Dimitri Drekonja

Fecal Microbiota Transplantation for Clostridium difficile Infection: A Systematic Review

Key Summary Points Fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI) is increasingly used, primarily for recurrent CDI but also for refractory CDI and treatment of the initial CDI episode. Although 35 studies of FMT for CDI were identified, only 2 were randomized, controlled trials (RCTs), with only 1 RCT having a non-FMT comparator group. Among the 36 patients who received FMT for recurrent CDI in the 2 RCTs, 27 (75%) had resolution of symptoms without recurrence. Among the 480 patients in 21 case-series studies who received FMT for recurrent CDI, 85% had resolution of symptoms without recurrence. Few studies reported on FMT for refractory CDI or for treatment of the initial CDI episode; among these, success rates were highly variable. Since its discovery as the cause of pseudomembranous colitis in 1978 (1, 2), Clostridium difficile has become an increasingly important pathogen. Initially largely confined to patients with health care exposure, C. difficile infection (CDI) now also affects persons with no or limited contact with the health care system (3). In 2013, the Centers for Disease Control and Prevention placed C. difficile into the top threat category (urgent) in its threat report on antimicrobial resistance (4). The high rate of recurrence15% to 30% of patients after their initial CDI episode and increasing thereafteris a major challenge (5, 6). Several treatment or recurrence episodes may result in repeated hospitalizations, clinic visits, deconditioning, malnourishment, and fecal incontinence. Antimicrobial treatment of recurrent disease yields success rates between 30% and 80%, depending on the number of recurrences and the agent and treatment duration selected (58). These suboptimal response rates have spurred investigation of additional treatment options, including fecal microbiota transplantation (FMT). Severe colonic microbiome (normal colonic bacteria) alterations are characteristic of CDI. Restoring the microbiome has been proposed to prevent recurrence, and probiotics are the most widely used intervention. However, probiotic microorganisms are less diverse than those of the organisms that characterize the colonic microbiome in healthy persons (9). Fecal microbiota transplantation is increasingly used as a treatment of recurrent CDI on the basis of the idea that importing the colonic microbiome of a healthy person is a simple method of reconstituting the normal colonic flora. Most FMT cases in the medical literature are from noncontrolled case-series studies (10). Reported success rates of up to 100% and the publication of a randomized, controlled trial (RCT) comparing FMT with antimicrobial treatment (11) have increased interest in FMT, even as regulations have evolved. The U.S. Food and Drug Administration currently requires an investigational new drug application for human studies of FMT but not for clinical use in treating CDI. The first reported use of FMT (delivered via enema) in medical literature was a small case-series study of hospitalized patients. Since then, various reports have described performing the procedure outside of the hospital, including at home by means of self-administered enema (12). Timing and frequency of FMT has also varied; most are administered in a single session, whereas others have relied on serial administration over several days. Several guidelines and reviews are available to help providers select appropriate patients for FMT, guide the selection and screening of stool donors, and choose from among the delivery methods (1315). The 2 most recent guidelines differ about the strength of evidence supporting FMTa European guideline stated that FMT is strongly recommended (A-I) after a second recurrence of CDI (13), whereas a guideline from the American College of Gastroenterology offered a more cautious recommendation, stating that if there is a third recurrence after a pulsed vancomycin regimen, fecal microbiota transplant (FMT) should be considered. (Conditional recommendation, moderate-quality evidence) (14). We did a systematic review of the evidence about the effectiveness of FMT for recurrent, refractory, and initial CDI and looked for evidence that effectiveness varied by method of transplantation. We also assessed harms of FMT and procedure acceptability. This report is derived from work done for a larger U.S. Department of Veterans Affairs Evidence-based Synthesis Program review. Methods Search Strategy We searched MEDLINE for articles published in English from 1980 to January 2015 that enrolled human participants and described FMT for known or suspected CDI (Appendix Table). We also searched the Cochrane Library and ClinialTrials.gov through January 2015. Our search included studies of any design, although we excluded case reports unless they reported harms. Additional articles, including some predating our search period or using nonstandard descriptors for CDI or FMT, were identified from hand-searching reference lists of existing systematic reviews and included studies as well as from suggestions by a technical expert panel. Appendix Table. Search Strategy Study Selection and Definitions Titles, abstracts, and articles were independently reviewed by 2 investigators, and disagreements were resolved by discussion and involvement of a third investigator, if needed. We considered initial CDI to be the first occurrence of CDI in a particular patient, recurrent CDI to be an episode occurring after previous treatment and favorable response for at least 1 previous episode, and refractory CDI to be an episode that did not respond to antimicrobial treatment. Data Abstraction and Quality Assessment Study characteristics, patient characteristics, and outcomes data were abstracted from included articles. Because all but 2 of the included studies were case-series studies, we did not formally assess quality but rather noted that conventional methods for rating strength of evidence would classify even well-conducted and reported case-series studies as high risk of bias (16). Therefore, strength of evidence would typically be considered insufficient or low. For the 2 RCTs, quality was assessed on the following criteria: allocation concealment, blinding, analysis approach, and description of withdrawalsa modification of the Cochrane approach to determining risk of bias (17). Our key outcomes included resolution of symptoms (primary outcome), time to resolution of symptoms, recurrence, all-cause mortality, and adverse events. We report results after a single administration of FMT or, in the case of studies that specified serial administration of FMT on successive days, a single prespecified series of administrations. In several studies, patients having recurrence were offered repeated FMT; these patients were categorized as having unsuccessful FMT because they met the recurrence outcome. Data Synthesis and Analysis Most findings are summarized narratively. Because the included studies report outcomes on small numbers of patients derived largely from case-series studies, any pooled estimate of the effect size and a surrounding CI was considered to be of questionable validity. Therefore, we report descriptive summaries of each included study and an overall percentage of patients remaining free of recurrent CDI. Role of the Funding Source This review was funded by the U.S. Department of Veterans Affairs. The funding source had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Members of a technical expert panel and peer reviewers of the evidence report provided advice and feedback. Technical expert panel members and peer reviewers were not compensated for their contributions. Results Our literature search yielded 190 abstracts or titles. We excluded 129 articles after abstract review and performed full-text reviews of 61 articles; of those, we excluded 51, leaving 10 articles. From hand-searching reference lists of systematic reviews and included studies and suggestions from technical expert panel members, we identified another 25 articles for a total of 35 included studies: 2 RCTs, 28 case-series studies, and 5 case reports (Figure). Figure. Summary of evidence search and selection. CDI = Clostridium difficile infection; FMT = fecal microbiota transplantation; RCT = randomized, controlled trial. * Included 1 RCT. FMT for Recurrent CDI Data From RCTs Two small RCTs with moderate risk of bias (11, 18) reported use of FMT for patients with recurrent CDI. The first compared FMT using a nasoduodenal tube with 2 control groups (43 patients; 1 withdrew after random assignment); 81% of FMT patients achieved resolution of symptoms within 3 months compared with 31% and 23% for the vancomycin and vancomycin-plus-bowel lavage control groups, respectively (P < 0.001 for FMT vs. both control groups) (11). The study, which we rated as moderate quality, was unblinded and done in the Netherlands. It was terminated after the investigators saw extremely low response rates in the control groups, which differed substantially from the 60% rate used for calculations of sample sizes. Patients had a mean age of 70 years, and 58% were men. Previous CDI episodes were numbered from 1 to 9. Administration of FMT was done after 4 to 5 days of oral vancomycin (500 mg 4 times daily), whereas the control groups received the same dose of vancomycin for 14 days. The second RCT compared 2 FMT treatment approaches, nasogastric tube and colonoscopy, in 20 patients. Overall, 70% of patients had resolution of symptoms; the difference between treatment approaches was not significant (60% in the nasogastric tube group and 80% in the colonoscopy group; P= 0.63) (18). This moderate-quality study was unblinded, did not include a non-FMT control group, and was done in the United States. The patients in this trial were

Comparative effectiveness of Clostridium difficile treatments: a systematic review

BACKGROUND Clostridium difficile infection is increasing in incidence and severity. The optimal treatment is unknown. PURPOSE To determine whether, among adults with C. difficile infection, treatment with certain antibiotics compared with others results in differences in initial cure, recurrence, and harms. DATA SOURCES MEDLINE, AMED, ClinicalTrials.gov, and Cochrane databases (search dates: inception through August 2011, limited to English-language reports); bibliography review. STUDY SELECTION Randomized, controlled trials of adults with C. difficile infection, independent of outcomes, who were treated with medications available in the United States. Observational studies reporting strain were included. DATA EXTRACTION Study design, inclusion and exclusion criteria, quality and strength of evidence as assessed by 2 reviewers, study definitions, and duration of treatment and follow-up. Outcomes included initial cure, recurrence, and treatment harms. DATA SYNTHESIS 11 trials that included 1463 participants were identified. Three trials compared metronidazole with vancomycin; 8 compared metronidazole or vancomycin with another agent, combined agents, or placebo. Strain was analyzed in 1 trial and 2 cohort studies. No study comparing 2 antimicrobial agents demonstrated a statistically significant difference for initial cure; all comparisons were of low to moderate strength of evidence. Moderate-strength evidence from 1 study demonstrated that recurrence was decreased with fidaxomicin versus vancomycin (15% vs. 25%; difference, -10 percentage points [95% CI, -17 to -3 percentage points]; P=0.005). Subgroup analysis of a single study comparing metronidazole with vancomycin for patients who have severe C. difficile infection showed no difference by intention-to-treat analysis; this was rated as insufficient-strength evidence. Harms, when reported, did not differ between treatments in any study. LIMITATIONS Definitions of diarrhea, C. difficile infection, initial cure, and relapse varied. Some studies reported insufficient detail to allow assessment of all randomly assigned participants or of harms. CONCLUSION No antimicrobial agent is clearly superior for the initial cure of C. difficile infection. Recurrence is less frequent with fidaxomicin than with vancomycin. PRIMARY FUNDING SOURCE U.S. Department of Health and Human Services.

Urinary Tract Infections

Urinary tract infection (UTI), with its diverse clinical syndromes and affected host groups, remains one of the most common but widely misunderstood and challenging infectious diseases encountered in clinical practice. Antimicrobial resistance is a leading concern, with few oral options available to treat infections caused by Gram-negative organisms resistant to trimethoprim-sulfamethoxazole and fluoroquinolones, especially for patients with upper tract disease. Efforts should be made not to detect or treat asymptomatic bacteriuria and funguria; to ensure an appropriate duration of therapy for symptomatic infections; and to limit the use of broad-spectrum agents, especially fluoroquinolones, if narrower spectrum agents are available. Further research is needed regarding rapid diagnosis of UTI, accurate presumptive identification of patients with resistant pathogens, and development of new antimicrobials for drug-resistant UTI.

Antimicrobial stewardship in outpatient settings: a systematic review.

OBJECTIVE Evaluate the effect of outpatient antimicrobial stewardship programs on prescribing, patient, microbial outcomes, and costs. DESIGN Systematic review METHODS Search of MEDLINE (2000 through November 2013), Cochrane Library, and reference lists of relevant studies. We included English language studies with patient populations relevant to the United States (eg, infectious conditions, prescription services) evaluating stewardship programs in outpatient settings and reporting outcomes of interest. Data regarding study characteristics and outcomes were extracted and organized by intervention type. RESULTS We identified 50 studies eligible for inclusion, with most (29 of 50; 58%) reporting on respiratory tract infections, followed by multiple/unspecified infections (17 of 50; 34%). We found medium-strength evidence that stewardship programs incorporating communication skills training and laboratory testing are associated with reductions in antimicrobial use, and low-strength evidence that other stewardship interventions are associated with improved prescribing. Patient-centered outcomes, which were infrequently reported, were not adversely affected. Medication costs were generally lower with stewardship interventions, but overall program costs were rarely reported. No studies reported microbial outcomes, and data regarding outpatient settings other than primary care clinics are limited. CONCLUSIONS Low- to moderate-strength evidence suggests that antimicrobial stewardship programs in outpatient settings improve antimicrobial prescribing without adversely effecting patient outcomes. Effectiveness depends on program type. Most studies were not designed to measure patient or resistance outcomes. Data regarding sustainability and scalability of interventions are limited.

Urinary tract infection in male veterans: treatment patterns and outcomes.

BACKGROUND Lengthier antimicrobial therapy is associated with increased costs, antimicrobial resistance, and adverse drug events. Therefore, establishing minimum effective antimicrobial treatment durations is an important public health goal. The optimal treatment duration and current treatment patterns for urinary tract infection (UTI) in men are unknown. We used Veterans Affairs administrative data to study male UTI treatment and outcomes. METHODS Male UTI episodes in the Veterans Affairs system (fiscal year 2009) were identified by combining International Classification of Diseases, Ninth Revision codes with UTI-relevant antimicrobial prescriptions. Episodes were categorized as index, early recurrence (<30 days), or late recurrence (≥30 days) cases. Drug name, treatment duration, and outcomes (recurrence and Clostridium difficile infection during 12 months) were recorded for index cases. Demographic, clinical, and treatment characteristics were assessed for associations with outcomes in univariate and multivariate analyses. RESULTS Among 4 854 765 outpatient male veterans, 39 149 UTI episodes involving 33 336 unique patients were identified, including 33 336 index cases (85.2%), 1772 early recurrences (4.5%), and 4041 late recurrences (10.3%). Highest-use antimicrobial agents were ciprofloxacin (62.7%) and trimethoprim-sulfamethoxazole (26.8%); 35.0% of patients received shorter-duration treatment (≤7 days), and 65.0% of patients received longer-duration treatment (>7 days). Of the index cases, 4.1% were followed by early recurrence and 9.9% by late recurrence. Longer-duration treatment was not associated with a reduction in early or late recurrence but was associated with increased late recurrence compared with shorter-duration treatment (10.8% vs 8.4%, P < .001), including in multivariate analysis (odds ratio, 1.20; 95% CI, 1.10-1.30). In addition, C difficile infection risk was significantly higher with longer-duration vs shorter-duration treatment (0.5% vs 0.3%, P = .02) and exhibited a similar suggestive trend in multivariate analysis (odds ratio, 1.42; 95% CI, 0.97-2.07). CONCLUSION Longer-duration treatment (>7 days) for male UTI in the outpatient setting was associated with no reduction in early or late recurrence.

Antimicrobial Stewardship Programs in Inpatient Hospital Settings: A Systematic Review

OBJECTIVE Evaluate the evidence for effects of inpatient antimicrobial stewardship programs (ASPs) on patient, prescribing, and microbial outcomes. DESIGN Systematic review. METHODS Search of MEDLINE (2000 through November 2013), Cochrane Library, and reference lists of relevant studies. We included English language studies with patient populations relevant to the United States (ie, infectious conditions and prescriptions required for antimicrobials) that evaluated ASP interventions and reported outcomes of interest. Study characteristics and outcomes data were extracted and reviewed by investigators and trained research personnel. RESULTS Few intervention types (eg, audit and feedback, guideline implementation, and decision support) substantially impacted patient outcomes, including mortality, length of stay, readmission, or incidence of Clostridium difficile infection. However, most interventions were not powered adequately to demonstrate impacts on patient outcomes. Most interventions were associated with improved prescribing patterns as measured by decreased antimicrobial use or increased appropriate use. Where reported, ASPs were generally associated with improvements in microbial outcomes, including institutional resistance patterns or resistance in the study population. Few data were provided on harms, sustainability, or key intervention components. Studies were typically of short duration, low in methodological quality, and varied in study design, populations enrolled, hospital setting, ASP intent, intervention composition and implementation, comparison group, and outcomes assessed. CONCLUSIONS Numerous studies suggest that ASPs can improve prescribing and microbial outcomes. Strength of evidence was low, and most studies were not designed adequately to detect improvements in mortality or other patient outcomes, but obvious adverse effects on patient outcomes were not reported.

Antimicrobial Use and Risk for Recurrent Clostridium difficile Infection

BACKGROUND Although antimicrobial use during and immediately after Clostridium difficile infection (CDI) is discouraged, the frequency and consequences of such use are poorly defined. We sought to determine the frequency of non-CDI antimicrobial therapy during and after treatment for CDI, and the association of such therapy with recurrent disease. METHODS Retrospective review of all CDI cases at a Veterans Affairs medical center from 2004-2006. Outcomes were non-CDI antimicrobial use during and within 30 days after completing CDI treatment, and recurrent CDI. RESULTS From 2004 to 2006, new-onset CDI occurred in 249 unique patients. No follow-up information was available for 3 patients, leaving 246 as study subjects. Of these, 141 (57%) received non-CDI antimicrobials, including 61 (25%) who received non-CDI antimicrobials during CDI treatment, and 80 (33%) who received non-CDI antimicrobial therapy after CDI treatment. With adjustment for age, disease severity, duration of CDI treatment, and recent hospital or intensive-care unit stay, receipt of non-CDI antimicrobials after CDI treatment was significantly associated with recurrent CDI (odds ratio [OR] 3.02; 95% confidence interval [CI], 1.66-5.52), compared with no antimicrobial use. Antimicrobial use during CDI treatment was not associated with recurrent CDI (OR 0.79; 95% CI, 0.40-1.52). Neither number of antimicrobial courses nor antimicrobial days was associated with recurrence. CONCLUSIONS Non-CDI antimicrobial therapy after an episode of CDI is common and is associated with a 3-fold increase in the odds of recurrent disease. The added risk associated with antimicrobial exposure (regardless of duration) should be considered if such therapy is contemplated.

Unnecessary Antimicrobial Use in Patients with Current or Recent Clostridium difficile Infection

OBJECTIVE To determine the fraction of unnecessary antimicrobial use among patients with current and/or recent Clostridium difficile infection (CDI). DESIGN Retrospective review from January 2004 through December 2006. SETTING Minneapolis Veterans Affairs Medical Center (MVAMC). PARTICIPANTS Patients with new-onset CDI diagnosed at the MVAMC without another CDI diagnosis in the prior 30 days. METHODS Pharmacy and medical records were reviewed to identify incident CDI cases, non-CDI antimicrobial use during and up to 30 days after completion of CDI treatment, and patient characteristics. Two infectious disease physicians independently assessed non-CDI antimicrobial use, which was classified as unnecessary if not fully indicated. Factors associated with only unnecessary use were identified through univariable and multivariable analysis. RESULTS Of 246 patients with new-onset CDI, 141 (57%) received non-CDI antimicrobials during and/or after their CDI treatment, totaling 2,147 antimicrobial days and 445 antimicrobial courses. The two reviewers agreed regarding the necessity of antimicrobials in more than 99% of antimicrobial courses (85% initially, 14% after discussion). Seventy-seven percent of patients received at least 1 unnecessary antimicrobial dose, 26% of patients received only unnecessary antimicrobials, and 45% of total non-CDI antimicrobial days included unnecessary antimicrobials. The leading indications for unnecessary antimicrobial use were putative urinary tract infection and pneumonia. Drug classes frequently used unnecessarily were fluoroquinolones and β-lactams. CONCLUSIONS Twenty-six percent of patients with recent CDI received only unnecessary (and therefore potentially avoidable) antimicrobials. Heightened awareness and caution are needed when antimicrobial therapy is contemplated for patients with recent CDI.

Antimicrobial urinary catheters: a systematic review

Catheter-associated urinary tract infection (CAUTI) is a common occurrence, often clinically unapparent and with a benign course. However, in a small fraction of patients catheter-associated bacteriuria/funguria (CABF) produces overt clinical manifestations and adverse consequences, including (at the extreme end of the spectrum) urosepsis and death. Antimicrobial-coated catheters have been proposed as a method to prevent CAUTI and are in use worldwide, although their clinical efficacy is not well known. Randomized and quasi-randomized clinical trials have demonstrated that antimicrobial-coated catheters do decrease the incidence of CABF; however, evidence that such devices provide clinically meaningful benefit is lacking. Moreover, uncertainty exists as to which of the currently marketed catheters is most effective against CABF, since no published trial has directly compared different antimicrobial-coated catheters. We conducted a systematic review to summarize and evaluate existing evidence, and to address areas of uncertainty. We found consistent but variable evidence that antimicrobial-coated catheters prevent CABF during short-term catheterization; however, no study demonstrated a clinical benefit. Future efforts in this field should include randomized trials with clinically relevant end points, as well as research to develop improved mechanisms for bladder drainage, preferably without the risks and discomfort currently associated with urinary catheters.

Preoperative Urine Cultures at a Veterans Affairs Medical Center

T he value of preoperative urine screening is unproven, except before urologic procedures, in which detection and treatment of asymptomatic bacteriuria is beneficial. Despite this, authors of multiple small case series advocate for screening before nonurologic procedures. However, patients with detected bacteriuria may undergo further testing and, if prescribed antimicrobial drugs, can develop diarrhea, allergic reactions, and Clostridium difficile infection (CDI). In addition, treatment of bacteriuria can delay procedures and extend hospitalization. Accordingly, we reviewed the medical records of patients who underwent cardiothoracic, orthopedic, and vascular procedures to document (1) the frequency of preoperative culture (UC) use, (2) the frequency of consequent antimicrobial therapy, and (3) any effect of preoperative urine screening, or consequent antimicrobial therapy, on postoperative complications.