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Recurrent Clostridium Difficile
... CDI can present acutely as a single episode or as a chronic illness with recurrences and relapses [12]. Short term outcomes have been extensively studied but little is known about long term outcomes [1,8,[11][12][13]. ...
... CDI can present acutely as a single episode or as a chronic illness with recurrences and relapses [12]. Short term outcomes have been extensively studied but little is known about long term outcomes [1,8,[11][12][13]. Two international single centre studies reported mortality outcomes of CDI at 6 months as 38% [14] and 34% [15]. ...
... For this reason, donors should usually be selected from patients wife, close relatives or immediate vicinity. Thus, new pathogen transfer to the recipient is relatively inhibited (6). The choice of donor for the treatment of the illness has a slightly higher proportion in close relatives (93%) than foreigners (84%). ...
... In a retrospective study involving 18 cases in 2003, patients were treated with fecal transplantation, and each patient received a 30-gram single fecal infusion via nasogastric tube. Significant improvement in symptoms was achieved at 12 to 24 hours after treatment, and treatment success was reported as 94% (6). ...
It is known that intestinal microbiota feeding habits in healthy humans have a direct effect on the formation of intestinal microbiota, while simultaneously playing the most important role in the development of the immune system. Our aim in this study was to investigate the effectiveness of this treatment method. Although there is no consensus on how to prepare a fecal transplantation material, the “Amsterdam protocol” is the most prevalent. The solution prepared according to this protocol is suspended using a filter or steel strainer to remove particles. These suspensions are used by injectors. Different diluent materials have been used in various studies, and it is recommended to use non-bacteriostatic 0.9% saline solution.Fecal transplantation was successfully applied to cases of subjects between 2 and 90 years of age when the work done up to these days was examined. The most common indication in childhood and geriatric population is pseudomembranous enterocolitis; inflammatory bowel disease, irritable bowel syndrome, chronic diarrhea/constipation, solitary rectal ulcer, and other chronic colon ulcers are associated with the gastrointestinal tract in adulthood. Studies demonstrating the efficacy of fecal transplantation are often focused on the treatment of Clostridium difficile infection, which is resistant to treatment or recurrence. Successful results obtained inspired many of the studies that followed fecal transplantation, and now fecal transplantation has been started to treat many diseases such as inflammatory bowel disease, irritable colon syndrome, chronic constipation, and non-alcoholic fatty liver disease, especially pseudomembranous enterocolitis due to C. difficile. If we think that our microbiota is a person-specific organ such as a fingerprint or eye retina, treatment of microbiota diseases will automatically differ from person to person. However, all characteristics such as age, donor selection, post-transplantation process management, environmental factors, especially the diseases that recipients and donors carry, amount of drug given during preparation process, and content of the material to be transplanted show how individualized treatment of fecal transplantation is.
... Clostridium difficile infection (CDI) is a leading cause of nosocomial illness [1]. The incidence and severity of CDI have increased since 2000 in many geographical areas, but not in others [2]. However, an epidemic of CDI has spread from North America into Europe and worldwide associated with a novel strain of ribotype 027 [3]. ...
... Functional disability 6 months before hospitalization was defined as the inability to execute activities of daily living (ADL) that included eating, washing, dressing, using toilet facilities, and/or the ability to move from a chair to a bed. We characterized functional disability as dichotomous variable: Bfull assistance^defined as assistance needed in five or all six ADLs; however, Bsome assistance or independentd efined as assistance needed in (1)(2)(3)(4) or no assistance needed for any ADL. ...
To estimate the rate and identified risk factors for recurrent Clostridium difficile infection (rCDI) in Israel. We conducted a retro-prospective case-control study of all adult (age ≥ 18 years) patients with an initial episode of CDI (iCDI) at Tel Aviv Sourasky Medical Center from January 1, 2012 to December 31, 2014. We collected demographic, clinical, and epidemiological information for patients who were classified as recurrent (cases) and non-recurrent (control) groups. In total, 648 patients with iCDI were identified in the study. During the 36-month study period, 82 (12.7%) patients had at least one rCDI identified. We identified several factors as independent variables significantly associated with recurrent CDI: functional disability, severity of the initial infection, continuous non-Clostridium difficile antibiotic treatment with third-generation cephalosporins or clindamycin, and iCDI treatment with metronidazole and vancomycin; however, neutropenia had high measure of effect as a predictor for rCDI (adjusted odds ratio, 7.9; 95% confidence interval, 1.27–49.58; p = 0.026). The identification of the main modifiable risk factors for recurrent CDI, continuous non-Clostridium difficile antibiotics after diagnosis of the initial infection, and antibiotic treatment with third-generation cephalosporins or clindamycin are critical in reducing the spread of recurrent infection with Clostridium difficile in hospital.
... For this reason, donors should usually be selected from patients wife, close relatives or immediate vicinity. Thus, new pathogen transfer to the recipient is relatively inhibited (6). The choice of donor for the treatment of the illness has a slightly higher proportion in close relatives (93%) than foreigners (84%). ...
... In a retrospective study involving 18 cases in 2003, patients were treated with fecal transplantation, and each patient received a 30-gram single fecal infusion via nasogastric tube. Significant improvement in symptoms was achieved at 12 to 24 hours after treatment, and treatment success was reported as 94% (6). ...
... Rates of CDAD recurrence reported in the literature range from 10% to 50%, but the median rate of recurrence is 21.6%, according to a recent meta-analysis. 5 In patients with a previous history of CDAD, the recurrence rate is markedly higher (it has been reported to be as high as 65%) and can rise with each subsequent episode of CDAD. 6 Prevention of the first episode of recurrent CDAD is therefore of paramount importance to minimize subsequent morbidity, and predicting which patients are at highest risk for recurrence might allow clinicians to address modifiable risk factors. In addition, identifying patients at high risk for recurrence may influence the choice of initial treatment for CDAD. ...
... Once a patient develops a recurrence of CDAD, the risks of subsequent recurrences and relapse are notably higher (as high as 65%) and can rise with each subsequent episode. 6 Accordingly, prevention of the first recurrence of CDAD could represent a meaningful strategy to minimize the costs, morbidity, and mortality associated with CDAD recurrences. The recurrence score prediction tool derived in this study may help identify patients at highest risk for recurrence, who could then be targeted for early interventions to decrease the risk of recurrence. ...
Purpose:
A scoring system for identifying patients at high or low risk for recurrent Clostridium difficile-associated diarrhea (CDAD) is described.
Methods:
A retrospective cohort study was performed using data on adults with CDAD admitted to a 3-hospital system from 2009 to 2014. The primary endpoint was the rate of recurrent CDAD within 60 days of clinical cure of CDAD. Risk factors for CDAD recurrence were identified, and a risk prediction tool was developed using multivariate logistic regression.
Results:
The CDAD cure rate in the study cohort (n = 340) was 92.3%; the 60-day recurrence rate was 16.9%. Five factors were significantly associated with high recurrence risk: presence of CDAD at admission, body temperature of >37.8 °C at admission, leukocytosis, nosocomial CDAD, and abdominal distention on CDAD presentation. From that information a risk prediction tool, the CDAD "recurrence score," was developed (1 point is assigned for each factor present, for a maximum score of 5). Validation testing of the recurrence score indicated an area under the receiver operating characteristic curve of 0.72 (95% confidence interval, 0.65-0.80). A score of ≥2 had a negative predictive value of 91%, while a score of ≥4 had a positive predictive value of 70%.
Conclusion:
If externally validated in future studies, a tool for predicting the risk of recurrent CDAD using data readily available at the time of presentation could allow clinicians to identify patients at high risk for recurrence, address modifiable risk factors, and select tailored treatments to improve patient outcomes.
... 151 Pregunta: ¿Cómo la diarrea asociada a la NE debería ser evaluada en el adulto críticamente enfermos ? [152][153][154][155][156][157] D6. Con base en el consenso de expertos, sugerimos que la NE no sea automáticamente interrumpida por la presencia de diarrea, la alimentación debe ser continuada mientras se evalúa la etiología de la diarrea, en un paciente de UCI para determinar un tratamiento adecuado. ...
... Debe hacerse un esfuerzo para distinguir la diarrea infecciosa de la diarrea osmótica. 157 E. ...
Los Epidemiologos Angela Maria Marin y Erick Valencia, publicadores a nivel internacional de los conocimientos de soporte Metabolico y Nutricional, hacen en este momento una actualización de la literatura medica con la traducción en español de las GUIAS publicadas por la ASPEN en el 2016. Esta traducción es completa y quedan gratis para el pueblo académico." Solo con ciencia y honestidad decimos la verdad"
... [8][9][10] This, tied with an increase in relapse of patients, as well as the reduced effectiveness of frontline treatments, highlights the threat of C. difficile. 11,12 One superior treatment option is fecal microbiota transplants (FMT) which have been shown to prevent recurrence in 80 to 90% of C. difficile infections. 5 FMTs restore diversity and facilitate the engrafting of beneficial bacteria and bacteriophages into a gut microbiome. ...
Vancomycin and metronidazole are commonly used treatments for Clostridioides difficile infection (CDI). However, these antibiotics have been associated with high levels of relapse in patients. Fidaxomicin is a new treatment for CDI that is described as a narrow spectrum antibiotic that is minimally active on the commensal bacteria of the gut microbiome. The aim of this study was to compare the effect of fidaxomicin on the human gut microbiome with a number of narrow (thuricin CD) and broad spectrum (vancomycin and nisin) antimicrobials. The spectrum of activity of each antimicrobial was tested against 47 bacterial strains by well-diffusion assay. Minimum inhibitory concentrations (MICs) were calculated against a select number of these strains. Further, a pooled fecal slurry of 6 donors was prepared and incubated for 24 h with 100 µM of each antimicrobial in a mini-fermentation system together with a no-treatment control. Fidaxomicin, vancomycin, and nisin were active against most gram positive bacteria tested in vitro, although fidaxomicin and vancomycin produced larger zones of inhibition compared to nisin. In contrast, the antimicrobial activity of thuricin CD was specific to C. difficile and some Bacillus spp. The MICs showed similar results. Thuricin CD exhibited low MICs (<3.1 µg/mL) for C. difficile and Bacillus firmus, whereas fidaxomicin, vancomycin, and nisin demonstrated lower MICs for all other strains tested when compared to thuricin CD. The narrow spectrum of thuricin CD was also observed in the gut model system. We conclude that the spectrum of activity of fidaxomicin is comparable to that of the broad-spectrum antibiotic vancomycin in vitro and the broad spectrum bacteriocin nisin in a complex community.
... A avaliação da diarreia infecciosa deve incluir um exame físico abdominal, quantificação de fezes, coprocultura e pesquisa de toxinas para Clostridium difficile (e/ou ensaio de toxina), painel laboratorial de eletrólitos séricos (para avaliar para perdas excessivas de eletrólitos ou desidratação) e revisão diária de medicamentos prescritos. Uma tentativa deve ser feita para distinguir infecções agudas de diarreia osmótica 139,140 . ...
... Within just a month of completing an antibiotic course for an initial episode, almost 15 -30% of the patients will experience a recurrence and, of these, up to 60% will sustain further relapses. 4,5 In addition to being debilitating and undermining the patients' life quality, such relapses pertain to higher mortalities and uprising health care expenditures. 6,7 The commonly employed drugs for treatment of CDIs include vancomycin and fidaxomicin, the former being toxic and the latter being overly expensive (150 times the cost of metronidazole). ...
Clostridioides difficile is a principal cause of hospital-acquired gastrointestinal infections, with sporulation and toxin production being key determinants in the disease pathogenesis. Although infections have been escalating and the complications can be life-threatening, the narrow pipeline of approved therapeutics has not witnessed an equivalent surge. With the unfolding of worrisome mutations and antimicrobial resistance, attention has been drawn to either discovering new therapeutics, or even better, repurposing already available ones. Consequently, this study was undertaken to assess the anti-clostridial activity of auranofin, an anti-rheumatic FDA-approved therapeutic; and baicalin, a natural flavone glycoside with reported anti-microbial potential. In comparison with vancomycin, the in vitro efficacy of auranofin and baicalin was tested against hypervirulent C. difficile (BAA-1870TM). Broth suspensions were prepared with and without the three agents and anaerobically incubated. At 24- and 48-hours post-incubation, serial dilutions were prepared and inoculated onto agar plates. Viable cell counts and viable spore counts were then quantified. Meanwhile, toxin production was assessed via ELISA. At a concentration as low as 3 μg/mL, auranofin demonstrated a potent anti-clostridial activity. Both auranofin and baicalin exhibited a remarkable reduction in C. difficile viable cell counts (P-value 0.03 for each) and spore counts (P-values 0.023 and 0.045 respectively). While auranofin and baicalin proved to be non-inferior to vancomycin as inhibitors of C. difficile growth, both drugs proved to be superior to vancomycin in decreasing the spore counts 48-hours post inoculation. Additionally, auranofin markedly reduced C. difficile toxin production (P-value 0.021); a feature that was deficient in both baicalin and vancomycin. To enrich the currently limited repertoire of anti-clostridial drugs, further research is encouraging to compare between the in vivo efficacy of auranofin and that of baicalin. Both agents represent promising approaches that could address the unfulfilled needs in controlling C. difficile infection.
... A Clostridioides difficile infection (CDI) is a major cause of nosocomial diarrhea, and its recurrence is a challenging issue [1,2]. Recurrence is experienced in up to 30% of the patients with previous CDIs [3]; it contributes to the mortality, morbidity, and increased healthcare costs associated with the disease [4]. Despite the reduced burden of CDI observed in a recent survey conducted in the United States, the incidence rate of recurrence did not change significantly [5]. ...
Background
Diagnosing Clostridioides difficile infection (CDI) is complicated. There have been reports on effects of compliance with anti- C. difficile prescription guidelines on patient outcomes. However, the causes of non-adherence and their impact on outcomes have rarely been explored. Therefore, an investigation on the risk factors for non-adherence with treatment guidelines and their influence on recurrence is important.
Methods
This case–control study was conducted with patients with a positive C. difficile culture from March 2020 to April 2021. We conducted analysis based on treatment categories using factors associated with recurrent CDI as variables. Univariate and multivariable analyses were conducted to identify risk factors for non-adherence with treatment guidelines.
Results
In total, culture positive stool samples from 172 patients were analyzed. Having positive glutamate dehydrogenase antigen (GDH Ag), negative toxin enzyme immunoassay (EIA), and positive nucleic acid amplification test (NAAT) (GDH+/toxin EIA−/NAAT +) results were associated with both under- (adjusted odds ratio [aOR] 3.49 [95% CI 1.62–7.51], p = 0.001) and over-treatment (aOR 0.17 [95% CI 0.06–0.48], p = 0.001). Patients with refractory diarrhea were over treated (aOR 2.71 [95% CI 1.02–7.20], p = 0.046). Patients with an increased risk of CDI recurrence were not over treated.
Conclusions
Our results suggest that non-adherence with CDI treatment guidelines depends on the duration of symptoms and rapid EIA test results. Patients with an increased risk of recurrence were neglected.
... The current paradigm for treating CDI is to administer additional antibiotics, mainly vancomycin and fidaxomicin. Although generally effective against primary CDI, over the past decades, the rate of CDI recurrence has greatly increased due to the emergence of antibiotic-resistant and so-called hypervirulent strains (20-25% relapse) (Loo et al., 2005;Maroo and Lamont, 2006;Blossom and McDonald, 2007;Hu et al., 2009;Johnson, 2009). The pathology of CDI is primarily due to the action of two bacterial secreted exotoxins, toxin A (TcdA) and toxin B (TcdB) (Kuehne et al., 2010). ...
Clostridioides difficile is an enteric bacterium whose exotoxins, TcdA and TcdB, inactivate small GTPases within the host cells, leading to bloody diarrhea. In prior work, our group engineered a panel of potent TcdB-neutralizing designed ankyrin repeat proteins (DARPin) as oral therapeutics against C. difficile infection. However, all these DARPins are highly susceptible to digestion by gut-resident proteases, i.e. trypsin and chymotrypsin. Close evaluation of the protein sequence revealed a large abundance of positively charged and aromatic residues in the DARPin scaffold. In this study, we significantly improved the protease stability of one of the DARPins, 1.4E, via protein engineering. Unlike 1.4E, whose anti-TcdB EC50 increased >83-fold after 1-hour incubation with trypsin (1 mg/ml) or chymotrypsin (0.5 mg/ml), the best progenies-T10-2 and T10b-exhibit similar anti-TcdB potency as their parent in PBS regardless of protease treatment. The superior protease stability of T10-2 and T10b is attributed to the removal of nearly all positively charged and aromatic residues except those directly engaged in target binding. Furthermore, T10-2 was found to retain significant toxin-neutralization ability in ex vivo cecum fluid and can be easily detected in mouse fecal samples upon oral administration. Both T10-2 and T10b enjoy a high thermo- and chemo-stability and can be expressed very efficiently in Escherichia coli (>100 mg/l in shaker flasks). We believe that, in additional to their potential as oral therapeutics against C. difficile infection, T10-2 and T10b can also serve as a new generation DARPin scaffold with superior protease stability.
... C. difficile causes recurrent infections in 15-30% patients [95,96]. Several patients were suffered from a mix of recurrence and reinfection in a huge amount of relapses infections. ...
... C. difficile causes recurrent infections in 15-30% patients (Lübbert et al., 2016;Maroo and Lamont, 2006). Several patients were suffered from a mix of recurrence and reinfection in a huge amount of relapses infections. ...
... C. difficile causes recurrent infections in 15-30% patients (Lübbert et al., 2016;Maroo and Lamont, 2006). Several patients were suffered from a mix of recurrence and reinfection in a huge amount of relapses infections. ...
Clostridium difficile is an important emerging infectious agent and might colonize in digestive tract of
humans. C. difficile exhibits a low level of gene conservation. Consequently, antibiotic therapy result has demonstrated
in 15-30% cases. In the current review we summarized up to date information about the drug resistance genotypes
of C. difficile for the first time. Our study revealed that there was a steady difference among various genotype. Which
demonstrated that mutations in the DNA genes was very common in the antibiotic resistance phenotypes. Together
our data revealed that antibiotic resistivity poses selective pressure on the genome of C. difficile that could lead to more
adoptable drug resistance strains. This study may open a new avenue for the research in understanding the mechanism
of C. difficile adaptation to antibiotics and the development of new antibacterial. However, their further research is
needed to exploring C. difficile genomic diversity changed from molecular typing assays to total-genome sequence
comparisons and comparative genome microarrays.
... In recent decades, there has been a marked increase in the incidence and severity of CDI worldwide [2], and community-acquired CDIs are now more common than hospital-acquired infections [3,4]. Recurrent CDI (R-CDI), defined by the Infectious Diseases Society of America (IDSA) as the presence of diarrhea and a positive C. difficile stool assay within 2-8 weeks of the initial episode, occurs in ~20%-30% of patients with CDI [5,6]. R-CDI is often poorly responsive to treatment and results in the need for additional medications, longer courses of therapy, and increased medical costs, morbidity, and mortality [7]. ...
Background
Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated and health care–associated diarrhea in humans. Recurrent CDI (R-CDI) occurs in ~20%–30% of patients with CDI and results in increased morbidity, mortality, and hospital costs. Genomic analyses have shown overlap of C. difficile isolates from animals and people, suggesting that a zoonotic reservoir may contribute to recurrence. The objective of this study was to determine whether pet ownership is a risk factor for recurrence of CDI.
Methods
We conducted a case–control study among patients with recurrent CDI (cases; n = 86) and patients with nonrecurrent CDI (controls; n = 146). Multivariable logistic regression modeling was used to determine the association between recurrence of CDI and pet ownership while accounting for patient-level risk factors.
Results
Pet ownership was not significantly associated with recurrence of CDI (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.38–2.72; P = 0.965) among all patients (n = 232). However, among the subset of patients with community-associated or community-onset health care facility–acquired CDI (n = 127), increasing contact with pets was increasingly protective against recurrence: for every point increase in a pet contact score (out of 7 possible points), the odds of recurrence decreased by 14% (OR, 0.86; 95% CI, 0.74–1.00; P = 0.051).
Conclusions
Close interactions with pets appear protective against the recurrence of community-acquired CDI. A potential mechanism may involve beneficial contributions to the microbiota of pet owners afflicted with CDI, as has been observed for other conditions such as atopy, obesity, and food allergies. However, more research is needed to understand the interactions between pets, owners, and their microbiota.
... Oral metronidazole or vancomycin has been widely used as primary treatment, with a variable cure rate of 70%-90% in most series, but 15%-30% of patients suffer a recurrence in the following months, 1-3 with higher rates in observational studies. [4][5][6][7] Predictors of recurrence include advanced age, detection of toxin in stool and persistence of diarrhoea beyond the fourth day of treatment 8 along with the presence of hepatic and renal disease, 9 disease severity 10 and concomitant antibiotic therapy. 11 A diverse commensal colonic microbiota is believed to confer resistance to CDI but the common treatments used to date, vancomycin and metronidazole, further deplete the microbiota. ...
Background:
Clostridium difficile infection (CDI) recurs after initial treatment in approximately one in four patients. A single-centre pilot study suggested that this could be reduced using 'follow-on' rifaximin treatment. We aimed to assess the efficacy of rifaximin treatment in preventing recurrence.
Methods:
A multisite, parallel group, randomised, placebo controlled trial recruiting patients aged ≥18 years immediately after resolution of CDI through treatment with metronidazole or vancomycin. Participants received either rifaximin 400 mg three times a day for 2 weeks, reduced to 200 mg three times a day for a further 2 weeks or identical placebo. The primary endpoint was recurrence of CDI within 12 weeks of trial entry.
Results:
Between December 2012 and March 2016, 151 participants were randomised to either rifaximin or placebo. Primary outcome data were available on 130. Mean age was 71.9 years (SD 15.3). Recurrence within 12 weeks was 29.5% (18/61) among participants allocated to placebo compared with 15.9% (11/69) among those allocated to rifaximin, a difference between groups of 13.7% (95% CI -28.1% to 0.7%, p=0.06). The risk ratio was 0.54 (95% CI 0.28 to 1.05, p=0.07). During 6-month safety follow-up, nine participants died in each group (12%). Adverse event rates were similar between groups.
Conclusion:
While 'follow-on' rifaximin after CDI appeared to halve recurrence rate, we failed to reach our recruitment target in this group of frail elderly patients, so the estimated effect of rifaximin lacks precision. A meta-analysis including a previous trial suggests that rifaximin may be effective; however, further, larger confirmatory studies are needed.
... Quizás el tratamiento más específico se puede realizar en el caso de infección por Clostridium dificcile que, de acuerdo con su gravedad, se puede clasificar en leve (no requiere más que la suspensión del antibiótico), moderada (requiere tratamiento con metronidazol) y grave (cuando se requiere realizar el tratamiento con vancomicina) (16,26). ...
La administración de nutrición enteral (NE) se menciona de modo frecuente como causa de aparición de diarrea en el paciente en la Unidad de Cuidados Intensivos (UCI), por lo cual existe la tendencia a disminuir su aporte o incluso suspenderla, conducta que en muchas ocasiones causa un retraso en la recuperación nutricional del paciente, incrementando además el riesgo de infecciones asociadas. Realizamos un estudio descriptivo de serie de casos, realizado en la UCI de la Clínica Reina Sofía entre los meses de julio y octubre de 2015, siendo el principal criterio de inclusión la aparición de diarrea en pacientes a quienes se les inició NE en la UCI. El análisis estadístico se realizó mediante distribuciones de frecuencias absolutas y relativas expresadas en porcentajes. En variables cuantitativas se utilizaron medidas de tendencia central (promedio y mediana) y medidas de dispersión (rango y desviación estándar). La nor- malidad se analizó con el estadístico de Shapiro-Wilks. Hay que agregar que durante el período de estudio se identificaron siete pacientes con NE y episodios de EDA. La edad promedio de los pacientes incluidos fue de 73 años. Sin embargo, en ninguno de los casos se pudo establecer una relación directa entre los episodios de EDA y la administración de nutrición enteral.
... The proportion of patients who have relapsed after an initial CDI is reported to be 15e30% and it is reported that these patients will experience 3 to 10 or more repeated CDI episodes that may continue over a period of years [3]. As a novel approach to the prevention of rCDI, the monoclonal antibodies [bezlotoxumab (bezlo) and actoxumab (acto)] directed against toxins TcdB and TcdA produced by C. difficile were developed. ...
Recurrent Clostridium difficile infection is considered as a significant health care burden. The global study (MODIFY II) of antibody treatment (bezlotoxumab) for the prevention of recurrent C. difficile infection includes Japanese patients (95 subjects); The aim of this subgroup analysis is to report the data obtained from Japanese patients.
Patients with C. difficile infection receiving standard of care antibiotic treatment and a single infusion of bezlotoxumab 10 mg/kg, actoxumab 10 mg/kg + bezlotoxumab 10 mg/kg or placebo. Recurrent C. difficile infection through Week 12 was evaluated. In the Full Analysis Set (93 subjects), 91% were older than 65 years of age and 93% were hospitalized at the time of study entry. The standard of care antibiotic for C. difficile infection was metronidazole for 57 subjects and vancomycin for 36 subjects. The recurrent C. difficile infection rate was 46% in the placebo, 21% in the bezlotoxumab (p = 0.0197) and 28% in the actoxumab + bezlotoxumab group. No additive recurrent C. difficile infection-reducing effect with the addition of actoxumab was demonstrated. There were no events representing safety concern in bezlotoxumab. Among 54 clinical isolates of C. difficile as a baseline culture in Japanese patients, the common ribotypes were 052 (28%), 018 (19%), 002 (15%) and 369 (9%). It showed distinctly different distribution from that in the United States and Europe.
The superior effect of bezlotoxumab 10 mg/kg in the prevention of recurrent C. difficile infection suggests that the agent will be useful in the rapidly aging Japanese society.
... Quizás el tratamiento más específico se puede realizar en el caso de infección por Clostridium dificcile que, de acuerdo con su gravedad, se puede clasificar en leve (no requiere más que la suspensión del antibiótico), moderada (requiere tratamiento con metronidazol) y grave (cuando se requiere realizar el tratamiento con vancomicina) (16,26). ...
The administration of enteral nutrition (EN) is frequently mentioned as a cause of diarrhea in patients in Intensive Care Units (ICUs). Because of this, there is a tendency to reduce the use of EN or to even suspend it which often delays patients nutritional recovery and incurs risks of associated infections. This is a descriptive study of seven patients that was conducted in the ICU of the Clínica Reina Sofía from July to October 2015. The main criterion for inclusion was the occurrence of diarrhea in patients had been started on EN in the ICU. Statistical analyses used distributions of absolute and relative frequencies expressed in percentages. Measures of central tendency (mean and median) and measures of dispersion (range and standard deviation) were used for quantitative variables. The Shapiro-Wilk test was used to analyze normality. During the study period seven patients receiving EN who had episodes of diarrhea were identified. The average age of the patients was 73 years. No direct relationships between episodes of of diarrhea and administration of enteral nutrition could be established
... Spores are arguably the most resilient cellular form known to us; they are hard to eradicate and can accumulate and persist in the environment for long periods of time, without losing viability [16,[44][45][46]. The spore thus has a central role in the persistence of the organism in the environment, infection, recurrence and transmission of the disease [37]. ...
... Highly resistant C. difficile spores shed in the faeces contaminate hospitals and healthcare facilities, which can cause infection though the faecal-oral route, reinfection or recurrence of CDI in patients following germination, and spore outgrowth [2,13]. Therefore, agents reducing C. difficile sporulation and spore outgrowth in the human gastrointestinal tract could effectively control C. difficile infection, transmission and relapse [14,15]. ...
Purpose:
Clostridium difficile is an anaerobic spore-forming pathogen that causes a serious toxin-mediated enteric disease in humans. Therapeutic agents that are capable of reducing C. difficile spore production could significantly minimize the transmission and relapse of C. difficile infections. This study investigated the efficacy of a food-grade, plant-derived compound, carvacrol (CR), in reducing C. difficile spore production, germination and spore outgrowth.
Methodology:
Two hyper-virulent C. difficile isolates (ATCC BAA 1870 and 1805) were grown with or without a sub-inhibitory concentration (SIC) of CR. Total viable counts and heat-resistant spore counts were determined at different time intervals. Moreover, spores and vegetative cells were visualized using phase-contrast microscopy. To determine the effect of CR on C. difficile germination and spore outgrowth, C. difficile spores were seeded in germination medium with or without the SIC and MIC of CR, and spore germination and spore outgrowth were measured by recording optical density at 600 nm. The effect of CR on C. difficile sporulation genes was also investigated using real-time qPCR.
Results:
Carvacrol significantly reduced sporulation in C. difficile and down-regulated critical genes involved in spore production (P<0.05). The SIC or MIC of CR did not inhibit C. difficile spore germination; however, the MIC of CR completely inhibited spore outgrowth.
Conclusion:
The results suggest that CR could potentially be used to control C. difficile by reducing spore production and outgrowth.
... Oral metronidazole or vancomycin has been widely used as primary treatment, with a variable cure rate of 70%-90% in most series, but 15%-30% of patients suffer a recurrence in the following months, 1-3 with higher rates in observational studies. [4][5][6][7] Predictors of recurrence include advanced age, detection of toxin in stool and persistence of diarrhoea beyond the fourth day of treatment 8 along with the presence of hepatic and renal disease, 9 disease severity 10 and concomitant antibiotic therapy. 11 A diverse commensal colonic microbiota is believed to confer resistance to CDI but the common treatments used to date, vancomycin and metronidazole, further deplete the microbiota. ...
Introduction
Clostridium difficile associated diarrhoea (CDAD) is a common nosocomial infection that recurs in more than 1 in 4 cases. Garey et al. found that a course of rifaximin after standard therapy reduced relapse rate though not significantly¹. We aimed to confirm or refute this finding.
Design
A parallel group, randomised, placebo controlled trial in 23 English hospitals.
Funding
NIHR RfPB Grant PB-PG-0110–21041. Norgine supplied drug and placebo without charge.
Population
age ≥18 with resolution of CDAD after treatment with metronidazole or vancomycin. CDAD diagnosis required evidence of toxin production or pseudomembranes at endoscopy. Exclusion criteria: pregnancy or breast feeding; life expectancy <4 weeks; unable to take intervention (hypersensitivity or swallowing disorder);>5 days elapsed since treatment. Randomisation was stratified by hospital using a remote, internet-based system. Participants, clinicians and researchers were blind to allocation.
Intervention
Rifaximin 1200 mg daily for two weeks then 600 mg daily for two weeks, in three divided doses.
Comparator
identical placebo.
Primary Outcome
relapse ≤12 weeks after treatment initiation.
Sample size
The planned sample size was 180 to detect a difference in relapse of 20% (30% placebo, 10% rifaximin) with 80% power, allowing for loss to follow-up of 20%. EudraCT 2012-003205-10; www.clinicaltrials.gov NCT01670149
Results
Recruitment occurred December 2012–March 2015. Of 2157 patients screened, 151 were eligible, willing and randomised before funding limits were reached (74 placebo, 77 rifaximin). Primary outcome data were available on 130. Mean age was 71.9 (SD 15.3). 36% were in-patients at start of intervention. 18/61 (29.5%) on placebo relapsed within 12 weeks compared to 11/69 (15.9%) on rifaximin, a difference between groups of −13.7% (95% CI −28.1% to 0.7%, p=0.06). The risk ratio was 0.54 (95% CI 0.28 to 1.05, p=0.07). During 6 month safety follow up 9 participants died in each group (12%). Adverse event rates were similar between groups.
Conclusion
CDAD relapse rate was 13.7% lower than on placebo. The confidence interval means that lack of effect remains possible but the estimated effect size is similar to Garey’s trial, and those reported for fidaxomicin, with longer follow-up². Age and mortality rate were higher in our trial which may reflect greater similarity to the population at risk. Comparative trials of cost effectiveness should follow.
References
• . Garey et al. J Antimicrob Chemother 2011;66:2850–2855.
• . Crook et al. CID 2012;55(S2):S93–103.
Disclosure of Interest
G. Major: None Declared, L Bradshaw: None Declared, N Boota: None Declared, K Sprange: None Declared, A Jawhari: None Declared, M Diggle: None Declared, A Montgomery: None Declared, R Spiller Conflict with: Norgine Pharmaceuticals Ltd supplied product and comparator free of cost
... 16 Most patients with IBD have sufficient clinical features to be categorized as moderate to severe CDI, warranting vancomycin therapy for initial infection and prolonged vancomycin pulsed-taper or fidaxomicin (Dificid, Merck) for recurrent infections. 17,18 A conditional trials in patients with ulcerative colitis, and antibiotics prevent recurrence of inflammation at previously affected sites in Crohn's disease. 32,33 Cumulatively, these data suggest that bacteria may play a role in the initiation and propagation of IBD, and therapeutic manipulation of the host microbiome may reduce or prevent the intestinal inflammation characteristic of this condition. ...
Fecal microbiota transplantation (FMT) has evolved from a case report in the medical literature to the basis of major innovations in the treatment of Clostridium difficile infection (CDI) and, potentially, inflammatory bowel disease (IBD). In the clinical setting, FMT was noted to significantly lower the risk of recurrent CDI, likely by increasing microbial diversity and altering the metabolic environment in the intestinal tract of recipients. In parallel, advances in the ability to quantify and characterize microbial communities in fecal samples led to the association of IBD with a state of intestinal dysbiosis. Consequently, a number of case series and randomized, controlled trials have evaluated FMT in treating active ulcerative colitis or Crohn's disease. Unlike in CDI, the efficacy of FMT in the treatment of IBD appears to be influenced by a number of factors, including donor microbial profiles, inflammatory burden, and the microbial diversity of the recipient. The therapeutic potential of the microbiome has led to a number of biotechnology and pharmaceutical companies isolating specific strains from healthy stool for use as targeted therapies for IBD in clinical trials. Ongoing studies are likely to determine the missing link between the efficacy of FMT and its impact on microbial communities and mucosal inflammation.
... Although the mechanism of development of recurrent C. difficile infection is not entirely understood, Maroo and Lamont argued that recurrence is more likely to be caused by external reinfection by C. difficile through feco-oral pathway than by reactivation of primary infection [23]. Longer hospital stay of patients with CDAD might additionally expose patients to spores of C. difficile, thus increasing the risk of disease relapse. ...
AIM: The aim of the present paper was to identify prognostic factors for relapse and mortality in patients with hospital-acquired infections caused by Clostridium difficile.
MATERIAL AND METHODS: This study included 133 patients with healthcare facility-associated disease caused by C. difficile. The medical records of all patients with their clinical history and laboratory data were analyzed.
RESULTS: Patients with one onset of disease were 105 (78.9%), 28 (21.1%) experienced a relapse and seven (5.2%) patients not survived infection. The average age in our patients was over 65 years (64.5 years in the survived patients and 78.8 in patient who died, p = 0.01). All of patients had received antibiotic treatment (cephalosporins – 83.4%, aminoglycosides – 21.5% and penicillins – 20.3%) and 40.6% of patients received acid-reducing therapy. There was no difference between patients with one onset of disease/patients with relaps; and survived/died in number of administered antibiotics, duration of administration, administration of acid-reducing treatment or length of hospital stay (p > 0.05). CRP levels were significantly higher in the group of patients who died compared with recovered (p < 0.001).
CONCLUSION: C. difficile-associated diarrhea is a common nosocomial disease with high relapse, and significant mortality rate particularly in the elderly.
... The Spores are resistant to most disinfectants and antibiotics, making them difficult to eliminate both from infected humans and the environment [6,7,8]. As a result, C. difficile spores disseminate readily from person to person and cause high rates of recurrent infections, which can lead to serious illness or even death [9,10]. Although spores are critical to the pathogenesis of C. difficile, their composition and formation remain poorly characterized. ...
Clostridium difficile is an intestinal bacterium that is a major cause of antibiotic associated diarrhoea, representing a major healthcare-associated problem. C. difficile produces highly infective and resistant spores and the infection with C. difficile is now endemic. The Spo0A protein contains a response regulator which plays an important role in sporulation initiation and could be influence other cellular processes. Inactivation of spo0A resulted in inactivation of the kinase which reduces the C. difficile sporulation capacity where it was suggested that this kinase also has a role in sporulation initiation. Here by using bioinformatics tools, spo0A protein in C. difficile can be used as the potential drug target and its structure was determined. Present research identified the same protein in three other more virulent strains namely R20291, 630 and CD196 strains in C. difficile. This spo0A gene encodes for a highly conserved transcriptional regulator protein in all three strains and may play vital role in the process of sporulation. The identified drug target can be used as therapeutic treatment for the development of anti-C.difficile drugs. © 2015, Journal of Chemical and Pharmaceutical Research. All Rights Reserved.
... The estimated recurrence rate of CDI among initially treated CDI patients has been reported to be as high as 35 %, and this increases in the case of hypervirulent BI/NAP1/027 C. difficile infections [23][24][25]. The recurrence rate in Korea, where the prevalent PCR ribotypes are 017 and 018, has been reported to be 10-20 %, lower than in Europe or North America [26,27]. ...
Purpose:
The purpose of this study was to investigate the impact of malignancy and chemotherapy on the clinical and microbiological characteristics of Clostridium difficile infections (CDI).
Methods:
CDI patients with a history of malignancy within 5 years were defined as the cancer group. The characteristics of the patients were compared according to the presence of malignancy.
Results:
Of 580 patients with CDI, 159 (27.4 %) belonged to the cancer group and 421 (72.6 %) to the non-cancer group. More of the patients in the cancer group than those in the non-cancer group had been hospitalized within the prior 2 months (P < 0.001). Leukocytosis was more common in the non-cancer group (P = 0.034), while infection by PCR ribotype 017 strains was more common in the cancer group, with marginal significance (P = 0.07). Recurrence was more frequent in the cancer group (20.4 % vs. 9.5 %, P =0.005) and cancer was an independent risk factor for recurrence of CDI (OR = 2.66, 95 % CI 1.34-5.29, P =0.005). Age also contributed to the recurrence of CDI (OR = 1.03, 95 % CI 1.00-1.06, P =0.026).
Conclusions:
Malignancy and age are independent risk factors for recurrence of CDI. Cancer patients require careful observation for recurrence after treatment of CDI.
... Clostridium difficile is a spore forming, Gram-positive, toxin-producing anaerobe that infects the gut when the natural flora has been disrupted, primarily through use of antibiotics. It is currently the leading cause of nosocomial infection in the United States, surpassing methicillin resistant Staphylococcus aureus (MRSA) [1][2][3]. The Centers for Disease Control and Prevention (CDC) lists C. difficile as one of three urgent threats in the United States and it is estimated to cause approximately 453,000 infections per year with 29,300 related deaths [4]. ...
Clostridium difficile is a gram-positive, spore forming anaerobe that infects the gut when the normal microbiota has been disrupted. C. difficile infection (CDI) in the United States is the most common cause of hospital acquired infection, and the leading cause of death due to gastroenteritis. Patients suffering from CDI have varying symptoms which range from mild diarrhea to pseudomembranous colitis and death. The involvement of the immune response to influence disease severity is just beginning to be investigated. There is evidence that the immune response can facilitate either protective or pathogenic phenotypes, suggesting it plays a multifaceted role during CDI. In addition to the immune response, the microbiota is pivotal in dictating the pathogenesis to CDI. A healthy microbiota effectively inhibits infection by restricting the ability of C. difficile to expand in the colon. Thus, understanding which immune mediators and components of the microbiota play beneficial roles during CDI will be important to future therapeutic developments. This review outlines how the microbiota can modulate specific immune mediators, such as IL-23 and others, to influence disease outcome.
Clostridioides difficile is a major One Health threat as an important gastrointestinal pathogen of both humans and agricultural animals. The C. difficile species can be subdivided into 5 main clades, with Clade 5 currently undergoing speciation from Clades 1-4. Since Clade 5 strains are found more frequently in agricultural animals and can cause zoonotic infections, Clade 5 strains likely have evolved phenotypes that distinguish them from Clade 1-4 strains. Here, we compare the growth properties of Clade 5 strains to Clade 1, 2, and 4 strains using an anaerobic time-lapse microscopy system coupled with automated image analysis. These analyses revealed that Clade 5 strains grow faster than Clade 1, 2, and 4 strains and are more likely to form long chains of cells. Notably, the chaining phenotype was not shared among all Clade 5 strains examined, since 1 of the 9 strains did not form chains. Genomic analyses of the Clade 5 strains revealed that the orientation of the cmr switch, an invertible DNA element controlling the expression of a signal transduction system that regulates chaining, correlates with the propensity of a given Clade 5 strain to form chains. Taken together, Clade 5 strains appear to have distinct growth properties that allow them to inhabit more diverse ecological niches.
Clostridioides difficile colonizes up to 30-40% of community-dwelling adults without causing disease. C. difficile infections (CDIs) are the leading cause of antibiotic-associated diarrhea in the U.S. and typically develop in individuals following disruption of the gut microbiota due to antibiotic or chemotherapy treatments. Further treatment of CDI with antibiotics is not always effective and can lead to antibiotic resistance and recurrent infections (rCDI). The most effective treatment for rCDI is the reestablishment of an intact microbiota via fecal microbiota transplants (FMTs). However, the success of FMTs has been difficult to generalize because the microbial interactions that prevent engraftment and facilitate the successful clearance of C. difficile are still only partially understood. Here we show how microbial community-scale metabolic models (MCMMs) accurately predicted known instances of C. difficile colonization susceptibility or resistance. MCMMs provide detailed mechanistic insights into the ecological interactions that govern C. difficile engraftment, like cross-feeding or competition involving metabolites like succinate, trehalose, and ornithine, which differ from person to person. Indeed, three distinct C. difficile metabolic niches emerge from our MCMMs, two associated with positive growth rates and one that represents non-growth, which are consistently observed across 14,862 individuals from four independent cohorts. Finally, we show how MCMMs can predict personalized engraftment and C. difficile growth suppression for a probiotic cocktail (VE303) designed to replace FMTs for the treatment rCDI. Overall, this powerful modeling approach predicts personalized C. difficile engraftment risk and can be leveraged to assess probiotic treatment efficacy. MCMMs could be extended to better understand personalized engraftment of other opportunistic bacterial pathogens, beneficial probiotic organisms, or more complex microbial consortia.
Fecal microbiota transplantation (FMT) is a successful method for treating recurrent Clostridioides difficile (C. difficile) infection (rCDI) with around 90% efficacy. Due to the relative simplicity of this approach, it is being widely used and currently, thousands of patients have been treated with FMT worldwide. Nonetheless, the mechanisms underlying its effects are just beginning to be understood. Data indicate that FMT effectiveness is due to a combination of microbiological direct mechanisms against C. difficile, but also through indirect mechanisms including the production of microbiota-derived metabolites as secondary bile acids and short chain fatty acids. Moreover, the modulation of the strong inflammatory response triggered by C. difficile after FMT seems to rely on a pivotal role of regulatory T cells, which would be responsible for the reduction of several cells and soluble inflammatory mediators, ensuing normalization of the intestinal mucosal immune system. In this minireview, we analyze recent advances in these immunological aspects associated with the efficacy of FMT.
Introduction
: This study was designed to investigate the molecular epidemiology of Clostridioides difficile in South Korea, and to evaluate the risk factors of rifaximin-nonsusceptible C. difficile infections (CDI).
Methods
: A total of 413 patients with CDI from two sentinel hospitals in South Korea were enrolled in this study. Putative clinical risk factors for CDI were identified using the digital medical records of the patients, and pathogen profiles, including antimicrobial susceptibility, toxin generation, and ribotype, were evaluated for each of the causative C. difficile isolates.
Results
: A total of 81 (19.6%) C. difficile isolates were shown to be rifaximin-nonsusceptible with the most common ribotypes being described as 018 (56.8%, 46/81), 017 (16.0%, n = 13), and 027 (6.2%, n = 5). Rifaximin-nonsusceptible C. difficile isolates exhibited higher nonsusceptibility rates to most of the other drugs tested in this study when compared to the rifaximin-susceptible isolates. Previous history of pulmonary tuberculosis and prior rifaximin treatment were shown to be linked with the occurrence of rifaximin-nonsusceptible CDIs than those with susceptible CDIs.
Conclusions
: The rifaximin-nonsusceptibility rates for the C. difficile isolates identified in this study were reasonably high with most of these resistant strains belonging to either the 018 or 017 RT. The widespread dissemination of these clones may be the result of the antimicrobial selection pressure introduced by the widespread use of rifaximin. These results suggest that a sustainable surveillance program for C. difficile infections and resistance is needed in order to better control CDIs and improve therapeutic efficacy.
Clostridium difficile, now reclassified as Clostridioides difficile, is the causative agent of C. difficile infections (CDI). CDI is particularly challenging in healthcare settings because highly resistant spores of the bacterium can persist in the environment, making it difficult to curb outbreaks. Dysbiosis of the microbiota caused by the use of antibiotics is the primary factor that allows C. difficile to colonize the gut and cause diarrhea and colitis. For this reason, antibiotics targeting C. difficile can be ineffective at preventing recurrent episodes because they exacerbate and prolong dysbiosis. The emergence of antibiotic resistance in C. difficile also presents a significant threat. The diverse array of bacteriophages (phages) that infect C. difficile could offer new treatment strategies and greater insight into the biology of the pathogen. In this review, we summarize the current knowledge regarding C. difficile phages and discuss what is understood about their lifestyles and genomics. Then, we examine how phage infection modifies bacterial gene expression and pathogenicity. Finally, we discuss the potential clinical applications of C. difficile phages such as whole phage therapy and phage-derived products, and we highlight the most promising strategies for further development.
Clostridioides difficile is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal C. difficile infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to C. difficile . Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.
The Gram-positive, spore-forming bacterium, Clostridioides difficile is the leading cause of healthcare-associated infections in the United States, although it also causes a significant number of community-acquired infections. C. difficile infections, which range in severity from mild diarrhea to toxic megacolon, cost more to treat than matched infections, with an annual treatment cost of approximately $6 billion for almost half-a-million infections. These high–treatment costs are due to the high rates of C. difficile disease recurrence (>20%) and necessity for special disinfection measures. These complications arise in part because C. difficile makes metabolically dormant spores, which are the major infectious particle of this obligate anaerobe. These seemingly inanimate life forms are inert to antibiotics, resistant to commonly used disinfectants, readily disseminated, and capable of surviving in the environment for a long period of time. However, upon sensing specific bile salts in the vertebrate gut, C. difficile spores transform back into the vegetative cells that are responsible for causing disease. This review discusses how spores are ideal vectors for disease transmission and how antibiotics modulate this process. We also describe the resistance properties of spores and how they create challenges eradicating spores, as well as promote their spread. Lastly, environmental reservoirs of C. difficile spores and strategies for destroying them particularly in health care environments will be discussed.
Regulatory agencies vary widely in their classification of FMT, with significant impact on patient access. This article conducts a global survey of national regulations and collates existing FMT classification statuses, ultimately suggesting that the human cell and tissue product designation best fits FMT's characteristics and that definitional objectives to that classification may be overcome.
Nutritional assessment and support are often overlooked in the critically ill due to other urgent priorities. Unlike oxygenation, organ dysfunction, infection, or consciousness, there is no consensus of indicators. Making it difficult to evaluate the effectiveness of an intervention. Nevertheless, appropriate nutritional support in the critically ill has been associated with less morbidity and lower mortality. But, nutritional support has been considered an adjunct, for body weight maintenance and to help patients during the inflammatory phase of illness. Thus, it has been assigned a lower priority, compared to mechanical ventilation or hemodynamic stability. Recent findings have shown that nutritional support may prevent cellular injury due to oxidative stress and help strengthen the immune response. Large-scale randomized trials and clinical guidelines have shown a shift from nutritional support to nutritional therapy, with an emphasis on the importance of protein, minerals, vitamins, and trace elements. Nutrition is also important in neurocritically ill patients. Since there are few studies or recommendations with regard to the neurocritical population, the general recommendations for nutritional support should be applied.
Background:
Cancer patients are susceptible to recurrent Clostridium difficile infection (CDI) that is increasing globally, necessitating new approaches to prevent fatal consequences. We examined the clinical characteristics of cancer patients with recurrent CDI (RCDI).
Patients and methods:
A retrospective review of cancer patients with C. difficile-positive test between January 2015 and May 2017 was carried out. CDI was defined as diarrhea and toxigenic C. difficile detection in the stool by nucleic acid amplification test and enzyme immunoassay. Patients having two CDI episodes were categorized as single recurrent CDI (SRCDI), and those having three or more CDI episodes were categorized as multiple recurrent CDI (MRCDI). Treatment failure was defined as the requirement of antimicrobial alteration or repetition.
Results:
We included 170 patients having 270 CDI episodes; 85 patients had non-RCDI, and 85 had RCDI; 14 of them had MRCDI. Previous hospitalization and immunosuppressant use were more frequent in MRCDI group than in SRCDI group (P=0.009 and 0.002, respectively). Physicians treated more SRCDI episodes than MRCDI episodes with metronidazole alone (P=0.017), whereas, more MRCDI episodes needed combination antimicrobials (P=0.072). The mean duration of CDI treatment was longer in the MRCDI group than in the SRCDI group (P=0.030). MRCDI was associated with treatment failure more than SRCDI (P=0.021). The risk for a recurrent episode of CDI was increased in patients who had the following features of the first CDI episode: previous use of antibiotic, NSAID, immunosuppressant, chemotherapy, comorbidities, CDI treatment failure, and severe CDI (P<0.05).
Conclusion:
Risk factors for RCDI in cancer patients are similar to those without cancer, with the exception of chemotherapy that is only given to cancer patients. Long CDI treatment and CDI treatment failure are associated with MRCDI.
Clostridium difficile (C. difficile), an enterobacteria, flourishes and produces potent toxins, toxin A (TcdA) and toxin B (TcdB), after the disruption of the normal colonic microbiota by antibiotic therapy. C. difficile infection (CDI) may induce life-threatening complications such as fulminant colitis through damage of the intestinal wall by the toxins, therefore the prevention of CDI recurrence is the most important in CDI treatment. Bezlotoxumab is a human monoclonal antibody that neutralizes the activity of TcdB directly. The antibody inhibited cytotoxicity by TcdB derived from various ribotypes of C. difficile at a concentration (EC50) of 1/150 or less of the serum concentration (Cmax: 169 μg/mL) in CDI patients at the clinical dose. Moreover the anti-cytotoxicity effects of the antibody were also observed against 81 clinically isolated C. difficile strains (incl. 018 [smz] and 369 [trf]: Japanese prevalent ribotypes; 027: hypervirulent ribotype) obtained in Japan and western countries. The antibody prolonged survival time of hamster and rat CDI models in a dose-dependent manner. In clinical phase III studies (MODIFY I and II), the recurrence rate of CDI up to 12 weeks after administration of the bezlotoxumab group was significantly lower (P<0.0001) than the placebo group. Bezlotoxumab is the world's first drug with an indication for reduce recurrence of CDI. In Japan, bezlotoxumab was approved for marketing in September, and launched in December in 2017. Bezlotoxumab is effective for broad ribotypes of C. difficile, therefore it expects to contribute to CDI treatment through the reduce recurrence of the CDI.
Clostridium difficile infection (CDI), a common cause of hospital-acquired infections, typically occurs after disruption of the normal gut microbiome by broad-spectrum antibiotics. Fidaxomicin is a narrow-spectrum antibiotic that demonstrates reduced impact on the normal gut microbiota and is approved for the treatment of CDI. To further explore the benefits of this property, we used a murine model to examine the effects of fidaxomicin versus vancomycin on gut microbiota and susceptibility to C. difficile colonization while tracking microbiota recovery over time.
Mice were exposed to fidaxomicin or vancomycin by oral gavage for 3 days, and subsequently challenged with C. difficile spores at predetermined time points up to 21 days post-antibiotic exposure. Fecal samples were subsequently collected for analysis. Twenty-four hours post-challenge, mice were euthanized and colon contents harvested. The microbiota was characterized using 16S rDNA gene sequencing.
All fidaxomicin exposed mice (except for one at Day 8) were resistant to C. difficile colonization. However, 9 of 15 vancomycin exposed mice were susceptible to C. difficile colonization until Day 12. All vancomycin exposed mice recovered colonization resistance by Day 16. Bacterial diversity was similar prior to antibiotic exposure in both arms and decreased substantially after exposure. A shift in taxonomic structure and composition occurred after both exposures; however, the shift was greater in vancomycin- than in fidaxomicin-exposed mice.
In summary, compared with vancomycin, fidaxomicin exposure had less impact on microbiota composition, promoted faster microbial recovery and had less impact on loss of C. difficile colonization resistance.
Despite major advances made in modern medicine over the past century, evaluation of diarrheal symptoms remains one of the most common reasons for referral to gastroenterologists. Regardless of the commonality of this condition, establishing an etiology remains challenging largely because of the extensive differential diagnosis. Therefore, a step-wise approach is essential and begins with a focus on symptom onset and duration in order to differentiate between an acute or chronic process. Identification of historical clues and physical findings help guide further testing, which ultimately leads to establishment of a diagnosis or ruling out of specific disorders. This chapter focuses on the causes of acute and chronic diarrhea followed by suggested diagnostic approaches and management options.
Enteric infections are a major cause of morbidity and mortality worldwide including 800 000 deaths, or 10.5% of all childhood deaths under 5 years of age. This chapter provides an overview of diagnostic considerations for all patients with diarrhea focusing on microbiological assessments, specific and nonspecific therapies, and general preventive measures. We then discuss the history, epidemiology, pathogenesis, clinical aspects, complications, diagnosis, and treatment of a diversity of bacterial and viral gastrointestinal pathogens including tradition and emerging pathogens.
Fecal microbiota transplantation (FMT) is a relatively simple, promising treatment for recurrent Clostridium difficile infection. While there are a wide variety of approaches including mode of delivery, the results are nonetheless encouraging, even amongst younger children. Experience with FMT in the pediatric population is increasing, showing similar success compared to adults. This article will provide an overview of C. difficile infection along with review of the rationale, methods and complications of FMT including the current experience of FMT in children.
In diesem Jahr jährt sich die Erstbeschreibung von Escherichia coli Nissle 1917 zum hundertsten Mal — ein guter Anlass, das Thema Probiotika auf seine wissenschaftliche Basis hin abzuklopfen.
Clostridium difficile (CD) is an anaerobic, spore-forming bacillus that is responsible for a spectrum of gastrointestinal illness ranging from asymptomatic carriage to toxic megacolon and death. The prevalence of CD infection is increasing in both hospitalized and community-based inflammatory bowel disease populations. Standard antibiotic therapy fails to cure or prevent recurrence in more than 50% of patients, thus increasing the need for alternative therapies. Recently, fecal microbiota transplantation has received renewed attention as a therapy for refractory or recurrent CD infection. A high success rate combined with a favorable safety profile makes this therapy an attractive option for patients who have failed standard antibiotic therapy. Increasingly, this therapy is used in patients with CD infection and inflammatory bowel disease, as the combination of active inflammation and toxin-producing CD provides a challenging mix for clinicians.
Objective.
—To determine the safety and efficacy of a new combination treatment for patients with Clostridium difficile—associated disease (CDD). The treatment combines the yeast Saccharomyces boulardii with an antibiotic (vancomycin hydrochloride or metronidazole).Design.
—A double-blind, randomized, placebo-controlled, parallel-group intervention study in patients with active CDD. Patients received standard antibiotics and S boulardii or placebo for 4 weeks, and were followed up for an additional 4 weeks after therapy. Effectiveness was determined by comparing the recurrence of CDD in the two groups using multivariate analysis to control for other risk factors for CDD.Setting.
—National referral study of ambulatory or hospitalized patients from three main study coordinating centers.Patients.
—A total of 124 eligible consenting adult patients, including 64 who were enrolled with an initial episode of CDD, and 60 who had a history of at least one prior CDD episode. Patients who were immunosuppressed due to acquired immunodeficiency syndrome or cancer chemotherapy within 3 months were not eligible.Intervention.
—Treatment with oral S boulardii (1 g/d for 4 weeks) or placebo in combination with a standard antibiotic.Main Outcome Measure.
—Recurrence of active CDD.Results.
—A history of CDD episodes dramatically increased the likelihood of further recurrences. Multivariate analysis revealed that patients treated with S boulardii and standard antibiotics had a significantly lower relative risk (RR) of CDD recurrence (RR, 0.43; 95% confidence interval, 0.20 to 0.97) compared with placebo and standard antibiotics. The efficacy of S boulardii was significant (recurrence rate 34.6%, compared with 64.7% on placebo; P=.04) in patients with recurrent CDD, but not in patients with initial CDD (recurrence rate 19.3% compared with 24.2% on placebo; P=.86). There were no serious adverse reactions associated with S boulardii.Conclusions.
—The combination of standard antibiotics and S boulardii was shown to be an effective and safe therapy for these patients with recurrent CDD; no benefit of S boulardii was demonstrated for those with an initial episode of CDD.(JAMA. 1994;271:1913-1918)
Human infants are relatively resistant to Clostridium difficile-associated diarrhea and colitis compared to adults. In that toxin A is the major cause of intestinal damage with this organism, we compared toxin A receptor binding and biological effects in newborn vs adult rabbit ileum. Purified toxin A (M(r) 308 kD) was labeled with tritium or biotin with full retention of biologic activity. Appearance of specific toxin A brush border (BB) binding was strongly age dependent with minimal [3H]toxin A specific binding at 2 and 5 d of life, followed by gradual increase in binding to reach adult levels at 90 d. Absence of toxin A binding sites in newborn and presence in adult rabbits was confirmed by immunohistochemical studies using biotinylated toxin A. Toxin A (50 ng to 20 micrograms/ml) inhibited protein synthesis in 90-d-old rabbit ileal loops in a dose-dependent fashion. In contrast, inhibition of protein synthesis in 5-d-old rabbit ileum occurred only at the highest toxin A doses (5 and 20 micrograms/ml) and at all doses tested was significantly less than the adult rabbit ileum. In addition, toxin A (5 micrograms/ml) caused severe mucosal damage in adult rabbit ileal explants but had no discernable morphologic effect on 5-d-old rabbit intestine. Our data indicate that newborn rabbit intestine lacks BB receptors for toxin A. The absence of the high-affinity BB receptor for toxin A in the newborn period may explain lack of biologic responsiveness to purified toxin, and the absence of disease in human infants infected with this pathogen.
This study reports 24 patients with antibiotic associated colitis due to Clostridium difficile. Fifteen patients were treated with vancomycin due to the severity of the colitis and in eight of these a clinical relapse of the colitis occurred after vancomycin therapy was stopped. Bacteriological investigations of these patients indicated that C difficile was able to persist in stool samples during vancomycin therapy in the absence of detectable cytotoxin. This was in contrast with the seven patients successfully treated with vancomycin without relapse, and those not treated with vancomycin where both stool cultures and cytotoxin assays became negative. These results suggest that patients being treated with vancomycin for antibiotic associated colitis due to C difficile should have stool cultures done during and after treatment. Persistence of the organism in the absence of detectable cytotoxin may identify those patients who relapse and lead to either recommencement of vancomycin or alternative therapeutic approaches.
Toxin A but not toxin B, appears to mediate intestinal damage in animal models of Clostridium difficile enteritis. The purpose of this study was to investigate the electrophysiologic and morphologic effects of purified C. difficile toxins A and B on human colonic mucosa in Ussing chambers. Luminal exposure of tissues to 16-65 nM of toxin A and 0.2-29 nM of toxin B for 5 h caused dose-dependent epithelial damage. Potential difference, short-circuit current and resistance decreased by 76, 58, and 46%, respectively, with 32 nM of toxin A and by 76, 55, and 47%, respectively, with 3 nM of toxin B, when compared with baseline (P < 0.05). 3 nM of toxin A did not cause electrophysiologic changes. Permeability to [3H]mannitol increased 16-fold after exposure to 32 nM of toxin A and to 3 nM of toxin B when compared with controls (P < 0.05). Light and scanning electron microscopy after exposure to either toxin revealed patchy damage and exfoliation of superficial epithelial cells, while crypt epithelium remained intact. Fluorescent microscopy of phalloidin-stained sections showed that both toxins caused disruption and condensation of cellular F-actin. Our results demonstrate that the human colon is approximately 10 times more sensitive to the damaging effects of toxin B than toxin A, suggesting that toxin B may be more important than toxin A in the pathogenesis of C. difficile colitis in man.
OBJECTIVE--To determine the safety and efficacy of a new combination treatment for patients with Clostridium difficile-associated disease (CDD). The treatment combines the yeast Saccharomyces boulardii with an antibiotic (vancomycin hydrochloride or metronidazole). DESIGN--A double-blind, randomized, placebo-controlled, parallel-group intervention study in patients with active CDD. Patients received standard antibiotics and S boulardii or placebo for 4 weeks, and were followed up for an additional 4 weeks after therapy. Effectiveness was determined by comparing the recurrence of CDD in the two groups using multivariate analysis to control for other risk factors for CDD. SETTING--National referral study of ambulatory or hospitalized patients from three main study coordinating centers. PATIENTS--A total of 124 eligible consenting adult patients, including 64 who were enrolled with an initial episode of CDD, and 60 who had a history of at least one prior CDD episode. Patients who were immunosuppressed due to acquired immunodeficiency syndrome or cancer chemotherapy within 3 months were not eligible. INTERVENTION--Treatment with oral S boulardii (1 g/d for 4 weeks) or placebo in combination with a standard antibiotic. MAIN OUTCOME MEASURE--Recurrence of active CDD. RESULTS--A history of CDD episodes dramatically increased the likelihood of further recurrences. Multivariate analysis revealed that patients treated with S boulardii and standard antibiotics had a significantly lower relative risk (RR) of CDD recurrence (RR, 0.43; 95% confidence interval, 0.20 to 0.97) compared with placebo and standard antibiotics. The efficacy of S boulardii was significant (recurrence rate 34.6%, compared with 64.7% on placebo; P = .04) in patients with recurrent CDD, but not in patients with initial CDD (recurrence rate 19.3% compared with 24.2% on placebo; P = .86). There were no serious adverse reactions associated with S boulardii. CONCLUSIONS--The combination of standard antibiotics and S boulardii was shown to be an effective and safe therapy for these patients with recurrent CDD; no benefit of S boulardii was demonstrated for those with an initial episode of CDD.
This study investigated whether differences in fecal and serum antitoxin A antibody levels may account for the duration of Clostridium difficile-associated diarrhea (CDAD) and the occurrence of relapses. By an enzyme linked-immunosorbent assay, we tested 40 patients with CDAD including 25 patients without immunodeficiency and 15 patients receiving antineoplastic drugs. Two hundred eighty serum samples and 80 normal stool samples were investigated as controls. In nonimmunocompromised patients, serum immunoglobulin (IgG) and fecal IgA antitoxin A antibody titers were significantly higher in patients who suffered a single episode (n = 21) than in those with relapsing CDAD (n = 4) whose titers were at control levels. Of these 25 patients, eight suffered from diarrhea which lasted for more than 2 weeks. These patients had significantly lower serum- and feces-specific antibody levels than the others who presented symptoms of shorter duration. In cytostatic-treated patients, antitoxin A antibody levels were similar to controls, but relapses occurred in a single case. These data suggest an association between a defective humoral response to toxin A and a more severe form of C. difficile infection. They also indicate that other host-related factors control the severity of CDAD and remain to be elucidated.
To evaluate the potential of biotherapeutic agents (microorganisms with therapeutic properties) for the prevention and/or treatment of selected intestinal and vaginal infections.
The MEDLINE database was searched for all relevant articles published between 1966 and September 1995. Search terms used were biotherapeutic agent, probiotic, Lactobacillus, Saccharomyces, Bifidobacterium, Candida, gastrointestinal- system, vaginitis, vaginosis-bacterial, and related terms. The bibliographies of obtained articles were also reviewed.
All placebo-controlled human studies on biotherapeutic agents were reviewed. English-language open trials, case series and reports, and animal studies were reviewed only if they were especially relevant to providing information on the potential efficacy, adverse effects, or mechanisms of action of these agents.
Placebo-controlled studies have shown that biotherapeutic agents have been used successfully to prevent antibiotic-associated diarrhea (Lactobacillus caseiGG, bifidobacterium longum, B longum with L acidophilus, and Saccharomyces boulardii), to prevent acute infantile diarrhea (Bifidobacterium bifidum with Streptococcus thermophilus), to treat recurrent Clostridium difficile disease (S boulardii), and to treat various other diarrheal illnesses (Enterococcus faecium SF68, L caseiGG, and S boulardii). There is also evidence for Lactobacillus acidophilus in the prevention of candidal vaginitis. Few adverse effects have been reported. However, many of the studies tested only small numbers of patients or volunteers.
There is now evidence that administration of selected microorganisms is beneficial in the prevention and treatment of certain intestinal and, possibly, treatment of vaginal infections. In an effort to decrease the reliance on antimicrobials, the time has come to carefully explore the therapeutic applications of biotherapeutic agents.
Recurrent Clostridium difficile diarrhea (RCDD) occurs in 20% of patients after they have received standard antibiotic treatment with vancomycin or metronidazole,
but the reasons for the recurrences are largely unknown. Patients receiving vancomycin or metronidazole for active C. difficile diarrhea (CDD) were referred to our study centers for treatment and a 2-month follow-up as part of a randomized placebo-controlled
trial. Sixty patients had RCDD (median number of episodes, 3.0; range, 2–9 episodes) and 64 were having their first episode
of CDD. Patients with RCDD had more-severe abdominal pain and were more likely to have fever but initially responded well
to antibiotic therapy. Data on sequential episodes showed no progression in disease severity. Five factors were associated
with a higher risk of RCDD: the number of previous CDD episodes, onset of the initial disease in the spring, exposure to additional
antibiotics for treatment of other infections, infection with immunoblot type 1 or 2 strains of C. difficile, and female gender. These factors may help to identify patients who are more likely to develop RCDD and require careful medical
supervision.
To describe the epidemiology, diagnosis, risk factors, patient impact, and treatment strategies for recurrent Clostridium difficile-associated disease (CDAD).
Data were collected as part of a blinded, placebo-controlled clinical trial testing a new combination treatment for recurrent CDAD. Retrospective data regarding prior CDAD episodes were collected from interviews and medical-chart review. Prospective data on the current CDAD episode, risk factors, and recurrence rates were collected during a 2-month follow-up.
National referral study.
Patients with recurrent CDAD.
Treatment with a 10-day course of low-dose (500 mg/d) or high-dose (2 g/d) vancomycin or metronidazole (1 g/d).
Recurrent CDAD was found to have a lengthy course involving multiple episodes of diarrhea, abdominal cramping, nausea, and fever. CDAD may recur over several years despite frequent treatment with antibiotics. Recurrence rates were similar regardless of the choice or dose of antibiotic. Recurrent CDAD is not a trivial disease: patients may have multiple episodes (as many as 14), may require hospitalization, and the mean lifetime cost of direct medical care was $10,970 per patient. Fortunately, the disease does not become progressively more severe as the number of episodes increase. Two risk factors predictive for recurrent CDAD were found: increasing age and a decreased quality-of-life score at enrollment.
Recurrent CDAD is a persistent disease that may result in prolonged hospital stays, additional medical costs, and rare serious complications.
Recurrent Clostridium difficile disease (CDD) is a difficult clinical problem because antibiotic therapy often does not prevent further recurrences. In a
previous study, the biotherapeutic agent Saccharomyces boulardii was used in combination with standard antibiotics and was found to be effective in reducing subsequent recurrences of CDD.
In an effort to further refine a standard regimen, we tested patients receiving a regimen of a standard antibiotic for 10
days and then added either S. boulardii (1 g/day for 28 days) or placebo. A significant decrease in recurrences was observed only in patients treated with high-dose
vancomycin (2 g/day) and S. boulardii (16.7%), compared with those who received high-dose vancomycin and placebo (50%; P = .05). No serious adverse reactions were observed in these patients. Comparison of data from this trial with data from previous
studies indicates that recurrent CDD may respond to a short course of high-dose vancomycin or to longer courses of low-dose
vancomycin when either is combined with S. boulardii.
Clostridium difficile is a major cause of nosocomial diarrhea in industrialized countries. Although most illnesses respond to available therapy, infection can increase morbidity, prolong hospitalization, and produce life-threatening colitis. Vaccines are being explored as an alternative means for protecting high-risk individuals. We assessed the safety, immunogenicity, and dose response of a parenteral vaccine containing C. difficile toxoids A and B. Thirty healthy adults were assigned to receive four spaced inoculations on days 1, 8, 30, and 60 with one of three doses of vaccine (6.25, 25, or 100 microg). At each dose level, subjects were randomized, in a double-blind fashion, to receive either the soluble toxoids (n = 5) or toxoids adsorbed to alum (n = 5). Subjects were monitored for clinical and immunologic responses to vaccination. Vaccination was generally well tolerated, with occasional, usually mild, systemic reactions (abdominal pain, arthralgia, and diarrhea). The most common local reaction, mild arm pain, was reported by all recipients of the toxoid-alum formulation. Nearly all subjects (> or = 90%) developed vigorous serum antibody responses to both toxins, as measured by immunoglobulin G (IgG) enzyme-linked immunosorbent assay and neutralization of cytotoxicity, whereas fecal IgA increases occurred in approximately 50%. Statistically significant effects of dose and formulation on immunogenicity were not seen, although antibody levels tended to be higher with the alum-adjuvanted formulations and with increasing doses of soluble toxoid. Serum antibody responses among the toxoid-alum group appeared to plateau at 25 microg. We concluded that the C. difficile toxoid vaccine is safe and immunogenic in healthy volunteers. Further development as a prophylactic vaccine or for producing C. difficile hyperimmune globulin is justified.
GT160-246, a high-molecular-weight soluble anionic polymer, was tested in vitro and in vivo for neutralization of Clostridium difficile toxin A and B activities. Five milligrams of GT160-246 per ml neutralized toxin-mediated inhibition of protein synthesis
in Vero cells induced by 5 ng of toxin A per ml or 1.25 ng of toxin B per ml. In ligated rat ileal loops, 1 mg of GT160-246
neutralized fluid accumulation caused by 5 μg of toxin A. At doses as high as 80 mg/loop, cholestyramine provided incomplete
neutralization of fluid accumulation caused by 5 μg of toxin A. GT160-246 protected 80% of the hamsters from mortality caused
by infection with C. difficile, whereas cholestyramine protected only 10% of animals. Treatment of C. difficile-infected hamsters with metronidazole initially protected 100% of the hamsters from mortality, but upon removal of treatment,
80% of the hamsters had relapses and died. In contrast, removal of GT160-246 treatment did not result in disease relapse in
the hamsters. GT160-246 showed no antimicrobial activity in tests with a panel of 16 aerobic bacteria and yeast and 22 anaerobic
bacteria and did not interfere with the in vitro activities of most antibiotics. GT160-246 offers a novel, nonantimicrobial
treatment of C. difficile disease in humans.
There is a strong association between serum antibody responses to toxin A and protection against Clostridium difficile diarrhea. A parenteral C. difficile toxoid vaccine induced very-high-level responses to anti-toxin A immunoglobulin G (IgG) in the sera of healthy volunteers.
After vaccination, the concentrations of anti-toxin A IgG in the sera of all 30 recipients exceeded the concentrations that
were associated with protection in previous clinical studies. Furthermore, the median concentration of serum anti-toxin A
IgG in the test group was 50-fold higher than the previous threshold. These findings support the feasibility of using a vaccine
to protect high-risk individuals against C. difficile-associated diarrhea and colitis.
Saccharomyces boulardii is widely used as a probiotic compound and is generally thought to be safe. We report one case of fungemia caused by Saccharomyces cerevisiae occurring in an elderly patient treated orally with S. boulardii in association with vancomycin for Clostridium difficile colitis. We do not recommend administering this viable yeast particularly in debilited patient with active colitis.
Objective.
—To evaluate the potential of biotherapeutic agents (microorganisms with therapeutic properties) for the prevention and/or treatment of selected intestinal and vaginal infections.Data Sources.
—The MEDLINE database was searched for all relevant articles published between 1966 and September 1995. Search terms used were biotherapeutic agent, probiotic, Lactobacillus, Saccharomyces, Bifidobacterium, Candida, gastrointestinal-system, vaginitis, vaginosis-bacterial, and related terms. The bibliographies of obtained articles were also reviewed.Study Selection and Data Extraction.
—All placebo-controlled human studies on biotherapeutic agents were reviewed. English-language open trials, case series and reports, and animal studies were reviewed only if they were especially relevant to providing information on the potential efficacy, adverse effects, or mechanisms of action of these agents.Data Synthesis.
—Placebo-controlled studies have shown that biotherapeutic agents have been used successfully to prevent antibiotic-associated diarrhea (Lactobacillus casei GG, Bifidobacteriumlongum, B longum with L acidophilus, and Saccharomyces boulardii), to prevent acute infantile diarrhea (Bifidobacterium bifidum with Streptococcus thermophilus), to treat recurrent Clostridium difficile disease (S boulardii), and to treat various other diarrheal illnesses (Enterococcus faecium SF68, L casei GG, and S boulardii). There is also limited evidence for Lactobacillus acidophilus in the prevention of candidal vaginitis. Few adverse effects have been reported. However, many of the studies tested only small numbers of patients or volunteers.Conclusions.
—There is now evidence that administration of selected microorganisms is beneficial in the prevention and treatment of certain intestinal and, possibly, treatment of vaginal infections. In an effort to decrease the reliance on antimicrobials, the time has come to carefully explore the therapeutic applications of biotherapeutic agents.(JAMA. 1996;275:870-876)
Two patients with relapsing
Clostridium difficile
diarrhoea following metronidazole and vancomycin therapy were colonised with a non-toxigenic avirulent
Clostridium difficile
strain given orally in three doses. Both patients appeared to respond without sideeffects. Oral bacteriotherapy with a defined nontoxigenic strain of
Clostridium difficile
would appear to represent an acceptable, alternative and novel way to treat hospitalised patients who relapse with
Clostridium difficile
diarrhoea after specific antibiotic therapy.
We have fingerprinted Clostridium difficile isolates from patients with symptomatic recurrences of infection, using random amplified polymorphic DNA (RAPD). The medical records of 55/79 patients were examined, from whom multiple C. difficile-positive faeces were received during hospitalization at least five days, but no more than two months, apart. In 20 of these cases symptoms either did not recur (i.e., absent for at least three days between episodes), or were explainable by other causes, such as laxative administration. Of the remaining 35 patients, 27 sets of C. difficile isolates (23 pairs and four triplicates) were available for RAPD fingerprinting. Differing C. difficile DNA fingerprints (at least three major bands difference) were obtained for 15/27 patients, and hence at least 56% of the clinical recurrences of infection were in fact due to re-infection as opposed to relapse. Since we found that an endemic C. difficile clone was present in 18 out of 27 patients (67%) and accounted for 53% (31/58) of all isolates, it is probable that the majority of symptomatic recurrences are in fact re-infections, with either a different or the same C. difficile strain. We conclude that more attention must be given to preventing the re-infection of C. difficile symptomatic patients. Isolation of symptomatic individuals is the preferred option for the protection of other patients, but measures must be taken to ensure that further strain acquisition by the index cases does not occur.
Seven patients treated with oral cholestyramine for antibiotic-associated pseudomembranous colitis are reported. Response was variable with only one patient having a totally satisfactory clinical outcome. Five of seven patients had continued systemic signs with fever and leukocytosis throughout the course of cholestyramine. Two observations were relatively consistent. First, six of the seven patient had a decrease in the number of daily stools during therapy. Second, all patients showed persistence of the cytopathic toxin in stools obtained after three to seven days of cholestyramine therapy. Six patients who were subsequently treated with oral vancomycin had a prompt clinical improvement and clearance of the cytopathic toxin in the stool.
Patients receiving antibiotics or having just completed a course of antibiotics should be observed for the development of diarrhea. The diagnosis of antibiotic-associated colitis can be made by careful proctoscopic examination. If colitis is found, the antibiotic should be discontinued, vigorous supportive therapy should be instituted, and the patient should be observed carefully. Following these guidelines, the prognosis for antibiotic-associated colitis should be favorable.
We tested the hypothesis that children with chronic relapsing colitis induced by Clostridium difficile toxin have defective antibody responses to C. difficile toxins as a cause of their underlying illness. Six such children were tested for serum IgG and IgA antibody to C. difficile toxin A. These six children had lower IgG anti-toxin A levels than 24 healthy children (p = 0.026) and 18 healthy adults (p = 0.0008). Five patients treated with 400 mg intravenously administered gamma-globulin per kilogram every 3 weeks had significant increases in IgG (p = 0.01) but not IgA anti-toxin A (p = 0.406) levels, and all five had clinical resolution of their gastrointestinal symptoms as well as clearing of C. difficile cytotoxin B from their stools. These observations suggest that a deficiency of IgG anti-toxin A may predispose children to the development of chronic relapsing C. difficile-induced colitis. In such cases, intravenous gamma-globulin therapy may be effective in producing clinical remission.
Saccharomyces boulardii, a nonpathogenic yeast, has been widely used in Europe to prevent antibiotic-associated diarrhea (AAD). We performed a prospective double-blind controlled study to investigate AAD in hospitalized patients and to evaluate the effect of S. boulardii, a living yeast, given in capsule form concurrently with antibiotics. Over 23 mo, 180 patients completed the study. Of the patients receiving placebo, 22% experienced diarrhea compared with 9.5% of patients receiving S. boulardii (p = 0.038). Risk factors found to be associated with AAD were multiple antibiotic combinations (containing clindamycin, cephalosporins, or trimethoprim-sulfamethoxazole) and tube feeding. Clostridium difficile, an anaerobe found in the stools of most patients with pseudomembranous colitis, was variably associated with AAD. We evaluated the role of C. difficile in AAD in the study population and found no significant association between the presence of C. difficile or cytotoxin with AAD. Approximately 33% of the patients without diarrhea harbored at least one C. difficile-positive stool and nearly 50% of these patients had detectable cytotoxin. Similar values were obtained in patients with diarrhea. Of C. difficile-positive patients, 31% (5/16) on placebo developed diarrhea compared with 9.4% (3/32) on S. boulardii; this difference was not statistically significant (p = 0.07). There were no discernable adverse effects of yeast administration. We conclude that S. boulardii reduces the incidence of antibiotic-associated diarrhea in hospitalized patients.
The purpose of this study was to compare the effects of Clostridium difficile toxin A and cholera toxin on fluid secretion, intestinal permeability, and arachidonate metabolites in rabbit ileum. Injection of 25 micrograms of either purified toxin into 10-cm ileal loops caused significant increases in fluid secretion and intestinal permeability to mannitol as well as release of prostaglandin E2 into the lumen. Toxin A, but not cholera toxin, caused a severe inflammatory reaction of the lamina propria and necrosis of enterocytes as well as increased release of leukotriene B4. The toxin A-mediated increases in prostaglandin E2 and leukotriene B4 could be blocked by prior instillation of 10 mg of 5-aminosalicylic acid into ileal loops. 5-Aminosalicylic acid also significantly diminished the expected increase in mannitol permeability after both toxins, but had no significant inhibitory effect on fluid secretion or, in the case of toxin A, intestinal inflammation. Our results indicate that C. difficile and cholera enterotoxins differ substantially in their effects on the rabbit intestine. Clostridium difficile toxin A, an inflammatory toxin, produces a striking infiltration of the lamina propria with neutrophils that is associated with increased release of leukotriene B4. In contrast, cholera toxin does not cause inflammation or leukotriene B4 release. Increased release of prostaglandin E2 occurs after exposure to both toxins and appears to be correlated with increased intestinal permeability.
Six patients with chronic relapsing diarrhoea caused by Clostridium difficile were treated with rectal instillation of homologous faeces (one patient) or a mixture of ten different facultatively aerobic and anaerobic bacteria diluted in sterile saline (five patients). The mixture led to a prompt loss of Cl difficile and its toxin from the stools and to bowel colonisation by Bacteroides sp, which had not been present in pre-treatment stool samples. Strains of Escherichia coli, Cl bifermentans, and Peptostreptococcus productus in the mixture inhibited the in-vitro growth of Cl difficile, which in turn inhibited the growth of Bacteroides ovatus, Bacteroides vulgatus, and Bacteroides thetaiotaomicron. The finding that Bacteroides sp had been absent during the patients' illness but was present after recovery suggests that the absence of Bacteroides sp may result in chronic relapsing Cl difficile diarrhoea, and that its presence may prevent colonisation by Cl difficile.
Two patients with relapsing Clostridium difficile diarrhoea following metronidazole and vancomycin therapy were colonised with a non-toxigenic avirulent Clostridium difficile strain given orally in three doses. Both patients appeared to respond without side-effects. Oral bacteriotherapy with a defined nontoxigenic strain of Clostridium difficile would appear to represent an acceptable, alternative and novel way to treat hospitalised patients who relapse with Clostridium difficile diarrhoea after specific antibiotic therapy.
Seven patients with multiple bacteriologic and symptomatic relapses of Clostridium difficile-associated diarrhea and/or colitis were treated with vancomycin and rifampin in combination. Diarrhea and abdominal pain promptly resolved in all, and neither C. difficile nor its toxin could be recovered from their stools shortly after therapy. However, stools of all patients subsequently became culture-positive for C. difficile and occasionally had demonstrable cytotoxin. Except in one instance following oral antibiotic use, all patients remained free of symptoms. Resistance to either vancomycin or rifampin was not encountered. Biotyping of isolates with clostridial bacteriophages and bacteriocins suggested true relapse with the same organism in all patients studied, rather than reinfection with another strain. Vancomycin and rifampin in combination appear to be useful in the therapy of relapsing antibiotic-associated diarrhea due to C. difficile.
We describe a patient with relapses of Clostridium difficile cytotoxin-positive pseudomembranous colitis (PMC) after treatment with vancomycin, a course of metronidazole and a trial of bacitracin. She remains free of disease after a prolonged course of cholestyramine. We suggest there may be a role for anion-exchange resins in patients with PMC relapsing after vancomycin therapy.
Twenty-two patients with multiple relapses of antibiotic-associated pseudomembranous colitis underwent a tapering dose of oral vancomycin for 21 days and a pulse dose of vancomycin for 21 days. In follow-up ranging from 2-12 months with a mean of 6 months, all patients have been without recurrence of the antibiotic-associated pseudomembranous colitis.
An enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies to toxins A and B of Clostridium difficile was developed. Serum samples from 340 patients were tested for determination of the age-related prevalence of antitoxin.
Antibody to toxin A was present in 64% of patients more than two years old and antibody to toxin B in 66% of patients more
than six months old. A strongly positive ELISA value correlated with the presence of cytotoxicity-neutralizing antibody (P < 0.001). Strongly positive ELISA values were obtained more commonly in convalescent sera from 16 patients with C difficite-induced colitis than in sera from the control population (antibody to toxin A, P < 0.05; antibody to toxin B, P < 0.001). Testing of paired sera revealed significant increases in the titer of IgG antibody to toxin A or B. Ten of the
16 patients with colitis had IgM titers of ⩾1:160 to one or both toxins. The data presented suggest that antibodies to toxins
A and B are present in the majority of older children and adults and that patients with C difficile-induced disease develop serologic responses to one or both toxins.
Twenty patients with antimicrobiol-associated diarrhea had a symptomatic relapse after oral vancomycin therapy. All patients had stool examinations which implicated C. difficile as the causative agent, and 16 had pseudomembranous colitis. Clinical courses were characterized by resolution of symptoms with recurrence of diarrhea at 4--21 days after vancomycin was discontinued. Studies of stools collected sequentially showed that vancomycin failed to eliminate C. difficile despite susceptibility to this agent with in vitro testing. A review of our records shows the incidence os symptomatic relapse is approximately 14%. This experience emphasizes the importance of adequate follow-up in patients treated with oral vancomycin for antibiotic-associated diarrhea or colitis due to C. difficile.
Eleven patients with relapses of antibiotic-associated pseudomembranous colitis were treated with a tapering dose schedule of vancomycin and cholestipol. All patients responded and have continued to be asymptomatic for follow-up periods of at least 6 wk. This tapering dose of vancomycin in conjunction with cholestipol appears to be warranted in patients with relapses of antibiotic-associated pseudomembranous colitis.
Clostridium difficile, the agent that causes pseudomembranous colitis associated with antibiotic therapy, has been identified in recent years as a common nosocomial pathogen. First described in 1935 by Hall and O'Toole, this gram-positive anaerobic bacillus was named “the difficult clostridium” because it resisted early attempts at isolation and grew very slowly in culture1. Although the organism released potent toxins in broth culture, the fact that it was found in stool specimens from healthy neonates led to its classification as a commensal. C. difficile subsequently passed into obscurity. In the 1960s and 1970s antibiotic-associated pseudomembranous colitis became a major clinical . . .
Clostridium difficile is now regarded as the most prevalent nosocomial pathogen, infecting as many as a quarter of hospitalized patients. The pathophysiology of infection with this unusual enteric pathogen involves alteration of the normal enteric flora by antibiotics, ingestion of spores, and colonization by C. difficile. The organism then releases potent exotoxins that produce an inflammatory colitis and diarrhea. A spectrum of host responses occurs, ranging from the asymptomatic carrier state to life-threatening pseudomembranous colitis. Effective therapy with vancomycin or metronidazole is available, but relapses occur in 15% to 20% of patients and may necessitate multiple courses of therapy.
We conducted a prospective, randomized study to compare the efficacy of oral fusidic acid, oral metronidazole, oral vancomycin,
and oral teicoplanin for the treatment of Clostridium difficile—associated diarrhea. Treatment resulted in clinical cure for 94% of the patients who were treated with vancomycin, 96% of
those treated with teicoplanin, 93% of those treated with fusidic acid, and 94% of those treated with metronidazole. Clinical
symptoms recurred in 16% of patients treated with vancomycin, 7% of those treated with teicoplanin, 28% of those treated with
fusidic acid, and 16% of those treated with metronidazole. There was asymptomatic carriage of C. difficile toxin in 13% of patients treated with vancomycin,4% of those treated with teicoplanin, 24% of those treated with fusidicacid,
and 16% of those treated with metronidazole. No adverse effectsrelated to therapy with vancomycin or teicoplanin were observed.
Considering the costs of treatment, our findings suggest that metronidazole is the drug of choice for C. difficile—associated diarrhea and that glycopeptides should be reserved for patients who cannot tolerate metronidazole or who do not
respond to treatment with this drug.
Guidelines for clinical practice are intended to suggest preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When data are not available that will withstand objective scrutiny, a recommendation may be made based on a consensus of experts. Guidelines are intended to apply to the clinical situation for all physicians without regard to specialty. Guidelines are intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. Given the wide range of choices in any health care problem, the physician should select the course best suited to the individual patient and the clinical situation presented. These guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee. These guidelines are also approved by the governing boards of American College of Gastroenterology and Practice Parameters Committee. Expert opinion is solicited from the outset for the document. Guidelines are reviewed in depth by the committee, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments at a later time. The following guidelines are intended for adults and not for pediatric patients.
Little is known about whether patients who develop Clostridium-difficile-associated diarrhoea (CDAD) are culture-positive or culture-negative before illness. The most important risk factor is antibiotic exposure. We aimed to find out whether patients identified as primary symptom-free C difficile carriers are at higher risk of developing CDAD than patients who are culture-negative.
We reviewed four longitudinal studies in which 810 patients admitted to hospital were followed up by prospective rectal-swab culture. At least two consecutive weekly cultures were obtained. We calculated the difference in risk of CDAD between colonised and non-colonised patients in each study and combined the results of the four studies in a random-effects model.
Of 618 non-colonised patients (mean follow-up 1.7 weeks [SD 1.3]), 22 (3.6%) developed CDAD, whereas only two (1.0%) of 192 primary symptom-free carriers (1.5 [1.5]) developed CDAD (pooled risk difference -2.3% [95% CI 0.3-4.3], p=0.021). Of patients who received antibiotics, the risk difference was increased: 22 (4.5%) of 491 non-colonised patients compared with two (1.1%) of 176 colonised patients developed CDAD (-3.2% [0.4-6.0], p=0.024). Of the primary symptom-free C difficile carriers, 95 were colonised with toxigenic strains, 76 with non-toxigenic strains, 12 with both toxigenic and non-toxigenic strains (non-concurrently), and nine with strains of undetermined toxigenicity. Nine of the 12 toxogenic strains of C difficile isolates that cause CDAD were also recovered from stools of symptom-free patients.
Primary symptomless C difficile colonisation is associated with a decreased risk of CDAD. Although the mechanism is unknown, risk reduction is found in colonisation with non-toxigenic and toxigenic strains.
Clostridium difficile infection can result in asymptomatic carriage, mild diarrhea, or fulminant pseudomembranous colitis. We studied whether antibody responses to C. difficile toxins affect the risks of colonization, diarrhea, and asymptomatic carriage.
We prospectively studied C. difficile infections in hospitalized patients who were receiving antibiotics. Serial stool samples were tested for C. difficile colonization by cytotoxin assay and culture. Serum antibody (IgA, IgG, and IgM) levels and fecal antibody (IgA and IgG) levels against C. difficile toxin A, toxin B, and nontoxin antigens were measured by an enzyme-linked immunosorbent assay (ELISA).
Of 271 patients, 37 (14 percent) were colonized with C. difficile at the time of admission, 18 of whom were asymptomatic carriers. An additional 47 patients (17 percent) became infected in the hospital, 19 of whom remained asymptomatic. The baseline antibody levels were similar in the patients who later became colonized and those who did not. After colonization, those who became asymptomatic carriers had significantly greater increases in serum levels of IgG antibody against toxin A than did the patients in whom C. difficile diarrhea developed (P<0.001). The adjusted odds ratio for diarrhea was 48.0 (95 percent confidence interval, 3.4 to 678) among patients with colonization who had a serum level of IgG antibody against toxin A of 3.00 ELISA units or less, as compared with patients with colonization who had a level of more than 3.00 ELISA units.
We find no evidence of immune protection against colonization by C. difficile. However, after colonization there is an association between a systemic anamnestic response to toxin A, as evidenced by increased serum levels of IgG antibody against toxin A, and asymptomatic carriage of C. difficile.
We have reported that symptom-free carriers of Clostridium difficile have a systemic anamnestic immune response to toxin A. The aim of this study was to determine whether an acquired immune response to toxin A, during an episode of C. difficile diarrhoea, influences risk of recurrence.
We prospectively studied 63 patients with nosocomial C. difficile diarrhoea. Serial serum IgA, IgG, and IgM concentrations against C. difficile toxin A, toxin B, or non-toxin antigens were measured by ELISA. Individuals were followed for 60 days.
19 patients died (30%). Of the 44 who survived, 22 had recurrent C. difficile diarrhoea. Patients with a single episode of C. difficile diarrhoea (n=22) had higher concentrations of serum IgM against toxin A on day 3 of their first episode of diarrhoea than those with recurrent diarrhoea (n=22, p=0.004). On day 12, serum IgG values against toxin A were higher in patients who had a single episode of diarrhoea (n=7) than in those who subsequently had recurrent diarrhoea (n=9, p=0.009). The odds ratio for recurrence associated with a low concentration of serum IgG against toxin A, measured 12 days after onset of C. difficile diarrhoea, was 48.0 (95% CI 3.5-663).
A serum antibody response to toxin A, during an initial episode of C. difficile diarrhoea, is associated with protection against recurrence.
Clostridium difficile diarrhoea is a common iatrogenic nosocomial disease. Fortunately, most affected patients respond well to medical therapy that includes discontinuation of the inciting antibiotic and treatment with metronidazole or vancomycin.1 However, despite successful treatment of initial episodes, 15–25% will have recurrence of diarrhoea following withdrawal of specific antibiotic therapy.1 2 Treatment of this form of C difficile disease can be particularly problematic.
Approaches to management include conservative therapy, treatment with specific anti- C difficile antibiotics, use of anion binding resins, therapy with microorganisms (probiotics), and immunoglobulin therapy (table 1).
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Table 1
Approach to management of recurrent Clostridium difficile diarrhoea
### CONSERVATIVE THERAPY
Conservative management of recurrent diarrhoea is preferable to retreatment with metronidazole or vancomycin as these agents perpetuate disturbance of the normal intestinal flora predisposing patients to further recurrences.2 However, it is often difficult to withhold antibiotic therapy as many patients with recurrent disease are not able to tolerate ongoing diarrhoea. Persistent or worsening …
To assess the efficacy of Lactobacillus GG in preventing antibiotic-associated diarrhea (AAD) in adults and, secondarily, to assess the effect of coadministered Lactobacillus GG on the number of tests performed to determine the cause of diarrhea.
In this prospective, randomized, double-blind, placebo-controlled trial conducted from July 1998 to October 1999, 302 hospitalized patients receiving antibiotics were randomized to receive Lactobacillus GG, 20 x 10(9) CFU/d, or placebo for 14 days. Subjects recorded the number of stools and their consistency daily for 21 days. The primary outcome was the proportion of patients who developed diarrhea in the first 21 days after enrollment. Weekly telephone follow-up was also performed. Results were analyzed in an intention-to-treat fashion.
Diarrhea developed in 39 (29.3%) of 133 patients randomized to receive Lactobacillus GG and in 40 (29.9%) of 134 patients randomized to receive placebo (P=.93). No additional difference in the rate of occurrence of diarrhea was found between treatment and placebo patients in a subgroup analysis of those treated with beta-lactam vs non-beta-lactam antibiotics. Too few patients had stool cultures, additional laboratory tests for diarrhea, or a positive diagnosis of Clostridium difficile infection to assess between-group differences.
Lactobacillus GG in a dose of 20 x 10(9) CFU/d did not reduce the rate of occurrence of diarrhea in this sample of 267 adult patients taking antibiotics initially administered in the hospital setting.
There is currently uncertainty as to the best treatment for patients with recurrent episodes of Clostridium difficile disease (RCDD). Our objective was to evaluate the success of treatment strategies in a cohort of 163 RCDD patients.
Data were used from patients who had participated in the placebo arm in two national referral clinical trials evaluating a new combination treatment. Patients with active RCCD were enrolled, prescribed either vancomycin or metronidazole, and randomized to either the investigational biological or a placebo. All patients were observed for at least 2 months for a subsequent episode of RCCD.
Of the 163 cases, 44.8% recurred. A tapering course of vancomycin resulted in significantly fewer recurrences (31%, p = 0.01), as did pulsed dosing of vancomycin (14.3%, p = 0.02). A trend (p = 0.09) for a lower recurrence frequency was observed for high-dose (> or =2 g/day) vancomycin and low-dose (< or =1 g/day) metronidazole. Vancomycin was significantly more effective in clearing C. difficile culture and/or toxin by the end of therapy than metronidazole (89% vs 59%, respectively; p < 0.001).
These data show that tapered or pulsed dosing regimens of vancomycin may result in a significantly better cure of RCDD. The persistence of C. difficile spores suggests that additional strategies to restore the normal colonic microflora may also be beneficial.
Studies suggest that asymptomatic colonization with Clostridium difficile (CD) decreases the risk of CD-associated disease (CDAD) in humans. A hamster model was used to test the efficacy of colonization
with 3 nontoxigenic CD strains for preventing CDAD after exposure to toxigenic CD. Groups of 10 hamsters were given 106 nontoxigenic CD spores 2 days after receiving a single dose of clindamycin. Five days later, the hamsters were given 100
spores of 1 of 3 toxigenic CD strains previously shown to cause mortality within 48 h. Each nontoxigenic strain prevented
disease in 87%–97% of hamsters that were challenged with toxigenic strains. Failure to prevent CDAD was associated with failure
of colonization with nontoxigenic CD. Colonization with nontoxigenic CD strains is highly effective in preventing CDAD in
hamsters challenged with toxigenic CD strains, which suggests that use of a probiotic strategy for CDAD prevention in humans
receiving antibiotics might be beneficial
Clostridium difficile–associated diarrhea and colitis have emerged as major complications associated with use of systemic antimicrobials. In this
study, the medical records for 18 subjects who received donor stool by nasogastric tube for recurrent C. difficile infection during a 9-year period at a single institution were retrospectively reviewed. During the period between the initial
diagnosis of C. difficile colitis and the stool treatments, the 18 subjects received a total of 64 courses of antimicrobials (range, 2–7 courses; median,
3 courses). During the 90 days after receipt of treatment with stool, 2 patients died of unrelated illnesses. One of the 16
survivors experienced a single recurrence of C. difficile colitis during 90-day follow-up. No adverse effects associated with stool treatment were observed. Patients with recurrent
C. difficile colitis may benefit from the introduction of stool from healthy donors via a nasogastric tube.
Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis, diseases afflicting millions of people each year. Although C. difficile releases 2 structurally similar exotoxins, toxin A and toxin B, animal experiments suggest that only toxin A mediates diarrhea and enterocolitis. However, toxin A-negative/toxin B-positive strains of C. difficile recently were isolated from patients with antibiotic-associated diarrhea and colitis, indicating that toxin B also may be pathogenic in humans.
Here we used subcutaneously transplanted human intestinal xenografts in immunodeficient mice to generate a chimeric animal model for C. difficile toxin-induced pathology of human intestine.
We found that intraluminal toxin B, like equivalent concentrations of toxin A, induced intestinal epithelial cell damage, increased mucosal permeability, stimulated interleukin (IL)-8 synthesis, and caused an acute inflammatory response characterized by neutrophil recruitment and tissue damage. Laser capture microdissection and real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) showed that intestinal epithelial cell-specific IL-8 gene expression also was increased significantly after luminal exposure to C. difficile toxins in vivo.
We conclude that C. difficile toxin B, like toxin A, is a potent inflammatory enterotoxin for human intestine. Future therapeutic or vaccine strategies for C. difficile infection therefore need to target both toxins.
A 48-year-old diabetic with multiple co-morbidities presented with generalized micro- and macroangiopathy including peripheral artery disease stage IV with necroses in several digits of both feet. He was admitted to the department of surgery for the insertion of femoropopliteal bypasses.
Infectious parameters were elevated (CRP 66.1 mg/l, sedimentation rate 90/96), accompanied by anemia (Hb 7.1 mmol/l), leukocytosis (14.8 Gpt/l) and thrombocytosis (514 Gpt/l). Body temperature was normal (36.8 degrees C). With insulin treatment the patient became nearly normoglycemic (HbA1c 6.8 %). TREATMENT AND FOLLOW UP: After receiving different broad-spectrum antibiotics over seven weeks the patient developed Clostridium difficile toxin-positive diarrhea that resolved after administration of oral metronidazole and Saccharomyces boulardii (Perenterol ((R))). Three days after bypass insertion, both legs had to be amputated due to infection and beginning sepsis. The condition of the patient improved. However, eight days after bypass-insertion the patient developed a toxic megacolon and sepsis. Blood cultures yielded the growth of Saccharomyces cerevisae. Despite of intensive care treatment the patient died five days later from to multi-organ failure.
S. boulardii (synonym: S. cerevisiae) is considered an non-pathogenic probiotic yeast, and live yeast cells are used for supportive therapy of diarrhea. The present case and a review of the literature demonstrate that fungemia and sepsis are rare complications of the administration of S. boulardii in immunocompromised patients. For this reason the therapeutic usage of probiotics should be carefully considered regarding its risk-benefit potential.
Clostridium difficile diarrhoea (CDD) cases treated with intravenous immunoglobulin during a 2 year period were reviewed to determine disease severity and response to treatment.
Of 580 CD cytotoxin-positive patients, five received intravenous immunoglobulin because of protracted and/or recurrent CDD (median duration 50 days, range 45-64); two had biopsy- proven pseudomembranous colitis. The five patients received a median three non-CDD antibiotic courses (range 2-8). Indices of CDD severity included hypoalbuminaemia (n = 5, median 27 g/L, range 11-29), marked hypokalaemia (n = 3, range 1.9-2.7 mM), markedly raised peripheral white cell count (n = 3, 18-34 x 10(9) cells/L), abdominal signs (n = 3) and pyrexia (n = 1). The five cases received metronidazole for median 17 days (range 0-63) plus vancomycin for median 14 days (range 10-42) before intravenous immunoglobulin. One also received rifampicin plus vancomycin and one was given Saccharomyces boulardii.
Intravenous immunoglobulin was given at a dosage of 300-500 mg/kg (most commonly 400 mg/kg) for one dose (two patients), two doses (two patients) and in one case for six doses. The latter patient died of intractable CDD, three had a good therapeutic response to intravenous immunoglobulin and CDD recurred within 6 weeks in one case. In the three successfully treated cases, CDD resolved within 11 days.
Intravenous immunoglobulin is useful for the treatment of intractable and severe CDD. Controlled studies are needed to assess the true value of this and other forms of passive immunotherapy.