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Elective Stoma Reversal Has a Higher Incidence of Postoperative Clostridium Difficile Infection Compared With Elective Colectomy: An Analysis Using the American College of Surgeons National Surgical Quality Improvement Program and Targeted Colectomy Databases
Abstract
Background:
Clostridium difficile infection is caused by the proliferation of a gram-positive anaerobic bacteria after medical or surgical intervention and can result in toxic complications, emergent surgery, and death.
Objective:
This analysis evaluates the incidence of C difficile infection in elective restoration of intestinal continuity compared with elective colon resection.
Design:
This was a retrospective database review of the 2015 American College of Surgeons National Surgical Quality Improvement Project and targeted colectomy database.
Settings:
The intervention cohort was defined as the primary Current Procedural Terminology codes for ileostomy/colostomy reversal (44227, 44620, 44625, and 44626) and International Classification of Diseases codes for ileostomy/colostomy status (VV44.2, VV44.3, VV55.2, VV55.3, Z93.2, Z93.3, Z43.3, and Z43.2).
Patients:
A total of 2235 patients underwent elective stoma reversal compared with 10403 patients who underwent elective colon resection.
Intervention:
Multivariate regression modeling of the impact of stoma reversal on postoperative C difficile infection risk was used as the study intervention.
Main outcome measures:
The incidence of C difficile infection in the 30 days after surgery was measured.
Results:
The incidence of C difficile infection in the 30-day postoperative period was significantly higher (3.04% vs 1.25%; p < 0.001) in patients undergoing stoma reversal. After controlling for differences in cohorts, regression analysis suggested that stoma reversal (OR = 2.701 (95% CI, 1.966-3.711); p < 0.001), smoking (OR = 1.520 (95% CI, 1.063-2.174); p = 0.022), steroids (OR = 1.677 (95% CI, 1.005-2.779); p = 0.048), and disseminated cancer (OR = 2.312 (95% CI, 1.437-3.719); p = 0.001) were associated with C difficile infection incidence in the 30-day postoperative period.
Limitations:
The study was limited because it was a retrospective database review with observational bias.
Conclusions:
Patients who undergo elective stoma reversal have a higher incidence of postoperative C difficile infection compared with patients who undergo an elective colectomy. Given the impact of postoperative C difficile infection, a heightened sense of suspicion should be given to symptomatic patients after stoma reversal. See at Video Abstract at http://links.lww.com/DCR/A553.
... Another retrospective colectomy database review of 2015 demonstrated that stoma reversal, smoking, steroids, and disseminated cancer were associated with CDI in the 30-day post-operative period [13]. ...
Background:
The aim of this study was to determine the incidence of Clostridium Difficile infection (CDI) after stoma reversal in patients who underwent transanal Total Mesorectal Excision (TaTME) and to evaluate variables correlated with this post-operative infection.
Methods:
Patients who underwent stoma reversal surgery following TaTME for rectal cancer between 2015 and 2023 at a high-volume Institution, were retrospectively reviewed for the post-operative occurrence of diarrhea and in-hospital CDI (positive toxin in the stools). Patients were divided into the following subgroups according to the post-operative course: Group A-no clinical symptoms; Group B-mild diarrhea (< 10 evacuations/day); Group C-severe watery diarrhea (> 10 evacuations/day) with CDI negative; and Group D-severe watery diarrhea (> 10 evacuations/day) CDI positive. Clinical and laboratory data were analyzed for their correlation with CDI. A machine learning approach was used to determine predictors of diarrhea following stoma reversal.
Results:
A total of 126 patients were selected, of whom 79 were assessed as Group A, 16 Group B, 25 Group C and 6 (4.8%) Group D. Univariable analysis documented that delayed stoma reversal correlated with CDI (Group A mean interval 44.6 weeks vs. Group D 68.4 weeks, p 0.01). The machine learning analysis confirmed the delay in stoma closure as a probability factor of presenting diarrhea; also, diarrhea probability was 80.5% in males, 77.8% in patients who underwent neoadjuvant therapy, and 63.9% in patients who underwent adjuvant therapy.
Conclusions:
Stoma reversal surgery can result in moderate rate of in-hospital CDI. Time-to stoma reversal is a crucial variable significantly related with this adverse outcome.
... Skancke et al. report the incidence of CDI as 3.04% in stoma reversal and that it is higher than 1.25% in elective colectomy with p < 0.0001. 2 In our case, this patient was infected with CDI after the emergency loop ileostomy. ...
... Notably, however, the CDI rate is still consistently reported to be much higher after colorectal surgery versus the healthy population (1 to 2.2 per cent), and is twofold more likely following colorectal procedures than after surgeries not involving the gastrointestinal tract 8 . Furthermore, patients who undergo ileostomy closure have a reported CDI incidence of up to 4 per cent [9][10][11] . ...
Background:
Diverting ileostomy during resection of rectal cancer is frequently performed in patients at risk of anastomotic failure. Clostridium difficile infection (CDI) is reported to be frequent in patients who receive ileostomy closure with a questionable association to postoperative anastomosis leak. The primary aim of this study was to determine the incidence of CDI following ileostomy closure in patients who underwent rectal cancer surgery; the secondary aim was to assess the rate of postileostomy closure CDI in patients who presented with leakage at the original colorectal anastomosis site.
Methods:
Medical records of patients with rectal cancer who underwent ileostomy closure between January 2015 and December 2019 were retrospectively reviewed. All patients had previously received resection and anastomosis for primary rectal cancer with diverting ileostomy. Data regarding CDI incidence, preoperative status, perioperative management, and clinical outcomes were collected. CDI positivity was determined by direct real-time PCR and enzyme-linked fluorescent assays for detecting toxin A and B.Statistical analyses were computed for CDI risk factors.
Results:
A total of 1270 patients were included and 208 patients were tested for CDI owing to colitis-related symptoms. The incidence of CDI was 3.6 per cent (46 patients). Multivariable analysis for CDI risk factors identified adjuvant chemotherapy (hazard ratio (HR) 2.28; P = 0.034) and colorectal anastomosis leakage prior to CDI (HR 3.75; P = 0.008). Finally, patients with CDI showed higher colorectal anastomosis leakage risk in multivariable analysis after ileostomy closure (HR 6.922; P = 0.001).
Conclusion:
Patients with CDI presented with a significantly higher rate of colorectal anastomosis leakage prior to ileostomy closure.
... One study investigated the impact of a proctectomy when a total abdominal colectomy was performed but did not find a significant difference in CDI risk between the two operations [6]. Another study that utilized the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database compared elective stoma reversals with elective colectomies and found that elective stoma reversals are associated with a higher incidence of CDI [7]. Neither of these studies has investigated the clinical impact of the removal of part of the terminal ileum on the rate of CDI after a colectomy. ...
Introduction
The removal of the terminal ileum may interfere with gut-associated lymphoid tissue function, reduce bile salt reabsorption, and change intraluminal pH, which may contribute to the development of Clostridium difficile infection (CDI) after ileocolic resections. Therefore, we compared CDI incidence among patients who underwent a colectomy with or without removal of the terminal ileum.
Methods
Using the 2016 American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Targeted Colectomy database, we identified 17,962 patients who underwent a left-sided colectomy without removal of the terminal ileum and 5,929 patients who underwent an ileocolic resection involving the removal of the terminal ileum. Patients who underwent an emergency operation or had enterocolitis as the indication for surgery were excluded.
Results
Patients who underwent an ileocolic resection developed higher rates of postoperative CDI than those who underwent a left hemicolectomy (p<0.001). Multivariate logistic regression analysis demonstrated that removing the ileum was associated with a 50% higher risk of developing CDI than patients who underwent a left-sided colectomy. Additional risk factors for developing postoperative CDI were advanced age (p=0.001) and mechanical bowel preparation (p=0.001). On the other hand, factors independently associated with a lower risk of postoperative CDI were male gender (p<0.001), preoperative oral antibiotics (p<0.001), and preoperative chemotherapy use within 90 days (p<0.013).
Conclusion
Overall, patients who undergo operations involving the removal of the ileum are at higher risk for developing CDI. To reduce the risk among these patients, we suggest employing preoperative oral antibiotics in part of bowel preparation. Furthermore, it is critical to maintain hygienic measures, such as handwashing and disinfecting surfaces, and attentive care for these patients.
... Furthermore, this work is limited by its inability to accurately investigate C. difficile recurrence rates among patients who underwent DLI, especially after ileostomy closure, as a secondary diagnostic code for C. difficile could be referencing the patient's personal history of disease rather than a true recurrent infection. This would be an important outcome to study because of the potential role of C. difficile prophylaxis in this subgroup of patients [24]. ...
IntroductionDiverting loop ileostomy (DLI) and colonic lavage has emerged as a valid alternative to total abdominal colectomy (TAC) for the surgical management of Clostridioides difficile colitis (CDC). However, little data are available on outcomes beyond the index admission. The objective of this study was to compare post-discharge outcomes between patients who underwent DLI and TAC for CDC.Methods
Adult patients who underwent DLI or TAC for CDC between 2011 and 2016 were identified from the Nationwide Readmissions Database, and only discharges between January and September in each calendar year were included to allow for a 90-day follow-up period for all cases. Ninety-day overall in-hospital mortality (index admission mortality plus 90-day post-discharge mortality) and 90-day unplanned readmissions were compared. To assess 6-month ileostomy reversal rates, the cohort was then truncated to exclude discharges after June in each calendar year. Multivariate regression was used to adjust for patient demographics and disease severity.ResultsIn total, 2070 patients were discharged between January and September of each included year: 1486 (71.8%) TAC compared to 584 (28.2%) DLI. Overall in-hospital mortality was higher among patients who underwent TAC (34.5% vs. 27.7%, p = 0.004); however, this association did not remain on multivariate regression (OR 1.14, 95% CI 0.91–1.43). Among the 1434 patients who were discharged alive, the 90-day unplanned readmission rate was similar in both groups (TAC: 26.1% vs. DLI: 23.1%, p = 0.26). After truncating the cohort to those patients discharged alive between January and June of each included year (n = 1016), patients who underwent DLI had a significantly greater 6-month ileostomy reversal rate (26.4% vs. 8.3%, p < 0.001). DLI was independently associated with higher odds of 6-month ileostomy reversal (OR 2.68, 95% CI 1.80–4.00).Conclusions
In the surgical management of CDC, DLI is associated with equivalent mortality and unplanned readmission, but greater likelihood of 6-month ileostomy reversal, compared to TAC.
... Rates of postoperative CDI were reported to be ranging from 0.54 to 2.37% [2]. Skancke et al. reported that stoma reversal was a risk factor for CDI [3]. To the best of our knowledge, there have been no previous reports of treatment with the administration of vancomycin through a transverse colostomy created after CDI. ...
... Recently, a retrospective colectomy database review of the 2015 American College of Surgeons National Surgical Quality Improvement Project [102] demonstrated that stoma reversal (OR = 2.701, 95% CI 1.966-3.711; p < 0.001), smoking (OR = 1.520, 95% CI 1.063-2.174; ...
In the last three decades, Clostridium difficile infection (CDI) has increased in incidence and severity in many countries worldwide. The increase in CDI incidence has been particularly apparent among surgical patients. Therefore, prevention of CDI and optimization of management in the surgical patient are paramount. An international multidisciplinary panel of experts from the World Society of Emergency Surgery (WSES) updated its guidelines for management of CDI in surgical patients according to the most recent available literature. The update includes recent changes introduced in the management of this infection.
Tobacco use is associated with poor surgical outcomes and is the leading cause of preventable morbidity and mortality in the United States. Because of the risk for postoperative complications, researchers continue to examine the association between surgical patients’ smoking status and adverse outcomes. This quantitative integrative review synthesizes evidence on the relationship between smoking status and postoperative outcomes according to information in the American College of Surgeons National Surgical Quality Improvement Program data set. The included studies involved 10 procedures and the evaluated outcomes comprise surgical complications (eg, surgical site infection), medical complications (eg, sepsis), and transitions in care (eg, discharge destination). The review results are mixed and are not generalizable because only two studies specified smoking status as a primary variable of interest. To develop policies for perioperative patient smoking cessation, perioperative nurses require additional research results on the relationships between smoking status and standardized variables.
Clostridioides difficile remains a major cause of morbidity and mortality in the intensive care unit, and therefore, C difficile guidelines are frequently being updated. Currently, fidaxomicin is the suggested treatment of initial and recurrent infection. Oral vancomycin is an acceptable alternative, followed by rifaximin and fecal microbiota transplantation. Bezlotoxumab is suggested in recurrent cases within 6 months. If patients fail to improve within 3 to 5 days of therapy, especially in patients who have had nasogastric tubes or emergent surgery, fulminant colitis is possible and surgical consultation should be considered for total colectomy.
Background
Clostridioides difficile infection is reported to occur after 2.2% of colorectal operations and is associated with longer length of hospital stay, greater overall healthcare cost, and significant morbidity and mortality. The incidence of Clostridioides difficile infection is greatest after elective stoma reversal. The purpose of this study was to evaluate the effect of prior Clostridioides difficile infection on patients undergoing stoma reversal. We hypothesized that patients with a history of Clostridioides difficile infection who underwent stoma reversal will be at an increased risk of postoperative Clostridioides difficile infection compared with patients without a history of Clostridioides difficile infection.
Methods
This was an observational cohort study of patients undergoing elective stoma reversal surgery by colorectal surgeons at a single academic institution during a 10-year period. A prospectively maintained institutional database was queried to identify 454 patients who underwent stoma reversal surgery between January 1, 2007 and December 31, 2017. The primary outcomes were Clostridioides difficile infection after stoma reversal and time to Clostridioides difficile infection after bowel refunctionalization. Secondary outcomes included postoperative complications, length of hospital stay, discharge destination, and 30-day readmission rate. Univariate and multivariable logistic regression analyses were conducted to identify factors associated with Clostridioides difficile infection after stoma reversal.
Results
A total of 445 patients were identified who underwent elective stoma reversal, 42 of whom had a history of Clostridioides difficile infection before the stoma reversal. There were no significant differences in patient age, number of days diverted, or use of perioperative antibiotics between patients with and without a history of Clostridioides difficile infection. The incidence of postreversal Clostridioides difficile infection was 23.4% in patients with a history of Clostridioides difficile infection compared with 9.6% in patients with no Clostridioides difficile infection history (P = .004); however, time to Clostridioides difficile infection after reversal did not differ. History of Clostridioides difficile infection was also associated with greater risk of postoperative complications (26.2% vs 9.4%, P < .01), increased length of stay (3 vs 5 days postoperatively, P < .01), increased likelihood of discharge to a skilled-care facility (11.9% vs 6.2%, P < .01), and readmission (13.7 vs 31.0%, P < .01) within 30 days. In a multivariable logistic regression model, history of Clostridioides difficile infection, increased length of hospital stay, and discharge to a skilled facility were associated with increased risk of Clostridioides difficile infection after reversal, while proton pump inhibitors use was associated with decreased risk of Clostridioides difficile infection.
Conclusion
Patients with a prior history of Clostridioides difficile infection who underwent stoma reversal exhibited higher rates of postoperative Clostridioides difficile infection and were at greater risk of postoperative complications, discharge to a skilled facility, and 30-day readmission. Furthermore, research into interventions aimed at improving outcomes in this unique, high-risk population is needed.
Background:
There is controversy surrounding the efficacy and safety of colonic stents as a bridge to surgery compared with immediate resection in patients presenting with an acute malignant large bowel obstruction.
Methods:
Retrospective longitudinal cohort study using the NYS SPARCS Database. Patients with acute malignant large bowel obstruction who either had stent followed by elective surgery within 3 weeks (bridge to surgery) or underwent immediate resection between October 2009 and June 2016 in the state of New York were included. The primary outcome was rate of stoma creation at index resection. Secondary outcomes were 90-day readmission, reoperation, procedural complications, and discharge disposition.
Results:
A total of 3059 patients were included, n = 2917 (95.4%) underwent an immediate resection and n = 142 (4.6%) underwent bridge to surgery. We analyzed 139 patients in propensity score-matched groups. Patients in the bridge to surgery group were less likely than those in the immediate resection group to get a stoma at the time of surgery (OR 0.33, 95% CI 0.18-0.60). They were also less likely to be discharged to a rehabilitation facility or require a home health aide upon discharge (OR 0.36, 95% CI 0.22-0.61). There were no differences in rates of 90-day readmission, reoperation, or procedural complications between groups.
Discussion:
Colonic stenting as a bridge to surgery leads to less stoma creation, a significant quality of life advantage, compared with immediate resection. Patients should be counseled regarding these potential benefits when the technology is available.
Introduction. In the last five years (from 1st of January 2013 to 31st of December 2017), we noticed 6 cases of rectal cancer, developed in patients who underwent stoma reversal more than two years before, for different pathologies.
The objective of the study. That was a starting point to analyze whether the restoration of a total digestive diversion, well known to improve life quality, also increases the risk of malignancy.
Material and methods. We studied all the patients with colostomy reversal hospitalized in the General Surgery Clinic of the Emergency Clinical Hospital “Sfântul Pantelimon“, Bucharest, Romania, in a ten years interval (1st of January 2008 – 31st of December 2017), no matter the primary cause of colostomy was.
Results. Our study showed that stoma reversal increase the risk of developing a rectal malignancy two years from restoration.
Conclusions. We recommend annual control by recto‑sigmoidoscopy both in patients with terminal permanent colostomy and in those with stoma reversal, in order to early discover a subsequent rectal cancer.
Primary bile acids serve important roles in cholesterol metabolism, lipid digestion, host-microbe interactions, and regulatory pathways in the human host. While most bile acids are reabsorbed and recycled via enterohepatic cycling, ∼5% serve as substrates for bacterial biotransformation in the colon. Enzymes involved in various transformations have been characterized from cultured gut bacteria and reveal taxa-specific distribution. More recently, bioinformatic approaches have revealed greater diversity in isoforms of these enzymes, and the microbial species in which they are found. Thus, the functional roles played by the bile acid-transforming gut microbiota and the distribution of resulting secondary bile acids, in the bile acid pool, may be profoundly affected by microbial community structure and function. Bile acids and the composition of the bile acid pool have historically been hypothesized to be associated with several disease states, including recurrent Clostridium difficile infection, inflammatory bowel diseases, metabolic syndrome, and several cancers. Recently, however, emphasis has been placed on how microbial communities in the dysbiotic gut may alter the bile acid pool to potentially cause or mitigate disease onset. This review highlights the current understanding of the interactions between the gut microbial community, bile acid biotransformation, and disease states, and addresses future directions to better understand these complex associations.
OBJECTIVE
To determine the typical microbial bioburden (overall bacterial and multidrug-resistant organisms [MDROs]) on high-touch healthcare environmental surfaces after routine or terminal cleaning.
DESIGN
Prospective 2.5-year microbiological survey of large surface areas (>1,000 cm ² ).
SETTING
MDRO contact-precaution rooms from 9 acute-care hospitals and 2 long-term care facilities in 4 states.
PARTICIPANTS
Samples from 166 rooms (113 routine cleaned and 53 terminal cleaned rooms).
METHODS
Using a standard sponge-wipe sampling protocol, 2 composite samples were collected from each room; a third sample was collected from each Clostridium difficile room. Composite 1 included the TV remote, telephone, call button, and bed rails. Composite 2 included the room door handle, IV pole, and overbed table. Composite 3 included toileting surfaces. Total bacteria and MDROs (ie, methicillin-resistant Staphylococcus aureus , vancomycin-resistant enterococci [VRE], Acinetobacter baumannii , Klebsiella pneumoniae , and C. difficile ) were quantified, confirmed, and tested for drug resistance.
RESULTS
The mean microbial bioburden and range from routine cleaned room composites were higher (2,700 colony-forming units [CFU]/100 cm ² ; ≤1–130,000 CFU/100 cm ² ) than from terminal cleaned room composites (353 CFU/100 cm ² ; ≤1–4,300 CFU/100 cm ² ). MDROs were recovered from 34% of routine cleaned room composites (range ≤1–13,000 CFU/100 cm ² ) and 17% of terminal cleaned room composites (≤1–524 CFU/100 cm ² ). MDROs were recovered from 40% of rooms; VRE was the most common (19%).
CONCLUSIONS
This multicenter bioburden summary provides a first step to determining microbial bioburden on healthcare surfaces, which may help provide a basis for developing standards to evaluate cleaning and disinfection as well as a framework for studies using an evidentiary hierarchy for environmental infection control.
Infect Control Hosp Epidemiol 2016;1426–1432
In 2009 the first European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guideline for diagnosing Clostridium difficile infection (CDI) was launched. Since then newer tests for diagnosing CDI have become available, especially nucleic acid amplification tests. The main objectives of this update of the guidance document are to summarize the currently available evidence concerning laboratory diagnosis of CDI and to formulate and revise recommendations to optimize CDI testing. This update is essential to improve the diagnosis of CDI and to improve uniformity in CDI diagnosis for surveillance purposes among Europe. An electronic search for literature concerning the laboratory diagnosis of CDI was performed. Studies evaluating a commercial laboratory test compared to a reference test were also included in a meta-analysis. The commercial tests that were evaluated included enzyme immunoassays (EIAs) detecting glutamate dehydrogenase, EIAs detecting toxins A and B and nucleic acid amplification tests. Recommendations were formulated by an executive committee, and the strength of recommendations and quality of evidence were graded using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. No single commercial test can be used as a stand-alone test for diagnosing CDI as a result of inadequate positive predictive values at low CDI prevalence. Therefore, the use of a two-step algorithm is recommended. Samples without free toxin detected by toxins A and B EIA but with positive glutamate dehydrogenase EIA, nucleic acid amplification test or toxigenic culture results need clinical evaluation to discern CDI from asymptomatic carriage.
Clostridium difficile infection (CDI) has increased in incidence and severity worldwide, causing direct costs estimated to range from US $3.2 billion to $4.8 billion. The aim of this study was to investigate and identify factors that predict recurrence of CDI.
This was a retrospective case-control study between 2007 and 2013 on patients admitted with CDI. Recurrent CDI is defined as a new episode of diarrhea within 90 days confirmed by a positive stool C. difficile toxin assay or polymerase chain reaction, after resolution of the initial CDI episode for at least 10 days and after discontinuation of the CDI therapy.
Three thousand twenty patients were diagnosed with CDI between January 2007 and December 2013. Two hundred nine of 2019 patients in the study had a recurrence of CDI within 90 days of the end of the initial CDI episode (10.3%). Multivariate analysis showed that most of the recurrences occurred in patients with comorbidities, particularly chronic kidney disease (odds ratio, 1.3; 95% confidence interval [CI], 1.0-2.4; P = 0.039). In addition, a higher percentage of patients in the recurrence group were prescribed proton-pump inhibitors (odds ratio, 1.65; 95% CI, 1.0-1.7; P = 0.002) and steroids (odds ratio, 1.65; 95% CI, 1.0-1.5; P = 0.047).
Our data suggest that the use of glucocorticoids, use of proton-pump inhibitors, and having end-stage renal disease are significant risk factors associated with recurrent CDI.
The magnitude and scope of Clostridium difficile infection in the United States continue to evolve.
In 2011, we performed active population- and laboratory-based surveillance across 10 geographic areas in the United States to identify cases of C. difficile infection (stool specimens positive for C. difficile on either toxin or molecular assay in residents ≥ 1 year of age). Cases were classified as community-associated or health care-associated. In a sample of cases of C. difficile infection, specimens were cultured and isolates underwent molecular typing. We used regression models to calculate estimates of national incidence and total number of infections, first recurrences, and deaths within 30 days after the diagnosis of C. difficile infection.
A total of 15,461 cases of C. difficile infection were identified in the 10 geographic areas; 65.8% were health care-associated, but only 24.2% had onset during hospitalization. After adjustment for predictors of disease incidence, the estimated number of incident C. difficile infections in the United States was 453,000 (95% confidence interval [CI], 397,100 to 508,500). The incidence was estimated to be higher among females (rate ratio, 1.26; 95% CI, 1.25 to 1.27), whites (rate ratio, 1.72; 95% CI, 1.56 to 2.0), and persons 65 years of age or older (rate ratio, 8.65; 95% CI, 8.16 to 9.31). The estimated number of first recurrences of C. difficile infection was 83,000 (95% CI, 57,000 to 108,900), and the estimated number of deaths was 29,300 (95% CI, 16,500 to 42,100). The North American pulsed-field gel electrophoresis type 1 (NAP1) strain was more prevalent among health care-associated infections than among community-associated infections (30.7% vs. 18.8%, P<0.001).
C. difficile was responsible for almost half a million infections and was associated with approximately 29,000 deaths in 2011. (Funded by the Centers for Disease Control and Prevention.).
Data on risk factors for Clostridium difficile infection (CDI) in diabetic patients are scarce. Recently, it has been shown that metformin increases the Bacteroidetes/Firmicutes ratio; therefore, it may yield a protective effect against CDI. We aimed to assess risk factors for CDI in diabetic patients beyond antibiotic treatment, and to determine the impact of metformin therapy on the development of CDI in these patients. In this retrospective, case-control study, all consecutive CDI diabetic patients, from January 2009 to December 2013, were included and compared to consecutive diabetic patients without CDI, hospitalized during the same period and in the same departments. Of 7,670 patients tested for C. difficile toxins, 486 were diabetics. Of them, 150 (30.8 %) were positive for C. difficile toxins and 336 (69.1 %) were negative. On multivariate analysis, metformin treatment was associated with a significant reduction in CDI [odds ratio (OR) = 0.58; 95 % confidence interval (CI), 0.37-0.93; p = 0.023], while heart failure was associated with significantly higher rates of CDI (OR = 1.654; 95 % CI, 1.007-2.716; p = 0.047), together with poor functional status, previous hospitalization, and abdominal surgery. Our findings suggest that, in diabetic patients, in addition to the well-recognized risk factors, heart failure is an additional risk factor for CDI, while metformin treatment seems to have a protective effect against the development of CDI. The exact mechanisms underlying this protective effect remain to be fully understood.
Clostridium difficile infection is the leading cause of health care-associated diarrhea, and the bacterium can also be carried asymptomatically. The objective of this study was to identify host and bacterial factors associated with health care-associated acquisition of C. difficile infection and colonization.
We conducted a 15-month prospective study in six Canadian hospitals in Quebec and Ontario. Demographic information, known risk factors, potential confounding factors, and weekly stool samples or rectal swabs were collected. Pulsed-field gel electrophoresis (PFGE) was performed on C. difficile isolates to determine the genotype. Levels of serum antibodies against C. difficile toxins A and B were measured.
A total of 4143 patients were included in the study; 117 (2.8%) and 123 (3.0%) had health care-associated C. difficile infection and colonization, respectively. Older age and use of antibiotics and proton-pump inhibitors were significantly associated with health care-associated C. difficile infection. Hospitalization in the previous 2 months; use of chemotherapy, proton-pump inhibitors, and H(2) blockers; and antibodies against toxin B were associated with health care-associated C. difficile colonization. Among patients with health care-associated C. difficile infection and those with colonization, 62.7% and 36.1%, respectively, had the North American PFGE type 1 (NAP1) strain.
In this study, health care-associated C. difficile infection and colonization were differentially associated with defined host and pathogen variables. The NAP1 strain was predominant among patients with C. difficile infection, whereas asymptomatic patients were more likely to be colonized with other strains. (Funded by the Consortium de Recherche sur le Clostridium difficile.).
Clostridium difficile infection (CDI) has increased in frequency and severity over the past decade. An understanding of the modifiable risk factors for disease severity has considerable clinical applicability.
We performed a retrospective case review of 485 cases in patients aged 1-99 years at the Naval Medical Center San Diego from November 2004 through December 2008. We compared potential risk factors for association with complications (megacolon, surgery, intensive care unit stay, and death) or mortality alone with use of univariable and multivariable logistic regression modeling.
Forty-seven patients (9.8%) developed ≥1 complication, and 23 (4.7%) died. We found independent associations between complications and acid suppression (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.2-4.79), admission for CDI (OR, 4.14; 95% CI, 2.17-7.92), older age (≥80 years; OR, 3.14; 95% CI, 1.46-6.73), and corticosteroid use (OR, 2.09; 95% CI, 1.01-4.35). Age ≥80 years (OR, 5.51; 95% CI, 2.25-13.49) and acid suppression (OR, 4.74; 95% CI, 1.57-14.37) were associated with increased odds of death.
Data published elsewhere have suggested that acid suppression therapy is a risk factor for CDI acquisition and relapse. These findings suggest an additional role in increased severity of disease, including mortality, and merit further study.
Glucocorticoids are commonly used to treat various illnesses in patients at risk for Clostridium difficile-associated disease (CDAD), but the effect of such immunosuppression on outcome has not been studied. We hypothesized that glucocorticoid use increases the risk of 30-day mortality in patients with CDAD.
We identified consecutive inpatients from 1 January 2004 to 30 September 2008, who had a positive Clostridium difficile toxin assay and recorded their demography, glucocorticoid usage before CDAD diagnosis, 30-day mortality, Charlson comorbidity score, and pertinent laboratory data. Three cohorts were created: Group 1: CDAD (+) without glucocorticoid use, Group 2: CDAD (+) with glucocorticoid use, and Group 3: CDAD (-) with symptomatic diarrhea and receiving glucocorticoids.
Groups 1, 2, and 3 consisted of 841, 285, and 898 patients, respectively. Significant multivariate predictors of short-term mortality were age in Group 1 (P<0.001); age (P=0.007), Charlson score (P=0.004), and an endocrine indication for glucocorticoid use (P<0.01) in Group 2; and age (P<0.001), sex, (P=0.02), Charlson score (P<0.001), weight-adjusted glucocorticoid dose (1.10+/-0.03), and prednisone use (P<0.01) in Group 3. When considering all patients with CDAD (Groups 1 and 2), the use of any glucocorticoid resulted in an increased mortality with a hazard ratio of 2.1+/-0.19 (P<0.001). Mortality rates were 9.6%, 19.3%, and 9.7% for Groups 1, 2, and 3 (P<0.001 for Groups 1 and 3 vs. Group 2), respectively. Through Kaplan-Meier survival analysis, comparing the three groups revealed that patients with CDAD who received glucocorticoids were at significantly increased risk of short-term mortality compared with the control groups (Groups 1 and 3, P<0.001).
Mortality of patients with CDAD on glucocorticoids, regardless of the severity of CDAD, was significantly higher than the mortality of patients with CDAD not on glucocorticoids and those on glucocorticoids with symptomatic diarrhea and without C. difficile infection.
The association between corticosteroid therapy and subsequent infections was calculated by pooling data from 71 controlled
clinical trials. The overall rate of infectious complications was 12.7% in the 2,111 patients randomly allocated to systemic
corticosteroids and 8.0% in the 2,087 controls (relative risk [RR], 1.6; 95% confidence interval [CI], 1.3–1.9; P < .001). The risk of infection was particularly high in patients with neurologic diseases (RR, 2.8; 95% CI, 1.9–4.3; P< .001) and less pronounced in patients with intestinal (RR, 1.4; 95% CI, 1.1–1.7; P = .02), hepatic (RR, 1.4; 95% CI, 0.9–2.3; P = .25), and renal (RR>1; P = .03) diseases. The rate was not increased in patients given a daily dose of <10 mg or a cumulative dose of <700 mg of prednisone.
With increasing doses the rate of occurrence of infectious complications increased in patients given corticosteroids as well
as in patients given placebo, a finding suggesting that not only the corticosteroid but also the underlying disease state
account for the steroid-associated infectious complications observed in clinical practice.
The association between the use of proton pump inhibitors and the risk of Clostridium difficile-associated disease (CDAD) is controversial. In this study we re-examined a previously reported association between the use of proton pump inhibitors and the development of community-acquired CDAD, this time using an alternative case definition of the disease.
We performed a case-control study of community-acquired CDAD using a United Kingdom clinical research database. Patients receiving oral vancomycin therapy were identified as having CDAD, the only indication for this drug. Each case subject was matched with up to 10 control subjects. Neither the cases nor the controls had been admitted to hospital in the year before the date of the vancomycin prescription (index date). Conditional logistic regression analysis was used to adjust for key covariates.
We identified 317 cases of community-acquired CDAD treated with oral vancomycin therapy and 3167 matched control subjects. Exposure to a proton pump inhibitor in the 90 days before the index date was associated with an increased risk of CDAD (odds ratio [OR] 3.5, 95% confidence interval [CI] 2.3-5.2). Antibiotic exposure in the 90 days before the index date was also a significant risk factor for community-acquired CDAD (OR 8.2, 95% CI 6.1- 11.0), even though 45% of the case subjects had not received a prescription for an antibiotic during that period. Certain comorbidities, in particular renal failure, inflammatory bowel disease and malignant disease, as well as prior methicillin-resistant Staphylococcus aureus infection, were also associated with an increased risk.
Proton pump inhibitor use was associated with an increased risk of community-acquired CDAD, when cases were defined by receipt of prescription for oral vancomycin therapy. Prior antibiotic exposure was also a significant risk factor, but a significant proportion of the patients with community-acquired CDAD had no such exposure.
INTRODUCTION
In 2010, we published an initial Point-Counterpoint on the laboratory diagnosis of Clostridium difficile infection (CDI). At that time, nucleic acid amplification tests (NAATs) were just becoming commercially available, and the idea of algorithmic approaches to CDI was being explored. Now, there are numerous NAATs in the marketplace, and based on recent proficiency test surveys, they have become the predominant method used for CDI diagnosis in the United States. At the same time, there is a body of literature that suggests that NAATs lack clinical specificity and thus inflate CDI rates. Hospital administrators are taking note of institutional CDI rates because they are publicly reported. They have become an important metric impacting hospital safety ratings and value-based purchasing; hospitals may have millions of dollars of reimbursement at risk. In this Point-Counterpoint using a frequently asked question approach, Ferric Fang of the University of Washington, who has been a consistent advocate for a NAAT-only approach for CDI diagnosis, will discuss the value of a NAAT-only approach, while Christopher Polage of the University of California Davis and Mark Wilcox of Leeds University, Leeds, United Kingdom, each of whom has recently written important articles on the value of toxin detection in the diagnosis, will discuss the impact of toxin detection in CDI diagnosis.
Objective:
To assess whether receipt of antibiotics by prior hospital bed occupants is associated with increased risk for CDI in subsequent patients who occupy the same bed.
Design, setting, and participants:
This is a retrospective cohort study of adult patients hospitalized in any 1 of 4 facilities between 2010 and 2015. Patients were excluded if they had recent CDI, developed CDI within 48 hours of admission, had inadequate follow-up time, or if their prior bed occupant was in the bed for less than 24 hours.
Main outcomes and measures:
The primary exposure was receipt of non-CDI antibiotics by the prior bed occupant and the primary outcome was incident CDI in the subsequent patient to occupy the same bed. Incident CDI was defined as a positive result from a stool polymerase chain reaction for the C difficile toxin B gene followed by treatment for CDI. Demographics, comorbidities, laboratory data, and medication exposures are reported.
Results:
Among 100 615 pairs of patients who sequentially occupied a given hospital bed, there were 576 pairs (0.57%) in which subsequent patients developed CDI. Receipt of antibiotics in prior patients was significantly associated with incident CDI in subsequent patients (log-rank P < .01). This relationship remained unchanged after adjusting for factors known to influence risk for CDI including receipt of antibiotics by the subsequent patient (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.02-1.45) and also after excluding 1497 patient pairs among whom the prior patients developed CDI (aHR, 1.20; 95% CI, 1.01-1.43). Aside from antibiotics, no other factors related to the prior bed occupants were associated with increased risk for CDI in subsequent patients.
Conclusions and relevance:
Receipt of antibiotics by prior bed occupants was associated with increased risk for CDI in subsequent patients. Antibiotics can directly affect risk for CDI in patients who do not themselves receive antibiotics.
Introduction:
Clostridium difficile infection (CDI) is a significant cause of healthcare-associated diarrhoea, and the emergence of endemic strains resulting in poorer outcomes is recognised worldwide. Patients with cancer are a specific high-risk group for development of infection.
Areas covered:
In this review, modifiable and non-modifiable risk factors for CDI in adult patients with haematological malignancy or solid tumours are evaluated. In particular, the contribution of antimicrobial exposure, hospitalisation and gastric acid suppression to risk of CDI are discussed. Recent advances in CDI treatment are outlined, namely faecal microbiota transplantation and fidaxomicin therapy for severe/refractory infection in cancer populations. Outcomes of CDI, including mortality are presented, together with the need for valid severity rating tools customised for cancer populations. Expert commentary: Future areas for research include the prognostic value of C. difficile colonisation in cancer patients and the potential impact of dedicated antimicrobial stewardship programs in reducing the burden of CDI in cancer units.
Importance
This study analyzes and reports Clostridium difficile infection (CDI) rates, risk factors, and associations with postoperative outcomes in the Veterans Health Administration (VHA).Objective
To report 30-day postoperative CDI rates and outcomes and identify associated risks by surgical procedures and preoperative patient demographics in a large integrated health care system.Design, Setting, and Participants
In a retrospective observational study conducted from September 2014 to April 2015, the Veterans Affairs Surgical Quality Improvement Program database and the Decision Support System pharmacy database were linked to analyze the association of postoperative CDI with patients’ demographics, preoperative comorbidities, operative characteristics, and preoperative medications. The Veterans Affairs Surgical Quality Improvement Program assessments from October 1, 2009, to September 30, 2013, were investigated. The study was conducted at 134 VHA surgery programs, and the study population represents 12 surgical specialties: general, gynecological, neurosurgical, oral, orthopedics, otolaryngologic, plastic, podiatric, thoracic, transplant, urologic, and peripheral vascular.Main Outcomes and Measures
Thirty-day postoperative CDI rates, risk factors of CDI, and association of CDI with postoperative morbidity and mortality.Results
Among 468 386 surgical procedures, the postoperative CDI rate was 0.4% per year and varied by the VHA Surgery Program (0.0% to 1.4%) and surgical specialty (0.0% to 2.4%). Thirty-day CDI rates were higher in emergency procedures, procedures with greater complexity and higher relative value units, and those with a contaminated/infected wound classification. Patients with postoperative CDI were significantly older, more frequently hospitalized after surgery (59.9% vs 15.4%), had longer preoperative hospital stays (9.1 days vs 1.9 days), and had received 3 or more classes of antibiotics (1.5% vs 0.3% for a single antibiotic class) (all P < .001). Patients with CDI had higher rates of other postoperative morbidity (86.0% vs 7.1%), 30-day mortality (5.3% vs 1.0%), and longer postoperative hospital stays (17.9 days vs 3.6 days). Independent risk factors for CDI included commonly identified patient factors (albumin, functional class, and weight loss), procedural characteristics (complexity, relative value units, emergency, and wound classification), surgical program complexity, the number of preoperative antibiotic classes, and length of preoperative hospital stay.Conclusions and Relevance
The number and class of antibiotics administered after surgery, preoperative length of stay, procedural characteristics, surgical program complexity, and patient comorbidities are associated with postoperative CDI in the VHA.
There is potential for person-to-person transmission in Clostridium difficile outbreak settings. A limited number of studies have examined the role of hospital roommates in the development of nosocomial infections. This retrospective cohort study evaluated room cooccupancy and duration of exposure to roommates as predictors of health care-onset C difficile infection (CDI). Among roommates of patients with CDI, duration of room cooccupancy was significantly longer in those developing CDI. Copyright
Diabetes-related hospitalization and hospital utilization is a serious challenge to the health care system, a situation which may be further aggravated by nosocomial Clostridium difficile (C. difficile) infection (CDI). Studies have demonstrated that diabetes increases the risk of recurrent CDI with OR (95% CI) 2.99 (1.88, 4.76). C. difficile is a gram-positive, spore-forming anaerobic bacterium which is widely distributed in the environment. Up to 7% of healthy adults and up to 45% of infants may have asymptomatic intestinal carriage of C. difficile. A large number of strains of C. difficile have been identified. A number of PCR or sequence-based molecular typing methods are available for typing C. difficile isolates. C. difficile virulence evolved independently in the highly epidemic lineages, associated with the expression of toxin genes and other virulence factors. This article briefly reviews recent progresses in the bateriology of C. difficile and highlights the limited knowledge of potential mechanisms for the increased risk of CDI in diabetes which warrants further research.
Background:
The incidence of Clostridium difficile infection (CDI) has risen dramatically during the last decade. Although patients respond well to medical therapy such as vancomycin, 20%-30% of patients treated suffer a recurrence of CDI.
Methods:
We developed a simple/practical scoring rule (logistic regression model) for recurrent CDI using data from 2 large phase 3 clinical trials. Seventy-seven baseline CDI factors were classified: demographics, comorbidity, medications, vital signs, laboratory tests, severity, and symptoms. Predictors with the highest discrimination in each class (using receiver operating characteristics curve) were selected. For the final model, stepwise selection was performed. Discrimination, calibration, and internal validation were used to assess the model.
Results:
The final model with a simple scoring rule was developed. It includes 4 independent risk factors that are readily available when the patient makes initial contact: age (<75 vs ≥75 years), number of unformed bowel movements during previous 24 hours (<10 vs ≥10), serum creatinine leves (<1.2 mg/dL vs ≥1.2 mg/dL) and prior episode of CDI (yes vs no). In addition, the model includes choice of treatment (vancomycin or fidaxomicin).
Conclusions:
The prediction model for recurrence may be useful for treatment decision.
Clinical trials registration:
NCT00314951 and NCT00468728.
Aim:
Previous reports describing Clostridium difficile colitis (CDC) developing after the closure of a loop ileostomy suggest it is severe. In this study the incidence of CDC following ileostomy closure and its effect on the postoperative outcome have been studied.
Method:
Patients undergoing closure of loop ileostomy from 2004 to 2008 were analysed using the Nationwide Inpatient Sample. Patients who developed postoperative CDC (n = 217) were matched 10:1 to a propensity-score-matched cohort of patients without CDC (n = 13 245). Linear and logistic regression were used to examine the effect of CDC on hospital cost (US dollars), length of stay and mortality rates. Population resampling was performed using nearest neighbour bootstrapping to confirm the validity of the results.
Results:
The incidence of CDC following ileostomy closure was 16 per 1000 patients. The mean length of stay was 11.5 days longer among CDC patients (P < 0.0001), with a greater cost of hospitalization of US$21 240 (P < 0.0001). There was no difference in mortality between the cohorts.
Conclusion:
CDC following ileostomy closure is an uncommon, costly and morbid complication. Patients undergoing stoma closure are at high risk for an adverse outcome if they have CDC. Should it develop they should be aggressively treated.
To investigate the impact of hospital-acquired Clostridium difficile infection (CDI) on hospital costs and patient length of stay.
Data from the 2007–2008 New York State Department of Health's Statewide Planning and Research Cooperative System (SPARCS) database was analyzed using regression analysis and descriptive statistics.
After analysis of 4 853 800 patient discharges, the incidence rate of hospital-acquired CDI was 0.8 cases per 1000 discharges. The estimated marginal cost associated with each hospital infection was approximately $29 000. The estimated annual cost of CDI in New York State was approximately $55 million with nearly 23 000 additional hospital days.
The development of hospital-acquired CDI is associated with a significant increase in hospital costs and patient length of stay. Extrapolation of these estimates to all US hospitals suggests this condition represents a major burden to the US healthcare system. Our findings may help hospitals understand the impact of these infections, as well as potential implications if deemed preventable by Centers for Medicare & Medicaid Services and/or private payers. Additionally, this information may benefit hospitals or health care systems transitioning to alternative payment models, such as episode-based payments or accountable care. Healthcare providers and hospitals would benefit from better understanding the impact and frequency of these infections in order to best target preventive strategies.
We sought to determine the burden of nosocomial Clostridium difficile infection in comparison to other healthcare-associated infections (HAIs) in community hospitals participating in an infection control network. Our data suggest that C. difficile has replaced MRSA as the most common etiology of HAI in community hospitals in the southeastern United States.
Tissue cultures were performed on stools from 189 patients to detect a cytopathic toxin which is neutralized by Clostridium sordellii antitoxin. Specimens satisfying these criteria were considered positive in the tissue culture assay. Stools from 26 of 27 patients with antibiotic-associated pseudomembranous colitis were positive and 16 of these specimens showed toxin titers of 10(-3) dilutions or greater. The tissue culture assay was positive with specimens from 9 of 63 patients with antibiotic-associated diarrhea without documented pseudomembrane formation. Stools from patients with neonatal necrotizing enterocolitis, ulcerative colitis, and healthy controls were uniformly negative in this assay. Cultures were performed on stools from 38 patients with antibiotic-associated diarrhea or colitis to detect clostridia which produce a cytopathic toxin in vitro. Clostridium difficile was recovered from 6 of 8 specimens which were positive in the tissue culture assay and 5 of 30 which were negative in this assay. C. sordellii was recovered in a single specimen. One hundred and nine clostridia strains were tested in the tissue culture assay and C. difficile was the only species which produced a cytopathic toxin. All strains of this organism were positive in the tissue culture assay and, in each instance, cytotoxicity was neutralized by C. sordellii antitoxin. These results indicate that C. difficile is the major cause of antibiotic-associated pseudomembranous colitis and offer an explanation for previous studies showing that the cytotoxin of stools from these patients is neutralized by C, sordellii antitoxin.
Colitis and infection due to Clostridium difficile have been reported in patients receiving antineoplastic chemotherapy for cancer without prior antibiotic treatment. Chemotherapeutic
agents can alter the normal bowel flora and cause extensive intestinal inflammatory changes, potentiating both the growth
of C. difficile and its production of toxin. This review includes all 23 known reported cases of C. difficile infection associated with antineoplastic chemotherapy and examines the pathogenesis, clinical features, and management of
this condition. Chemotherapy-associated C. difficile colitis has been documented in association with a variety of neoplasms. Various classes of antineoplastic agents have been
incriminated, methotrexate most commonly. A spectrum of illness ranging from mild to fulminant has been reported. Symptoms,
management, and outcome have appeared to be no different than for antibiotic-associated cases, but the available data are
limited. Chemotherapy-associated infection with C. difficile may be underreported because it is not suspected and/or because frequent concomitant use of antibiotics masks its true incidence.
C. difficile infection should be kept in mind whenever a patient undergoing antineoplastic chemotherapy develops diarrhea. Prompt, appropriate
diagnostic testing and early treatment may avert morbidity and death.
Recent reports suggest an increasing occurrence and severity of Clostridium difficile-associated disease. We assessed whether the use of gastric acid-suppressive agents is associated with an increased risk in the community.
To determine whether the use of gastric acid-suppressive agents increases the risk of C difficile-associated disease in a community population.
We conducted 2 population-based case-control studies using the United Kingdom General Practice Research Database (GPRD). In the first study, we identified all 1672 cases of C difficile recorded between 1994 and 2004 among all patients registered for at least 2 years in each practice. Each case was matched to 10 controls on calendar time and the general practice. In the second study, a subset of these cases defined as community-acquired, that is, not hospitalized in the prior year, were matched on practice and age with controls also not hospitalized in the prior year.
The incidence of C difficile and risk associated with gastric acid-suppressive agent use.
The incidence of C difficile in patients diagnosed by their general practitioners in the General Practice Research Database increased from less than 1 case per 100,000 in 1994 to 22 per 100,000 in 2004. The adjusted rate ratio of C difficile-associated disease with current use of proton pump inhibitors was 2.9 (95% confidence interval [CI], 2.4-3.4) and with H2-receptor antagonists the rate ratio was 2.0 (95% CI, 1.6-2.7). An elevated rate was also found with the use of nonsteroidal anti-inflammatory drugs (rate ratio, 1.3; 95% CI, 1.2-1.5).
The use of acid-suppressive therapy, particularly proton pump inhibitors, is associated with an increased risk of community-acquired C difficile. The unexpected increase in risk with nonsteroidal anti-inflammatory drug use should be investigated further.
Antibiotic-associated diarrhea and colitis were well established soon after antibiotics became available. Early work implicated Staphylococcus aureus, but in 1978 Clostridium difficile became the established pathogen in the vast majority of cases. In the first 5 years (1978 through 1983), the most common cause was clindamycin, the standard diagnostic test was the cytotoxin assay, and standard management was to withdraw the implicated antibiotic and treat with oral vancomycin. Most patients responded well, but 25% relapsed when vancomycin was withdrawn. During the next 20 years (1983 through 2003), the most commonly implicated antibiotics were the cephalosporins, which reflected the rates of use; the enzyme immunoassay replaced the cytotoxin assay because of speed of results and technical ease of performance; and metronidazole replaced vancomycin as standard treatment, and principles of containment hospitals became infection control and antibiotic control. During the recent past (2003 to 2006), C. difficile has been more frequent, more severe, more refractory to standard therapy, and more likely to relapse. This pattern is widly distributed in the United States, Canada, and Europe and is now attributed to a new strain of C. difficile designated BI, NAP1, or ribotype 027 (which are synonymous terms). This strain appears more virulent, possibly because of production of large amounts of toxins, and fluoroquinolones are now major inducing agents along with cephalosporins, which presumably reflects newly acquired in vitro resistance and escalating rates of use. The recent experience does not change principles of management of the individual patient, but it does serve to emphasize the need for better diagnostics, early recognition, improved methods to manage severe disease and relapsing disease, and greater attention to infection control and antibiotic restraint.
Intestinal flora in new-born infants.
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