: oral vancomycin with taper

same

These recommendations should be treated with caution because there is poor evidence supporting recommendations for the treatment of severe disease due to the exclusion of such patients in the included studies. Patients in all included studies were treated with oral antibiotics alone, those too ill to tolerate oral medications were excluded. In addition the criteria for defining the most severely ill patients in the Zar 2007 study were not at that time clearly associated with prognosis. Most importantly the stratification occurred after randomization and after a number of exclusions, constituting a post hoc subgroup analysis by disease severity. The results of such analyses have been described as best used for exploratory purposes and should not affect trial conclusions (Assmann 2000). No statistical tests of interaction were performed. Yet one trial (Louie 2009) and three recent published guidelines (HPA 2010; Bauer 2009; Cohen 2010) have adopted this principal of stratification and the guidelines endorse the efficacy of vancomycin for severe disease.

Older guidelines discuss treatment of unresponsive disease with an increased dose of vancomycin 500 mg four times daily, intravenous metronidazole 500 mg three times daily and rifampicin 300 mg twice daily. However, this regimen was shown to have no clinical benefit in primary CDAD (Lagrotteria 2006). The criteria defining severity stratification have differed in each publication that is cited in this review that assesses or recommends treatment by disease severity (Musher 2009; Zar 2007; Bauer 2009; HPA 2010; Cohen 2010). Lactate > 5 is certainly a valid marker of extreme severity, but with an associated 75% operative mortality, an earlier marker and proven therapy would be of more use (Cohen 2010). This badly needs clarification, and the evidence does not exist in available studies to clarify the criteria for severity stratification and whether different antibiotic regimens should be applied to each severity stratum.

The placebo-controlled study by Keighley 1978, although flawed, raises some interesting points. The study suggests that vancomycin is not a very good therapy for non-specific diarrhea or antibiotic-associated diarrhea that arises from a mechanism other than C. difficile overgrowth. Whilst vancomycin did seem to be effective among C. difficile positive individuals for the early control of diarrhea, it was not effective for long term bacteriologic control. The Johnson 1992 study provides complementary information, being the only other placebo controlled trial (see description of excluded studies - above). Johnson 1992 suggests that the best means of accomplishing the second goal of treatment - elimination of the C. difficile bacterium from the stool of hospitalized patients to prevent spread of infection, is best accomplished with no antibiotic at all. While vancomycin has high in vitro activity against C. difficile, it is still not certain that CDAD is best treated with this or any other antibiotic (Bartlett 1980). Antibiotic synergy has only been investigated in one study (Lagrotteria 2006), and no clinical benefit was seen by adding rifampin to metronidazole. All of the included studies use oral antibiotics and, as yet, there has been no research into the use of intravenous antibiotics as an alternative.

Wenisch 1996 is an important study because it directly compares several antibiotics. This avoids making unrealistic assumptions about relative efficacy made across several randomized trials (Baker 2002). The increasing virulence of C. difficile and failure to demonstrate that any single antibiotic is superior to others, with the possible exception of teicoplanin underlines the need to consider new treatments. Data on two new antibiotics: nitazoxanide (Musher 2006; Musher 2009) and OPT-80 (Louie 2009) are included in this update. The concept of toxin binding has been investigated and deserves further attention (Louie 2006). A C. difficile vaccine has also been developed and may provide another alternative to antibiotic treatment (Sougioultzis 2005).

The most recent data show a drop in CDAD mortality in 2008, after a rapid rise in mortality up to 2004 (Karas 2010; Redelings 2007). This may be due to a greater than 50% drop in incidence in the UK that is the result of effective prevention and isolation measures (HPA 2010), and improving awareness of causative antibiotics (Privitera 1991; Thomas 2003; Novell 2010). Novel therapies, some long forgotten, such as fecal repopulation (Khoruts 2010; Bowden 1981) are reappearing.

The three studies included in this update do not alter the overall conclusion of this review, but provide a clearer picture of the further research that should be carried out in the future.

Authors' conclusions

Implications for practice

Although antibiotic therapy for CDAD is universally prescribed, this review cannot establish the efficacy of antibiotic therapy for CDAD, as the only placebo-controlled study is inadequate. This review cannot define the efficacy of cessation of the initial, offending antibiotic because the above studies did not apply a strict or consistent protocol in regard to its continuation. As a corollary, this review cannot establish the proper amount of time between cessation of the initial antibiotic and beginning antibiotic therapy for CDAD (to see if the offending antibiotic might be causing diarrhea by a mechanism other than C. difficile overgrowth), as the above studies did not address this research question. Finally, this review cannot definitively make a specific antibiotic recommendation for the treatment of CDAD, as the results suggest that several antibiotics are more or less equally effective at achieving early symptomatic cure as well as other secondary outcomes. Current guidelines generally recommend metronidazole or vancomycin depending on the clinical situation, but there is no strong evidence base to support these recommendations. Teicoplanin may be a more effective alternative to vancomycin. Although its use is currently limited by cost and availability, it may be a possibility in the future.

Implications for research

Given the uncertainty involved in antibiotic therapy for CDAD, adequately powered, placebo controlled, randomized trials that assess (1) cessation of the initial antibiotic, (2) timing and duration of CDAD therapy and (3) efficacy of several antibiotic treatments is recommended. Such trials would require the randomization of a large number of patients. Vancomycin should be included, as it is the only antibiotic that has previously been compared to placebo. Metronidazole should be included because it is an inexpensive and generally well tolerated alternative to vancomycin. Teicoplanin should be included because it may be superior to both of these antibiotics. Nitazozanide should also be included, as it may be a cheaper possible alternative to vancomycin. These comparisons may help to determine which antibiotic is most suitable for treating CDAD. There should be strict criteria for the diagnosis of CDAD: prior exposure to antibiotics, persistent diarrhea that does not respond to removal of the offending antibiotic and supportive therapy, and C. difficile that is identified by toxin assay. The primary outcomes should be symptomatic cure, defined as cessation of symptoms during the time of treatment and for 30 or 60 days after, and evidence of bacteriologic cure. The secondary outcomes should be initial symptom resolution, initial bacteriologic resolution, surgery and death. Given the broad use of antibiotics, hopefully this proposed study will elucidate the treatment of choice for CDAD and improve the lives of many of those suffering from a major cause of antibiotic-associated diarrhea. If disease severity is to be a factor in antibiotic choice, this should be assessed prior to randomization. However, in light of recent developments in C. difficile virulence and prevalence it is uncertain if a placebo controlled trial will be undertaken.

It would be useful to develop a universal system for grading the severity of CDAD. The increasing severity of the disease also highlights the need to investigate antibiotic treatment in severely ill patients with CDAD, as data on this group are currently lacking. Other issues that need to be addressed in future trials include: the treatment of recurrent symptoms, the use of intravenous compared to oral antibiotics, antibiotic resistance, synergistic antibiotic combinations and other types of interventions (e.g. the use tolevamer combined with antibiotics).

Acknowledgements

Funding for the IBD/FBD Review Group (September 1, 2010 - August 31, 2015) has been provided by the Canadian Institutes of Health Research (CIHR) Knowledge Translation Branch (CON - 105529) and the CIHR Institutes of Nutrition, Metabolism and Diabetes (INMD); and Infection and Immunity (III).

Miss Ila Stewart has provided support for the IBD/FBD Review Group through the Olive Stewart Fund.

Data and analyses

Download statistical data

Comparison 1. Vancomycin versus Placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2 Bacteriologic Initial Response1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
Analysis 1.1.

Comparison 1 Vancomycin versus Placebo, Outcome 1 Symptomatic Initial Response.

Analysis 1.2.

Comparison 1 Vancomycin versus Placebo, Outcome 2 Bacteriologic Initial Response.

Comparison 2. Metronidazole versus Vancomycin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response3335Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.86, 1.02]
2 Bacteriologic Initial Cure162Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.70, 1.30]
3 Bacteriologic Cure2163Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.62, 1.17]
4 Cure (symptomatic and bacteriologic cure)1172Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.75, 1.02]
4.1 Mild disease190Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.76, 1.08]
4.2 Severe disease182Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.64, 1.09]
5 Symptomatic Cure minus recurrences including Zar with all exclusions treated as failures3335Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.81, 1.03]
Analysis 2.1.

Comparison 2 Metronidazole versus Vancomycin, Outcome 1 Symptomatic Initial Response.

Analysis 2.2.

Comparison 2 Metronidazole versus Vancomycin, Outcome 2 Bacteriologic Initial Cure.

Analysis 2.3.

Comparison 2 Metronidazole versus Vancomycin, Outcome 3 Bacteriologic Cure.

Analysis 2.4.

Comparison 2 Metronidazole versus Vancomycin, Outcome 4 Cure (symptomatic and bacteriologic cure).

Analysis 2.5.

Comparison 2 Metronidazole versus Vancomycin, Outcome 5 Symptomatic Cure minus recurrences including Zar with all exclusions treated as failures.

Comparison 3. Bacitracin versus Vancomycin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response2104Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.60, 1.12]
2 Symptomatic Cure2104Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.34, 0.99]
3 Bacteriologic Initial Response2104Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.31, 0.86]
4 Symptomatic Recurrence2104Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.50, 2.48]
Analysis 3.1.

Comparison 3 Bacitracin versus Vancomycin, Outcome 1 Symptomatic Initial Response.

Analysis 3.2.

Comparison 3 Bacitracin versus Vancomycin, Outcome 2 Symptomatic Cure.

Analysis 3.3.

Comparison 3 Bacitracin versus Vancomycin, Outcome 3 Bacteriologic Initial Response.

Analysis 3.4.

Comparison 3 Bacitracin versus Vancomycin, Outcome 4 Symptomatic Recurrence.

Comparison 4. Teicoplanin versus Vancomycin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response2110Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.95, 1.19]
2 Symptomatic Cure2110Risk Ratio (M-H, Fixed, 95% CI)1.21 [1.00, 1.46]
3 Bacteriologic Initial Response2110Risk Ratio (M-H, Fixed, 95% CI)1.43 [1.14, 1.81]
4 Bacteriologic Cure159Risk Ratio (M-H, Fixed, 95% CI)1.82 [1.19, 2.78]
5 Symptomatic Recurrence2110Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.14, 1.36]
6 Bacteriologic Recurrence159Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.11, 1.23]
Analysis 4.1.

Comparison 4 Teicoplanin versus Vancomycin, Outcome 1 Symptomatic Initial Response.

Analysis 4.2.

Comparison 4 Teicoplanin versus Vancomycin, Outcome 2 Symptomatic Cure.

Analysis 4.3.

Comparison 4 Teicoplanin versus Vancomycin, Outcome 3 Bacteriologic Initial Response.

Analysis 4.4.

Comparison 4 Teicoplanin versus Vancomycin, Outcome 4 Bacteriologic Cure.

Analysis 4.5.

Comparison 4 Teicoplanin versus Vancomycin, Outcome 5 Symptomatic Recurrence.

Analysis 4.6.

Comparison 4 Teicoplanin versus Vancomycin, Outcome 6 Bacteriologic Recurrence.

Comparison 5. Fusidic Acid versus Vancomycin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response2191Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.83, 1.08]
2 Symptomatic Cure160Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.61, 1.17]
3 Bacteriologic Initial Response2191Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.78, 1.18]
4 Bacteriologic Cure160Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.44, 1.06]
5 Symptomatic Recurrence2191Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.64, 1.86]
6 Bacteriologic Recurrence160Risk Ratio (M-H, Fixed, 95% CI)1.87 [0.61, 5.73]
Analysis 5.1.

Comparison 5 Fusidic Acid versus Vancomycin, Outcome 1 Symptomatic Initial Response.

Analysis 5.2.

Comparison 5 Fusidic Acid versus Vancomycin, Outcome 2 Symptomatic Cure.

Analysis 5.3.

Comparison 5 Fusidic Acid versus Vancomycin, Outcome 3 Bacteriologic Initial Response.

Analysis 5.4.

Comparison 5 Fusidic Acid versus Vancomycin, Outcome 4 Bacteriologic Cure.

Analysis 5.5.

Comparison 5 Fusidic Acid versus Vancomycin, Outcome 5 Symptomatic Recurrence.

Analysis 5.6.

Comparison 5 Fusidic Acid versus Vancomycin, Outcome 6 Bacteriologic Recurrence.

Comparison 6. Nitazoxanide versus Vancomycin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Nitazoxanide versus Vancomycin149Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.76, 1.43]
1.2 Not severe disease129Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.64, 1.49]
1.3 Severe disease120Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.69, 1.90]
2 Recurrence of diarrhea within 31 days1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Nitazoxanide versus Vancomycin149Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.06, 6.33]
2.2 Not severe disease129Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.02, 10.45]
2.3 Severe disease120Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 13.87]
3 Sustained response1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Nitazoxanide versus Vancomycin149Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.75, 1.58]
3.2 Not severe disease129Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.68, 1.66]
3.3 Severe disease120Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.61, 2.23]
Analysis 6.1.

Comparison 6 Nitazoxanide versus Vancomycin, Outcome 1 Symptomatic Initial Response.

Analysis 6.2.

Comparison 6 Nitazoxanide versus Vancomycin, Outcome 2 Recurrence of diarrhea within 31 days.

Analysis 6.3.

Comparison 6 Nitazoxanide versus Vancomycin, Outcome 3 Sustained response.

Comparison 7. Rifaximin versus Vancomycin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response120Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.69, 1.18]
2 Bacteriologic Initial Response120Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.69, 1.18]
Analysis 7.1.

Comparison 7 Rifaximin versus Vancomycin, Outcome 1 Symptomatic Initial Response.

Analysis 7.2.

Comparison 7 Rifaximin versus Vancomycin, Outcome 2 Bacteriologic Initial Response.

Comparison 8. Metronidazole versus Nitazoxanide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Initial resolution of diarrhea1142Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.71, 1.19]
2 Recurrence of Diarrhea at 31 d.1142Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.24, 1.98]
Analysis 8.1.

Comparison 8 Metronidazole versus Nitazoxanide, Outcome 1 Initial resolution of diarrhea.

Analysis 8.2.

Comparison 8 Metronidazole versus Nitazoxanide, Outcome 2 Recurrence of Diarrhea at 31 d..

Comparison 9. Metronidazole versus Metronidazole + Rifampin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Resolution of Diarrhea139Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.64, 1.65]
2 Recurrence of diarrhea within 40 days139Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.33, 2.77]
Analysis 9.1.

Comparison 9 Metronidazole versus Metronidazole + Rifampin, Outcome 1 Resolution of Diarrhea.

Analysis 9.2.

Comparison 9 Metronidazole versus Metronidazole + Rifampin, Outcome 2 Recurrence of diarrhea within 40 days.

Comparison 10. Metronidazole versus Teicoplanin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response159Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.86, 1.09]
2 Symptomatic Cure159Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.69, 1.09]
3 Bacteriologic Initial Cure159Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.60, 0.98]
4 Bacteriologic Cure159Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.58, 1.00]
5 Symptomatic Recurrence159Risk Ratio (M-H, Fixed, 95% CI)2.26 [0.48, 10.73]
Analysis 10.1.

Comparison 10 Metronidazole versus Teicoplanin, Outcome 1 Symptomatic Initial Response.

Analysis 10.2.

Comparison 10 Metronidazole versus Teicoplanin, Outcome 2 Symptomatic Cure.

Analysis 10.3.

Comparison 10 Metronidazole versus Teicoplanin, Outcome 3 Bacteriologic Initial Cure.

Analysis 10.4.

Comparison 10 Metronidazole versus Teicoplanin, Outcome 4 Bacteriologic Cure.

Analysis 10.5.

Comparison 10 Metronidazole versus Teicoplanin, Outcome 5 Symptomatic Recurrence.

Comparison 11. Metronidazole versus Fusidic Acid
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response2190Risk Ratio (M-H, Random, 95% CI)1.09 [0.60, 1.99]
2 Symptomiatic Cure2190Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.78, 1.30]
3 Bacteriologic initial Cure2190Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.83, 1.25]
4 Bacteriologic Cure159Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.87, 2.11]
5 Symptomatic Recurrence2190Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.53, 1.55]
Analysis 11.1.

Comparison 11 Metronidazole versus Fusidic Acid, Outcome 1 Symptomatic Initial Response.

Analysis 11.2.

Comparison 11 Metronidazole versus Fusidic Acid, Outcome 2 Symptomiatic Cure.

Analysis 11.3.

Comparison 11 Metronidazole versus Fusidic Acid, Outcome 3 Bacteriologic initial Cure.

Analysis 11.4.

Comparison 11 Metronidazole versus Fusidic Acid, Outcome 4 Bacteriologic Cure.

Analysis 11.5.

Comparison 11 Metronidazole versus Fusidic Acid, Outcome 5 Symptomatic Recurrence.

Comparison 12. Teicoplanin versus Fusidic Acid
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response157Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.92, 1.17]
2 Symptomatic Cure157Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.02, 1.83]
3 Bacteriologic Initial Cure157Risk Ratio (M-H, Fixed, 95% CI)1.68 [1.19, 2.37]
4 Bacteriologic Cure157Risk Ratio (M-H, Fixed, 95% CI)1.73 [1.19, 2.51]
5 Symptomatic Recurrence157Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.06, 1.11]
Analysis 12.1.

Comparison 12 Teicoplanin versus Fusidic Acid, Outcome 1 Symptomatic Initial Response.

Analysis 12.2.

Comparison 12 Teicoplanin versus Fusidic Acid, Outcome 2 Symptomatic Cure.

Analysis 12.3.

Comparison 12 Teicoplanin versus Fusidic Acid, Outcome 3 Bacteriologic Initial Cure.

Analysis 12.4.

Comparison 12 Teicoplanin versus Fusidic Acid, Outcome 4 Bacteriologic Cure.

Analysis 12.5.

Comparison 12 Teicoplanin versus Fusidic Acid, Outcome 5 Symptomatic Recurrence.

Comparison 13. Dose finding studies
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic Initial Response2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Vancomycin156Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.72, 1.17]
1.2 Teicoplanin192Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.49, 1.29]
2 Symptomatic Recurrence3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Vancomycin156Risk Ratio (M-H, Fixed, 95% CI)0.8 [0.24, 2.67]
2.2 Teicoplanin192Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.47, 2.78]
2.3 OPT-80148Risk Ratio (M-H, Fixed, 95% CI)0.2 [0.03, 1.43]
3 Symptomatic Cure3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Vancomycin156Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.65, 1.38]
3.2 Teicoplanin192Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.29, 1.29]
3.3 OPT-80148Risk Ratio (M-H, Fixed, 95% CI)1.26 [1.03, 1.54]
4 Bacteriologic Cure2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Vancomycin156Risk Ratio (M-H, Fixed, 95% CI)0.8 [0.24, 2.67]
4.2 Teicoplanin192Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.51, 1.88]
Analysis 13.1.

Comparison 13 Dose finding studies, Outcome 1 Symptomatic Initial Response.

Analysis 13.2.

Comparison 13 Dose finding studies, Outcome 2 Symptomatic Recurrence.

Analysis 13.3.

Comparison 13 Dose finding studies, Outcome 3 Symptomatic Cure.

Analysis 13.4.

Comparison 13 Dose finding studies, Outcome 4 Bacteriologic Cure.

What's new

DateEventDescription
13 October 2010New search has been performed2010 Update with 3 added studies, 3 new published guidelines and discussion of severity stratification
13 October 2010New citation required but conclusions have not changedNew authors for updated review

Contributions of authors

Dr Rick Nelson prepared the update for Issue 3, 2007.

E Bricker, R Garg, R Nelson, J Hansen, A Loza, and T Novak all contributed to the original version of the review published in Issue 1, 2005 of the Cochrane Library.

This update was prepared by R.Nelson with the collaboration of the other named authors, students at the Unverisity of Sheffield School of Medicine as part of the Master Class Symposium

Declarations of interest

None known.

Sources of support

Internal sources

  • none, UK.

External sources

  • none, UK.

Differences between protocol and review

none

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anonymous 1994

MethodsRCT
ParticipantsCDAD
Interventionsteicoplanin dose study 100 mg bid (n=49) versus qid (n = 43)
Outcomescure
bacteriologic resolution
relapse
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAbstract reports randomized, but not how
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskAbstract reports double blind
Incomplete outcome data (attrition bias)
All outcomes
High risk47% dropouts, 20/43 in 100 mg bid group and 25/49 in 100 mg qid group
Other biasUnclear riskCriteria for 'improved' outcome not described

Boero 1990

MethodsRCT
ParticipantsCDAD
Interventionsvancomycin (n = 10) versus rifaximin (n =10)
Outcomescombined symptomatic and bacteriologic resolution
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
High riskNo mention of blinding of patients or outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts
Other biasHigh risk

Did not exclude other pathogens in the stool as causes of diarrhoea

Unclear inclusion criteria and unclear cure criteria

de Lalla 1992

MethodsRCT
ParticipantsCDAD
Interventionsvancomycin (n = 24) versus teicoplanin (n = 27)
Outcomescure
bacteriologic resolution
relapse
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description given
Allocation concealment (selection bias)Unclear riskNo description given
Blinding (performance bias and detection bias)
All outcomes
High riskNo mention of blinding of patients or outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
Low risk5/51 dropouts; 4/24 in vancomycin group and 1/27 in teicoplanin group
Other biasUnclear riskNot described

Dudley 1986

MethodsRCT
ParticipantsCDAD
Interventionsvancomycin (n = 31) versus bacitracin (n = 31)
Outcomescure
bacteriologic resolution
relapse
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated
Allocation concealment (selection bias)Low riskA - Adequate
Blinding (performance bias and detection bias)
All outcomes
Unclear riskUnclear whether assessor was blinded
Incomplete outcome data (attrition bias)
All outcomes
High risk52% dropouts, groups not specified
Other biasHigh risk

Did not exclude other pathogens in the stool as causes of diarrhoea

Good randomisation technique, but did not test for C. difficile in stool until after randomisation

Fekety 1989

MethodsRCT
ParticipantsCDAD
Interventionsvancomycin dose study (125 (n = 28) versus 500 mg (n = 28) qid
Outcomescure
bacteriologic resolution
relapse
Noteshigh dropout rate
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers table
Allocation concealment (selection bias)High riskNot used
Blinding (performance bias and detection bias)
All outcomes
High riskOutcome assessor not blinded
Incomplete outcome data (attrition bias)
All outcomes
High risk18% dropouts, groups not specified
Other biasHigh risk

Did not exclude other pathogens in the stool as causes of diarrhoea

Wide range of treatment duration

Keighley 1978

MethodsRCT
ParticipantsCDAD
Interventionsvancomycin (n = 22) versus placebo (n = 22)
Outcomescure
bacteriologic resolution
Notes60% dropouts
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Low riskCentralized randomization by pharmacy
Blinding (performance bias and detection bias)
All outcomes
Unclear riskPatients were blinded, but it was unclear whether the outcome assessor was too
Incomplete outcome data (attrition bias)
All outcomes
High risk52% dropouts; 10/22 in vancomycin group and 13 of 22 in placebo, with additional lost data
Other biasHigh risk

Did not exclude other pathogens in the stool as causes of diarrhoea

Good grouping of patients according to stool testing.

Poor follow up procedures leading to only 4/12 patients having follow up data in treatment arm

Lagrotteria 2006

MethodsRCT
ParticipantsCDAD
Interventionsmetronidazole (n = 20) versus metronidazole plus rifampin (n = 19)
39 randomized
Outcomesresolution of diarrhea within 10 days and relapse within 40 days
Notes0 dropouts
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Randomization was computer generated, and blinded study staff enrolled patients using numbered packages."
Allocation concealment (selection bias)Low risk

Quote: "The sequence of randomization numbers was concealed until the end of the study"

Comment: As study staff were blinded before enrollment, there does not seem to be a source of bias

Blinding (performance bias and detection bias)
All outcomes
High risk

Single-blinded

Quote: "A placebo was not used"

Comment: This could have been placebo controlled although good justification was given"

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts
Other biasHigh riskDid not exclude other pathogens in the stool as causes of diarrhoea

Louie 2009

MethodsRCT
ParticipantsCDAD
InterventionsOPT 80 at 3 doses (100 mg, 200 mg and 400 mg) n = 16 in each group
OutcomesResolution of diarrhoea and abdominal discomfort within the 10 day treatment period without requiring any additional therapy and relapse within 6 weeks of end of treatment
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial used "interactive voice randomization system"
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
High risk"the study was a dose-finding, randomized, open-label study"
Incomplete outcome data (attrition bias)
All outcomes
Low risk4% dropouts not included in analysis
Other biasUnclear risk

Patients with severe disease were excluded and only patients with a primary episode or first relapse were included

Patients were excluded if they had > 24 hrs antibiotic (metronidazole or vancomycin) prior to enrolment

Musher 2006

MethodsRCT
ParticipantsCDAD
InterventionsNitazoxanide in two doses (n = 44) versus metronidazole (n = 98)
OutcomesResolution of diarrhea at 7 and 31 days and time to resolution
Notes32 dropouts
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "patients were randomized to 1 of 3 groups, in double-blinded fashion"

Comment: No mention is made of how randomization was established

Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind: tablets made to look identical
Incomplete outcome data (attrition bias)
All outcomes
High risk23% dropouts, groups not specified
Other biasHigh riskDid not exclude other pathogens in the stool as causes of diarrhoea

Musher 2009

MethodsRCT
ParticipantsCDAD
InterventionsVancomycin 125 mg 6 hourly (n = 27) versus nitazoxanide 500 mg 12 hourly (n = 22)
Outcomes

Complete resolution of symptoms and signs attributable to C difficile within 3 days after completion of therapy

Relapse

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Low riskCentralized randomization (randomization codes held by study sponsor)
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, double-dummy: all patients had active and placebo tablets for the duration of the study
Incomplete outcome data (attrition bias)
All outcomes
Low risk2% dropout not included in analysis
Other biasLow riskThe study appears to be free of other sources of bias

Teasley 1983

MethodsRCT
ParticipantsCDAD
Interventionsvancomycin (n = 56) versus metronidazole (n = 45)
Outcomescure
bacteriologic resolution
Notesno relapse data
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low risk7% dropouts; 4 from vancomycin group and 3 from metronidazole group
Other biasHigh risk

Did not exclude other pathogens in the stool as causes of diarrhoea

Also unclear as to which patients had original antibiotic removed

Wenisch 1996

MethodsRCT
ParticipantsCDAD
Interventionsvancomycin versus metronidazole versus teicoplanin versus fusidic acid. N for each group a bit unclear as 126 randomized and 7 dropped out, leaving the specified numbers for analysis.
Outcomescure
bacteriologic resolution
relapse
Notescost data presented
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "patients were randomized according to a table of random numbers"
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
High riskNo mention of blinding of patients or outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk5.5% dropouts, groups not specified
Other biasHigh risk

Did not exclude other pathogens in the stool as causes of diarrhoea

Did exclude patients with no WBCs in stool sample "to insure inclusion of patients with significant disease due to C. difficile"

Did however explicitly report that original offending antibiotic had been stopped

Wullt 2004

MethodsRCT
ParticipantsCDAD
Interventionsfusidic acid (n = 67) versus metronidazole (n = 64)
131 randomized
Outcomescessation of diarrhea and conversion to toxin (-)
Notes17 dropouts
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "An independent statistician provided a computer-generated list of random set numbers"
Allocation concealment (selection bias)Low riskQuote: "the investigator teams were unaware of the treatment allocation"
Blinding (performance bias and detection bias)
All outcomes
Low riskAll medication packs were coded and contained identical-looking pills.
Incomplete outcome data (attrition bias)
All outcomes
High risk26% dropouts; 20/67 in fusidic acid group and 14/64 from metronidazole group
Other biasHigh riskDid not exclude other pathogens in the stool as causes of diarrhoea

Young 1985

MethodsRCT
ParticipantsCDAD
Interventionsvancomycin versus bacitracin; 21 in each group
Outcomescure
bacteriologic resolution
relapse
Notescost data presented
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskPatients blinded but unclear whether assessors were too - although the abstract reports it was double-blind
Incomplete outcome data (attrition bias)
All outcomes
Low riskno dropouts
Other biasLow riskControls for diarrhoea resolution on removal of offending antibiotic

Zar 2007

MethodsRCT
ParticipantsCDAD
Interventionsvancomycin (n = 82) versus metronidazole (n = 90)
Outcomes

cessation of diarrhoea

conversion to C. difficile toxin A negative stool

relapse at 21 days post cure

Notes12.5% dropout, but achieved power
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "a member of pharmacy staff randomized participants by selecting a card from a sealed envelope..."
Allocation concealment (selection bias)Low riskCentralized randomization by pharmacy using sealed envelope
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "patients received either vancomycin liquid and a placebo tablet that was similar in appearance to metronidazole or a metronidazole tablet and an unpleasantly-flavored placebo liquid"
Incomplete outcome data (attrition bias)
All outcomes
Low risk13% dropouts, missing outcome data balanced in numbers across intervention groups with similar reasons for missing data across groups
Other biasUnclear risk

No patients with suspected or life-threatening intraabdominal complications (perforation or obstruction) were included

No patients in ITU or with pseudomembranous colitis were included

Unclear whether prior antibiotics had been stopped

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Johnson 1992Participants were asymptomatic carriers of Clostridium difficile without diarrhea
Louie 2006RCT with a non antibiotic arm (tolevamer)
Lowy 2010Does not compare two antibiotics and focuses on the recurrence of Clostridium difficile rather than treatment of the existing infection
Mattila 2008RCT with a non antibiotic arm (Clostridium difficile immune whey)
McFarland 2002Non-randomized study
Noren 2006Publication of antibiotic resistance development from a group previously reported by Wullt2004.
Numan 2007Assessment of immune whey efficacy