Efficacy and Safety of Metronidazole

Monotherapy versus Vancomycin

Monotherapy or Combination Therapy
in
Patients with Clostridium difficile
Infection: A
Systematic Review and Meta-Analysis
Rui Li1, Laichun Lu2, Yu Lin1, Mingxia Wang1, Xin Liu1*
1 College of Pharmacy, Chongqing Medical University, Chongqing, China, 2 Department of
Pharmacy, Third
Affiliated Hospital, Third Military Medical University, Chongqing, China
* liuxin8829@sina.com

Abstract
Background
La infeccin con Clostridium difficile ha llegado a ser un problema epidemiolgico
global tanto para pacientes hospitalizados como para pacientes ambulatorios.
Los medicamentos ms comnmente usados para tratar CDI son el metronidazol
y la vancomicina. El propsito de este estudio fue comparar la eficacia y
seguridad de la monoterapia de metronidazol con la monoterapia de vancomicina
y la terapia combinada en pacientes CDI.

Methods
A comprehensive search without publication status or other restrictions was
conducted.
Studies comparing metronidazole monotherapy with vancomycin monotherapy or
combination
therapy in patients with CDI were considered eligible. Meta-analysis was
performed
using the Mantel-Haenszel fixed-effects model, and odds ratios (ORs) with 95%
confidence
intervals (95% CIs) were calculated and reported.
Se llev a cabo una bsqueda exhaustiva sin restricciones de status de
publicacin u otras restricciones. Se consideraron elegibles los estudios que
comparan la monoterapia de metronidazol con la monoterapia de vancomicina o
con la terapia combinada en pacientes con CDI. El metanlisis se realiz
utilizando el modelo de efectos fijos de Mantel-Haenszel, y se calcularon e
informaron odds ratios (OR) con intervalos de confianza del 95% (IC del 95%).

Results
Of the 1910 records identified, seventeen studies from thirteen articles (n = 2501
patients)
were included. No statistically significant difference in the rate of clinical cure was
found
between metronidazole and vancomycin for mild CDI (OR = 0.67, 95%CI (0.45,
1.00), p =
0.05) or between either monotherapy and combination therapy for CDI (OR =
1.07, 95%CI
(0.58, 1.96), p = 0.83); however, the rate of clinical cure was lower for
metronidazole than for
vancomycin for severe CDI (OR = 0.46, 95%CI (0.26, 0.80), p = 0.006).
De los 1910 registros identificados, se incluyeron 17 estudios llevados a cabo en
los 13 artculos elegidos (ms de un estudio en algunos artculos) (n=2501
pacientes). No se encontr diferencia estadsticamente significativa en la tasa de
curacin clnica entre el metronidazol y la vancomicina para CDI leve ((OR =
0.67, 95%CI (0.45, 1.00), p = 0.05) o entre cualquier monoterapia y la terapia
combinada para CDI. (OR = 1.07, 95%CI (0.58, 1.96), p = 0.83), sin embargo la
tasa de curacin clnica fue ms baja con el metronidazol que con la vancomicina
para CDI severa. (OR = 0.46, 95%CI (0.26, 0.80), p = 0.006).

No statistically significant difference in the rate of CDI recurrence was found

between metronidazole and vancomycin for mild CDI (OR = 0.99, 95%CI (0.40,
2.45), p = 0.98) or severe CDI (OR = 0.98, 95% CI (0.63, 1.53), p = 0.94) or
between either monotherapy and combination therapy for CDI (OR = 0.91, 95%CI
(0.66, 1.26), p = 0.56).
No se encontr diferencia estadsticamente significativa en cuanto a la tasa de
recurrencia de CDI entre el metronidazol y la vancomicina para CDI leve (OR =
0.98, 95% CI (0.63, 1.53), p = 0.94) o entre cualquier monoterapia vs. la terapia
combinada para CDI (OR = 0.91, 95%CI (0.66, 1.26), p = 0.56).
In addition, there was no significant difference in
the rate of adverse events (AEs) between metronidazole and vancomycin (OR =
1.18, 95%
CI (0.80, 1.74), p = 0.41). In contrast, the rate of AEs was significantly lower for
either monotherapy than for combination therapy (OR = 0.30, 95%CI (0.17, 0.51),
p<0.0001).
Adicionalmente no hubo diferencia significativa en la tasa de eventos adversos
entre el metronidazol y la vancomicina. (OR = 1.18, 95% CI (0.80, 1.74), p =
0.41). En contraste, la tasa de eventos adversos fue significativamente ms baja
con cualquier monoterapia en comparacin con la terapia combinada (OR =
0.30, 95%CI (0.17, 0.51), p<0.0001).

Conclusions
Metronidazole and vancomycin are equally effective for the treatment of mild CDI,
but vancomycin is superior for the treatment of severe CDI. Combination therapy
is not superior to monotherapy because it appears to be associated with an
increase in the rate of AEs.
El metronidazol y la vancomicina son igualmente efectivos para el tratamiento de
CDI leve, pero la vancomicina es superior para el tratamiento de CDI severa. La
terapia combinada no es superior a la monoterapia ya que parece estar asociada
con un incremento en la tasa de eventos Adversos.

Introduction
Clostridium difficile is an anaerobic, gram-positive, spore-forming bacillus[1]. The
incidence
and severity of C. difficile infection (CDI) appear to be on the rise[2], and CDI has
become an epidemiological problem for both hospitalized patients and outpatients
worldwide[2].
Clostridium difficile es un bacilo anaerobio, gram positivo, formador de esporas.
La incidencia y severidad de CID (infeccin por C. difficile) parece estar en
aumento y CDI ha llegado a ser un problema epidemiolgico tanto para los
pacientes hospitalizados como los pacientes ambulatorios (***Un paciente
ambulatorio es aquel que debe acudir regularmente a un centro de salud por
razones de diagnstico o tratamiento pero que no necesita pasar la noche all (es
decir, no queda internado). Por esta razn, tambin se conoce al paciente
ambulatorio como diurno o de da***)
Oral metronidazole is recommended for patients undergoing initial therapy and for
those
with mild infections, whereas oral vancomycin is recommended for seriously ill
patients.
El metronidazol oral se recomienda para pacientes sometidos a tratamiento inicial
y para aquellos con infecciones leves, mientras que la vancomicina oral se
recomienda para pacientes gravemente enfermos.

Furthermore, the combination of oral vancomycin and intravenous metronidazole

is suggested for the treatment of severe or complicated infections[3,4]. As risk of
the development of vancomycin- resistant enterococci (VRE) associated with both
metronidazole and vancomycin treatment has emerged[5], studies examining
fidaxomicin[6,7], rifaximin[8,9], rifampin[10], nitazoxanide[
11,12], tolevamer[13], and teicoplanin[14] therapies have been performed.

Adems, se sugiere la combinacin de vancomicina oral y metronidazol

intravenoso para el tratamiento de infecciones graves o complicadas. Dado que
ha surgido el riesgo de desarrollar enterococos resistentes a la vancomicina
(VRE) asociado con el tratamiento con metronidazol y vancomicina, se han
realizado estudios que examinan las terapias de Fidaxomicina, rifaximina,
rifampicina, nitazoxanuro, tolevamer y teicoplanina.

Furthermore, in patients with recurrent CDI, infusion of donor feces has resulted
in improved treatment outcomes. In particular, patients with multiple relapses of
CDI have benefited from this approach [15]. Unfortunately, prospective clinical
trials of most of the above-mentioned antibiotics evaluating their applicability for
general use have not yet been performed[4], and several questions regarding
fecal transplantation remain unanswered; for example, the optimal protocol for
donor feces infusion is unknown[15]. Therefore, the treatment of CDI has relied
primarily on metronidazole and vancomycin[16].
Adems, en pacientes con CDI recurrente, la infusin de heces de donante ha
dado mejores resultados del tratamiento. En particular, pacientes con mltiples
recadas de CDI se han beneficiado de esta aproximacin. Desafortunadamente,
todava no se han realizado ensayos clnicos prospectivos de la mayora de los
antibiticos antes mencionados que evalen su aplicabilidad para uso general y
varias preguntas sobre el trasplante fecal permanecen sin respuesta; Por
ejemplo, se desconoce el protocolo ptimo para la infusin de heces de
donantes. Por lo tanto, el tratamiento del CDI se ha basado principalmente en
metronidazol y vancomicina.

Although the Healthcare Epidemiology of America (SHEA)/Infectious Diseases

Society of
America (IDSA) guidelines recommend the use of oral vancomycin for severe
CDI, this recommendation is based on the results of few clinical trials[17,18]. In
addition, despite the frequent use of combination therapy in clinical settings, it is
unclear whether combination therapy is more effective than monotherapy
because, as emphasized by the European Society of Clinical Microbiology and
Infectious Diseases (ESCMID)[4], few randomized controlled trials (RCTs) have
been performed to compare them. Moreover, the many associated adverse
events (AEs) [16] necessitate safety analyses of these two drugs. To address this
knowledge gap, we performed a systematic review and meta-analysis to compare
the efficacy and safety of metronidazole monotherapy with vancomycin
monotherapy and combination therapy for the treatment of patients with CDI.
Aunque las directrices de la SHEA / IDSA recomiendan el uso de vancomicina
oral para CDI grave, esta recomendacin est basada en los resultados de pocos
ensayos clnicos. Adicionalmente, a pesar del uso frecuente de la terapia
combinada en la prctica clnica, no est claro si la terapia combinada es ms
eficaz que la monoterapia porque, como subray la Sociedad Europea de
Microbiologa Clnica y Enfermedades Infecciosas (ESCMID), se han realizado
pocos ensayos controlados aleatorios (ECA) para compararlas. Adems, estos
dos frmacos requieren un anlisis de seguridad, debido a los muchos eventos
adversos asociados(AE) a ambos. Para abordar esta brecha de conocimiento, se
realiz una revisin sistemtica y meta-anlisis para comparar la eficacia y la
seguridad de la monoterapia de metronidazol con la monoterapia de vancomicina
y terapia combinada para el tratamiento de pacientes con CDI.

Methods
Our study protocol and analysis were planned in accordance with the Preferred
Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines[19], and
no ethical
approval was needed.
Nuestro protocolo de estudio y anlisis fueron planeados de acuerdo con las
directrices de PRISMA (tems de reporte preferidos para Revisiones sistemticas
y Meta-anlisis) y no fue necesaria una aprobacin tica.

Search strategy
A systematic literature search of the following electronic databases was
conducted to identify relevant literature published in English or Chinese before
November 2014: PubMed, Embase, Web of Science, and Cochrane Library.
Three Chinese language databasesChina National Knowledge Infrastructure
(CNKI; available at www.cnki.net), Chinese Scientific Journals Database (VIP;
available at www.cqvip.com), and WANFANG DATA (available at www.
wanfangdata.com.cn)were also searched. The search strategy included the
following medical subject headings and key words: pseudomembranous
enterocolitis, antibiotic-associated diarrhea, antibiotic-associated colitis,
Clostridium difficile, metronidazole, and vancomycin.
Se realiz una bsqueda bibliogrfica sistemtica de las siguientes bases de
datos electrnicas para identificar la literatura relevante publicada en ingls o
chino antes de noviembre de 2014: PubMed, Embase, Web of Science, y la
biblioteca Cochrane Library. Adems, se busc en 3 bases de datos en chino
(China National Knowledge Infrastructure (CNKI; available at www.cnki.net),
Chinese Scientific Journals Database (VIP; available at www.cqvip.com), and
WANFANG DATA (available at www. wanfangdata.com.cn)). La estrategia de
bsqueda incluy los siguientes encabezamientos mdicos y palabras clave:
"enterocolitis pseudomembranosa", "diarrea asociada a antibiticos", "colitis
asociada a antibiticos", "Clostridium difficile", "metronidazol" y "vancomicina".

These search terms were combined using Boolean logic as follows: both the
medical subject headings and the terms related to the patient population of
interest (Clostridium difficile, pseudomembranous colitis, antibiotic-associated
diarrhea, and antibiotic-associated colitis) were combined with those describing
interventions (metronidazole OR vancomycin). The complete search strategy
used to search each database is described in S1 Table. Furthermore, the
references in the initially identified articles, including relevant reviews, were
manually searched and reviewed. Academic dissertations and abstracts
presented at scientific conferences were also searched using ProQuest
Dissertation & Theses Database and The Conference and Academic Dissertation
Database of CNKI, respectively, to ensure that no relevant study was missed (up
to May 2015).
Estos trminos de bsqueda se combinaron utilizando la lgica booleana de la
siguiente manera: se combinaron tanto los encabezamientos de las materias
mdicas como los trminos relacionados con la poblacin de pacientes de inters
(Clostridium difficile, colitis pseudomembranosa, diarrea asociada a antibiticos y
colitis asociada a antibiticos) (Metronidazol O vancomicina). La estrategia de
bsqueda completa utilizada para buscar cada base de datos se describe en la
Tabla S1. Adems, las referencias en los artculos inicialmente identificados,
incluidas las revisiones pertinentes, fueron buscadas manualmente y revisadas.
Tambin se realizaron bsquedas de tesis acadmicas y resmenes presentados
en conferencias cientficas utilizando: ProQuest Dissertation & Theses Database
y The Conference and Academic Dissertation Database of CNKI, respectivamente
para asegurar que no se perdi ningn estudio relevante (hasta mayo de 2015).

Study selection
Two reviewers (RL and LCL) assessed all potentially relevant studies and
reached a consensus on all items. They then independently searched the
literature and examined relevant studies to obtain data on the rates of clinical
cure, CDI recurrence and AEs. In the case of disagreement between the two
reviewers, the senior coauthor (XL) was consulted, and the disagreement was
resolved by consensus. Studies were included if they met the following criteria: (1)
contained original data, (2) contained data regarding the use of metronidazole or
vancomycin for the treatment of CDI, (3) contained data regarding clinical
therapeutic outcomes or AEs, and (4) reported on RCTs or case-control studies.
Studies were excluded if they (1) were unrelated to CDI, (2) were duplicate
reports, (3) were not written in English or Chinese, or (4) were not case-control
studies.
Dos revisores (RL y LCL) evaluaron todos los estudios potencialmente relevantes
y llegaron a un consenso sobre todos los tems.A continuacin, buscaron de
forma independiente la literatura y examinaron los estudios pertinentes para
obtener datos sobre las tasas de curacin clnica, recurrencia de CDI y EAs. En
caso de desacuerdo entre los dos revisores, se consult al coautor senior (XL), y
el desacuerdo se resolvi por consenso.
-Los estudios se incluyeron si cumplan los siguientes criterios:
(1) contenan datos originales, (2) contenan datos sobre el uso de metronidazol o
vancomicina para el tratamiento del CDI, (3) contenan datos sobre los resultados
clnicos teraputicos o EAs y (4 ) Informaron sobre ECA o estudios de casos y
controles.
- Se excluyeron los estudios si:
(1) no estaban relacionados con el CDI, (2) eran informes duplicados, (3) no
estaban escritos en ingls o chino, o (4) no eran estudios de casos y controles.

Data extraction (Extraccin de datos)

Two reviewers (RL and LCL) independently abstracted data from each eligible
study. Each
investigator was blinded to the other investigators extracted data. A standardized
form was
used to record the following information: (1) first author; (2) year of publication; (3)
disease
severity (although there were four classifications according to disease severity,
including mild CDI, severe CDI, complicated CDI, and recurrent CDI[3,4], none of
the included studies evaluated complicated CDI, and fecal microbiota
transplantation has been performed for recurrent CDI. Additionally, one included
study referred to mild-moderate because the treatment of mild CDI and
moderate CDI is identical[20], and we categorized this classification of CDI into
the mild CDI group; thus, this systematic review and meta-analysis was primarily
focused on the treatment of mild or severe CDI);
Dos revisores (RL y CL) extrajeron informacin de manera independiente de cada
estudio elegible. Cada investigador desconoca los datos extrados por el otro
investigador. Se utiliz un formulario estandarizado para registrar la siguiente
informacin: (1) primer autor; (2) ao de publicacin; (3) gravedad de la
enfermedad (aunque hubo cuatro clasificaciones segn la gravedad de la
enfermedad, incluyendo CDI leve, CDI severo, CDI complicado y CDI recurrente,
ninguno de los estudios incluidos evalu CDI complicado ni tampoco trasplante
de microbiota fecal para CDI recurrente.Adems, un estudio incluido se refiri a
"leve a moderada", porque el tratamiento de CDI leve y CDI moderado es idntico
[20], y se clasific esta clasificacin de CDI en el grupo CDI leve; por lo tanto esta
revisin sistemtica y metaanlisis se enfoc primariamente en el tratamiento de
CDI leve o severa).

(4) mean age; (5) male (%); (6) follow-up duration; (7) number of enrolled
patients; (8) drug regimen; (9) rate of clinical cure; (10) rate of CDI recurrence;
(11) AEs related to the study medications; (12) case definitions; (13) quality of the
evidence; and (14) overall risk of bias. (4) edad media; (5) (%)masculino ; (6)
duracin del seguimiento; (7) nmero de pacientes inscritos; (8) rgimen de
frmaco; (9) tasa de curacin clnica; (10) tasa de recurrencia del CDI; (11) AEs
relacionados con los medicamentos del estudio; (12) definiciones de caso; (13)
calidad de la evidencia; Y (14) riesgo general de sesgo.
The extracted data (and specifically, the rates of clinical cure and CDI recurrence)
were analyzed based on the intention-to-treat population.
Los datos extrados (y especficamente, las tasas de curacin clnica y
recurrencia CDI) se analizaron sobre la base de la intencin de tratar la
poblacin.

Quality appraisal (Evaluacin de calidad)

The included studies were independently appraised for methodological quality by
two authors (RL and LCL), without blinding to the source journal or authorship.
Discrepancies were resolved by discussion or consultation with the third reviewer
(XL) if required. The quality of each included study was evaluated according to
the modified Jadad score[21]. The overall risk of bias of each included study was
also evaluated[22]. Potential publication bias was assessed by visual inspection
of asymmetry in Beggs funnel plots, and Eggers test was then used to provide
statistical evidence of funnel plot symmetry (p<0.05 indicating bias and p>0.05
not indicating bias)[23,24].
Los estudios incluidos fueron evaluados de manera independiente por los 2
autores (RL y LCL) en trminos de su calidad metodolgica, sin ciego sobre la
revista de origen o autor. Las discrepancias fueron resueltas mediante discusin
o consulta con el tercer revisor (XL), si era necesario. La calidad de cada estudio
incluido se evalu de acuerdo con el puntaje de Jadad modificado. Tambin se
evalu el riesgo global de sesgo de cada uno de los estudios incluidos. El posible
sesgo de publicacin se evalu mediante inspeccin visual de la asimetra en los
diagramas de embudo de Begg, y la prueba de Egger se utiliz para proporcionar
evidencia estadstica de la simetra del diagrama de embudo (p <0,05 indicando
sesgo y p> 0,05 sin indicacin de sesgo)

We also performed sensitivity analyses on subgroups from the studies according

to explicit or inexplicit classification of severity and follow-up duration to explore
underlying sources of heterogeneity. All of these analyses, except for publication
bias analysis (which was performed using STATA software: version 12.0,
StataCorp, College Station, TX, USA), were performed using Review Manager
software (RevMan, version 5.1, Oxford, UK; The Cochrane Collaboration, 2008).
Tambin realiz anlisis de sensibilidad en subgrupos de los estudios de acuerdo
a la clasificacin explcita o implcita de la severidad y la duracin del seguimiento
para explorar las fuentes subyacentes de heterogeneidad. Todos esos anlisis,
excepto el anlisis de sesgo de publicacin (el cual se realiz utilizando el
software STATA: versin 12.0, StataCorp, College Station, TX, EE.UU.), fueron
realizados usando Review Manager software (RevMan, version 5.1, Oxford, UK;
The Cochrane Collaboration, 2008).

Outcomes analyzed (Resultados analizados)

Regarding the outcome measures used to assess efficacy, in this meta-analysis,
the rate of clinical cure was used as the primary outcome measure, and the rate
of CDI recurrence was used as the secondary outcome measure. We present the
following two comparisons based on the rates of clinical cure and CDI recurrence:
a comparison between metronidazole and vancomycin monotherapy for the
treatment of patients with mild or severe CDI and a comparison of vancomycin or
metronidazole monotherapy with combined vancomycin and metronidazole
therapy or either drug combined with another antibiotic for the treatment of
patients with CDI.
Con respecto a las medidas de resultado utilizadas para evaluar la eficacia, en
este metaanlisis se utiliz la tasa de curacin clnica como medida de resultado
primaria y se utiliz la tasa de recurrencia del CDI como medida de resultado
secundaria. Presentamos las siguientes dos comparaciones basadas en las tasas
de curacin clnica y la recurrencia de CDI: 1. una comparacin entre la
monoterapia de metronidazol y de vancomicina para el tratamiento de pacientes
con CDI leve y severa y 2. una comparacin de la monoterapia de metronidazol
o de la monoterapia de vancomicina con la terapia combinada (metronidazol y
vancomicina) o con cualquiera de estas drogas combinada con otro antibitico
para el tratamiento de pacientes con CID.

For the latter comparison, we performed subgroup analysis according to the

therapeutic intervention. AEs were used as the primary safety outcome measure
in this meta-analysis. Here, we also present the following two comparisons based
on AEs: metronidazole vs. vancomycin and monotherapy vs. combination therapy.
We performed subgroup analysis according to AEs for both comparisons.
Para la ltima comparacin se realiz un anlisis de subgrupos de acuerdo con la
intervencin teraputica. Los eventos adversos (AEs) se utilizaron como la
medida primaria de resultado de seguridad en este meta-anlisis.Aqu
presentamos las siguientes dos comparaciones basadas en AEs: metronidazol
vs. vancomicina y la monoterapia vs. la terapia combinada. Se realiz el anlisis
de subgrupos de acuerdo con AEs para ambas comparaciones.

Data analysis and statistical methods (Anlisis de datos y mtodos

estadsticos)
Statistical analysis was accomplished using Review Manager version 5.1
software. Both I2 and Q statistics were considered. In our analyses, we used the
I2 statistic to quantitatively describe heterogeneity across studies.
El anlisis estadstico se realiz utilizando la versin 5.1 del software Review
Manager. Se consideraron las estadsticas I2 ( medida de inconsistencia) y Q. En
nuestro anlisis, se utiliz la estadstica I2 para describir cuantitativamente la
heterogeneidad entre los estudios.

An I2 value of greater than 50% indicated high heterogeneity; a value ranging

from 25% to 50% indicated moderate heterogeneity; and a value of less than 25%
signified low heterogeneity[22]. Pooled odds ratios (ORs; calculated by adding 0.5
to each cell of the 22 table for the trial when one arm of the study contained no
events[25]) and 95% confidence intervals (CIs; if 95% CIs did not include the null
value, the results were considered to be significantly different) were also used in
meta-analysis. The Mantel-Haenszel fixed-effects model was used for analysis of
the total groups because the I2 values in our subgroup metaanalysis ranged from
0% to 6%.
Un valor de I2 superior al 50% indic una alta heterogeneidad; un valor entre
25% y 50% indica una heterogeneidad moderada; y un valor de menos del 25%
signific baja heterogeneidad. La odds Ratio agrupada (ORs; calculado mediante
la adicin de 0,5 a cada celda de la tabla 2 2 para el ensayo cuando un brazo
del estudio no contena eventos) y tambin se usaron intervalos de confianza en
el metaanlisis. (CIs, si IC del 95% no inclua el valor nulo, los resultados se
consideraron significativamente diferentes). El modelo de efectos fijos de Mantel-
Haenszel se us para el anlisis del total de grupos porque los valores de I2 en
nuestro subgrupo de metaanlisis oscilaron entre 0% y 6%.

Results (Resultados)
Search results (Resultados de bsqueda)
A total of 1910 records were identified (Fig 1). After excluding duplicates and
screening the
titles of the studies, 635 articles were reviewed. After screening the abstracts of
these potentially relevant articles, 36 were selected for full-text review based on
relevance to the study topic (Fig 1). Thirteen articles containing seventeen studies
(one article included three separate studies and two articles each included two
separate studies) and 2501 patients were included [10,13,20,2635]. In addition,
we attempted to contact the corresponding authors of five potentially relevant
studies via e-mail. The authors of four studies did not respond to our e-mail
communication [3639], and the corresponding author of the fifth study
communicated that we would require approval by their institutional review board
for additional individual patient data[40]. Therefore, all five studies had to be
excluded from our final set of included studies. Fig 1 shows the selection process
for the studies included in the meta-analysis.
Se identific un total de 1910 registros (Fig 1). Despus de excluir duplicados y
seleccionar los ttulos de los estudios, 635 artculos fueron revisados.Despus de
seleccionar los resmenes de estos artculos potencialmente relevantes, 36
fueron seleccionados para la revisin de texto completo basado en la relevancia
para el tema del estudio (Fig 1). Trece artculos que contenan diecisiete estudios
(un artculo incluy tres estudios separados y dos artculos, cada uno incluy dos
estudios separados) y 2501 pacientes fueron incluidos [10, 13, 20, 26 - 35].
Adems, tratamos de contactar a los autores correspondientes de cinco estudios
potencialmente relevantes por correo electrnico. Los autores de cuatro estudios
no respondieron a nuestra comunicacin por correo electrnico [36-39], y el autor
correspondiente del quinto estudio comunic que requeriramos la aprobacin de
su junta de revisin institucional para datos adicionales del paciente individual
[40]. Por lo tanto, los cinco estudios tuvieron que ser excluidos de nuestro
conjunto final de estudios incluidos Fig. 1 muestra el proceso de seleccin de los
estudios incluidos en el metanlisis.
Study quality assessment and risk of bias assessment (Evaluacin de la
calidad del estudio y evaluacin del riesgo de sesgo)
Using the modified Jadad score (S2 Table), the results of the quality assessment
of each included study indicated that five studies were of high quality
[10,13,26,27,33] and that the remaining eight studies were of moderate quality
[20,2832,34,35] (Table 1, S2 Table). The results of the assessment of the overall
risk of bias for each included study indicated that three reports exhibited a low risk
of bias [10,13,26] and that the remaining ten reports exhibited an unclear risk of
bias [20,2735] (Table 1, S1 Fig). The main characteristics of the included studies
are shown in Table 1.
Utilizando el puntaje de Jadad modificado (Tabla S2), los resultados de la
evaluacin de calidad de cada estudio incluido indicaron que cinco estudios
fueron de alta calidad [10,13,26,27,33] y que los restantes ocho estudios fueron
de calidad moderada [ 20,28 - 32,34,35] (Tabla 1, Tabla S2). Los resultados de la
evaluacin del riesgo global de sesgo para cada estudio incluido indic que tres
informes exhibieron un bajo riesgo de sesgo [10, 13, 26] y que los diez informes
restantes presentaron un riesgo poco claro de sesgo [20, 27-35 ] (Tabla 1, Fig.
S1). Las principales caractersticas de los estudios incluidos se muestran en la
Tabla 1.
Efficacy outcomes (Resultados de la eficacia)
Rate of clinical cure. Regarding the comparison of metronidazole with
vancomycin, the meta-analysis results suggested that there was no significant
difference in the rate of clinical cure for the treatment of mild CDI (5
studies[13,20,26,31,32], 703 patients, OR = 0.67, 95% CI (0.45, 1.00), p = 0.05,
I2 = 0%) (Fig 2A). However, the rate of clinical cure was lower for metronidazole
than for vancomycin for the treatment of severe CDI (4 studies[13,20,26,29], 324
patients, OR = 0.46, 95% CI (0.26, 0.80), p = 0.006, I2 = 0%) (Fig 2B). Regarding
the comparison of monotherapy with combination therapy, three articles were
included[10,33,35], and the cases were divided into three subgroups according to
therapeutic intervention used. The metaanalysis results did not show a significant
difference in the rate of clinical cure between monotherapy and combination
therapy (4 studies (one article included two separate studies[35]), 190 patients,
OR = 1.07, 95% CI (0.58, 1.96), p = 0.83, I2 = 0%) (Fig 2C).

Rate of CDI recurrence. Regarding the comparison of metronidazole with

vancomycin,
the meta-analysis results did not show any significant difference in the rate of CDI
recurrence for the treatment of mild CDI (4 studies[20,26,27,32], 276 patients, OR
= 0.99, 95% CI (0.40, 2.45), p = 0.98, I2 = 6%) (Fig 3A) or severe CDI (4
studies[20,26,28,29], 430 patients, OR = 0.98, 95% CI (0.63, 1.53), p = 0.94, I2 =
0%) (Fig 3B). Regarding the comparison of monotherapy with combination
therapy, five articles were included[10,28,3335], and the cases were divided into
three subgroups according to the therapeutic intervention. The meta-analysis
results did not show any significant difference in the rate of CDI recurrence
between monotherapy and combination therapy (8 studies (three articles each
included two separate studies [28,34,35]), 804 patients, OR = 0.91, 95% CI (0.66,
1.26), p = 0.56, I2 = 0%) (Fig 3C).

Safety outcomes
AEs. The reported AEs from the included studies consisted of death, colectomy,
diarrhea,
any complication, ileus, colonic perforation, nausea and vomiting,
pseudomembranous colitis,
toxic megacolon, rash and severe enterocolitis. We performed subgroup analysis
according to
the AEs. The meta-analysis results did not show any significant difference in the
rate of AEs
between metronidazole and vancomycin (the results from 7 studies were
separated into six subgroups[
13,20,2630], 1330 patients, OR = 1.18, 95% CI (0.80, 1.74), p = 0.41, I2 = 0%)
(Fig 4A).
However, the rate of AEs was significantly lower for monotherapy than for
combination therapy (the results from 3 studies were separated into eight
subgroups [10,28,33], 439
patients, OR = 0.30, 95% CI (0.17, 0.51), p<0.0001, I2 = 0%) (Fig 4B); in fact, this
rate was
more than 4-fold higher for combination therapy than for monotherapy (46.9%
vs.11.1%).
Publication bias and sensitivity analyses
The shape of Beggs funnel plot and the Eggers test results (all p>0.05) did not
demonstrate
any evidence of publication bias (S1 File). Considering that meta-analysis showed
little heterogeneity
(I2 = 6%) between the studies for the comparison of the rate of CDI recurrence
between
metronidazole and vancomycin. Thus, we conducted sensitivity analyses of the
subgroups
from these studies according to explicit or inexplicit classifications of severity and
follow-up
duration to explore underlying sources of heterogeneity. These analyses showed
that the primary
results were not influenced by the inexplicit classification of severity or by the
follow-up
durations (S2 File).

Discussion
The aim of this study was to compare the efficacy and safety of metronidazole
monotherapy with vancomycin monotherapy and combination therapy in CDI
patients. Based on the analyses according to disease severity and the treatment
methods used, this study has revealed that metronidazole and vancomycin are
equally effective for the treatment of mild CDI but that vancomycin is superior for
severe CDI. Additionally, these findings suggest that combination therapy is not
superior to monotherapy.
El propsito de este estudio fue comparar la eficacia y la seguridad de la
monoterapia de metronidazol con la terapia de vancomicina y la terapia
combinada en pacientes con CDI. Basado en el anlisis de acuerdo a la
severidad de la enfermedad y los mtodos de tratamiento utilizados, este estudio
ha revelado que el metronidazol y la vancomicina son igualmente efectivos para
el tratamiento de CDI leve pero que la vancomicina es superior para CDI severa.
Adicionalmente, esos hallazgos sugieren que la terapia combinada no es superior
a la monoterapia.

Regarding efficacy, the results of this meta-analysis demonstrated that the

treatments were
equivalent for mild disease but not for severe disease. Moreover, regarding the
cost of the medications, metronidazole is less expensive than vancomycin[41],
and oral vancomycin may be more likely to promote the generation and
overgrowth of VRE than metronidazole[5]. As a result, metronidazole is
recommended for treating mild CDI, and vancomycin is recommended for treating
severe CDI. This meta-analysis also demonstrated that combination therapy
might not be more effective than monotherapy.
En cuanto a la eficacia, los resultados de este meta-anlisis demostraron que los
tratamientos fueron equivalentes para la enfermedad leve pero no para la
enfermedad grave. Por otra parte, con respecto al costo de los medicamentos, el
metronidazol es menos costoso que la vancomicina, y la vancomicina oral puede
ser ms propensa a promover la generacin y el crecimiento excesivo de VRE
que el metronidazol. Como resultado, se recomienda el metronidazol para tratar
el CDI leve, y se recomienda la vancomicina para tratar el CDI grave. Este meta-
anlisis tambin demostr que la terapia combinada podra no ser ms eficaz que
la monoterapia.

Regarding safety, although there was no statistically significant difference in the

rate of AEs between metronidazole and vancomycin, there was an increase in the
rate of AEs in association with combination therapy, and the combination therapy
group experienced more fatal AEs, such as death and complications.
Con respecto a la seguridad, aunque no hubo diferencias estadsticamente
significativas en la tasa de EA entre el metronidazol y la vancomicina, hubo un
aumento en la tasa de AE en asociacin con la terapia combinada y el grupo
tratado con terapia combinada experiment Eventos adversos ms fatales, como
la muerte y complicaciones .

Therefore, monotherapy appears to be safe and well tolerated. Nonetheless, it is

worth mentioning that because of the limited number of included studies, we did
not compare monotherapy with combination therapy for all four categories of
disease severity. Moreover, our results may have been influenced by the medical
conditions or treatment (e.g., nasogastric feeds[10]) of the patients receiving
combination therapy, who may have suffered from more serious illnesses than
those receiving monotherapy; therefore, these influences may have been
associated with the increased risk of experiencing AEs or developing
complications among those receiving combination therapy.
Por lo tanto, la monoterapia parece ser segura y bien tolerada. Sin embargo, vale
la pena mencionar que debido al nmero limitado de estudios incluidos, no
comparamos la monoterapia con la terapia combinada para las cuatro categoras
de severidad de la enfermedad.Por otra parte, nuestros resultados pueden haber
sido influenciados por las condiciones mdicas o el tratamiento de los pacientes
que recibieron terapia de combinacin, que pueden haber sufrido de
enfermedades ms graves que aquellos que recibieron monoterapia; por lo tanto,
estas influencias pueden haber sido asociadas con el riesgo aumentado de:
experimentar eventos adversos o de desarrollar complicaciones, entre aquellos
que recibieron terapia de combinacin.

Our study has several limitations. First, although the quality of the majority of the
studies was high or medium and although the total sample size was sufficient, the
sample size of each subgroup was relatively small and was thus susceptible to
false-positive or false-negative results. Second, although sensitivity analyses
indicated that the primary results were not influenced by the inexplicit
classification of severity or by the follow-up duration, we roughly determined
disease severity based on the proportion of patients, which potentially resulted in
bias. For example, if 77% of the patients had mild CDI[27], we categorized all of
the patients into the mild CDI group.
Nuestro estudio tiene varias limitaciones. En primer lugar, aunque la calidad de la
mayora de los estudios fue alta o media y aunque el tamao total de la muestra
fue suficiente, el tamao de la muestra de cada subgrupo era relativamente
pequeo y, por lo tanto, fue susceptible a resultados falsos positivos o falsos
negativos. En segundo lugar, aunque los anlisis de sensibilidad indican que los
resultados primarios no estaban influenciados por la clasificacin implcita de la
severidad o por la duracin del seguimiento, nosotros determinamos
aproximadamente la gravedad de la enfermedad basndonos en la proporcin de
pacientes, lo cual potencialmente result en sesgo. Por ejemplo, si 77% de los
pacientes tenan CDI leve, se clasific a todos los pacientes en el grupo de CDI
leve.

Moreover, the follow-up duration for CDI treatment varied greatly (from 312
weeks) among the different studies, which may have resulted in bias. Third,
because very few articles presented research on combination therapy, we could
not compare the subgroups according to disease severity between monotherapy
and combination therapy; therefore, the general patient conditions may have
caused prescription bias.
Por otra parte, la duracin de seguimiento para el tratamiento de CDI vari en
gran medida (de 3 a 12 semanas) entre los diferentes estudios, lo que puede
haber llevado a sesgo. En tercer lugar, debido a que muy pocos artculos
presentaban investigacin sobre la terapia combinada, no pudimos comparar los
subgrupos de acuerdo a la severidad de la enfermedad entre la monoterapia y la
terapia combinada; Por lo tanto, las condiciones generales del paciente pueden
haber causado sesgo de prescripcin.

Fourth, only studies published in English were included, which might have
rendered the results vulnerable to bias related to language and ethnicity. Fifth,
additional data on combination therapy using other novel antibiotics are needed.
En cuarto lugar, solo los estudios publicados en ingls fueron incluidos, lo cual
podra haber rendido los resultados vulnerables a sesgos relacionados con el
idioma y la etnia. En quinto lugar, se necesitan datos adicionales sobre la terapia
de combinacin utilizando otros antibiticos nuevos.

In conclusion, these findings have important clinical implications and support the
recommendations of the current CDI treatment guidelines[3,4]. However,
validation of the routine use of combination therapy may require additional
evidence. To compensate for the shortcomings of our study, further large-scale
clinical trials and well-designed research studies are needed to identify more
effective therapies for patients with CDI.
En conclusin, estos hallazgos tienen importantes implicaciones clnicas y
apoyan las recomendaciones de las actuales directrices para el tratamiento de
CDI. Sin embargo, la validacin del uso rutinario de la terapia combinada puede
requerir evidencia adicional. Para compensar las deficiencias de nuestro estudio,
se necesitan ms ensayos clnicos a gran escala y estudios de investigacin bien
diseados para identificar terapias ms eficaces para los pacientes con CDI.

Supporting Information (Informacin de soporte)

S1 PRISMA Checklist. PRISMA checklist for the meta-analysis.
(DOC)
S1 Fig. Risk of bias summary. Review about each risk of bias item for each
included study.
(TIF)
S1 File. Publication bias.
(DOC)
S2 File. Sensitivity analysis.
(DOC)
S1 Table. Search strategy.
(DOC)
S2 Table. The quality assessment of evidence for each included study by the
modified
JADAD score.
(DOC)

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