Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial.

BACKGROUND: Fecal transplantation (FT) is a promising treatment for recurrent Clostridium difficile infection (CDI), but its true effectiveness remains unknown. We compared 14 days of oral vancomycin followed by a single FT by enema with oral vancomycin taper (standard of care) in adult patients experiencing acute recurrence of CDI. METHODS: In a phase 2/3, single-center, open-label trial, participants from Ontario, Canada, experiencing recurrence of CDI were randomly assigned in a 1:1 ratio to 14 days of oral vancomycin treatment followed by a single 500-mL FT by enema, or a 6-week taper of oral vancomycin. Patients with significant immunocompromise, history of fulminant CDI, or irreversible bleeding disorders were excluded. The primary endpoint was CDI recurrence within 120 days. Microbiota analysis was performed on fecal filtrate from donors and stool samples from FT recipients, as available. RESULTS: The study was terminated at the interim analysis after randomizing 30 patients. Nine of 16 (56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group experienced recurrence of CDI, corresponding with symptom resolution in 43.8% and 58.3%, respectively. Fecal microbiota analysis of 3 successful FT recipients demonstrated increased diversity. A futility analysis did not support continuing the study. Adverse events were similar in both groups and uncommon. CONCLUSIONS: In patients experiencing an acute episode of recurrent CDI, a single FT by enema was not significantly different from oral vancomycin taper in reducing recurrent CDI. Further research is needed to explore optimal donor selection, FT preparation, route, timing, and number of administrations. CLINICAL TRIALS REGISTRATION: NCT01226992.

Clinical cure rates in subjects treated with azithromycin for community-acquired respiratory tract infections caused by azithromycin-susceptible or azithromycin-resistant Streptococcus pneumoniae: analysis of Phase 3 clinical trial data.

BACKGROUND: Community-acquired respiratory tract infections (CARTI) are commonly caused by Streptococcus pneumoniae (SPN) and empirically treated with azithromycin. This study assessed clinical cure rates in azithromycin-treated subjects with CARTI caused by azithromycin-susceptible (Azi-S) or azithromycin-resistant (Azi-R) SPN. METHODS: 1127 subjects with CARTI (402 acute otitis media, 309 community-acquired pneumonia, 255 acute bacterial exacerbations of chronic bronchitis and 161 acute bacterial sinusitis) in 13 Phase 3 clinical trials (1993-2007) had a confirmed pathogen, received azithromycin and were assessed for clinical cure/failure. 34.4% of subjects (388/1127) had a positive culture for SPN; 33.4% (376/1127) had Azi-S or Azi-R SPN. RESULTS: 28.9% (112/388) of subjects with SPN had Azi-R SPN: 35.7% (40/112) were low-level Azi-R SPN (LLAR; MIC 2-8 mg/L), while 64.3% (72/112) were high-level Azi-R SPN (HLAR; MIC ≥16 mg/L). Among Azi-S and Azi-R SPN CARTI subjects, clinical cure rates were: 86.2% (324/376) overall; 89.4% (236/264) for subjects with Azi-S SPN; 78.6% (88/112) for subjects with Azi-R SPN (P = 0.003, versus Azi-S); 77.5% (31/40) for subjects with LLAR SPN (P < 0.001); and 79.2% (57/72) for subjects with HLAR SPN (P = 0.122). CONCLUSIONS: Clinical cure rates in CARTI subjects treated with azithromycin were higher for Azi-S SPN (89.4%) versus Azi-R SPN (78.6%; P = 0.003). However, cure rates were not different for subjects infected with LLAR-SPN versus HLAR-SPN. At the observed prevalence of Azi-R SPN of 28.9%, an additional 3.1 clinical failures would be predicted, as a consequence of azithromycin resistance (LLAR and HLAR), per 100 subjects treated empirically with azithromycin.

Previous antibiotic exposure and antimicrobial resistance in invasive pneumococcal disease: results from prospective surveillance.

BACKGROUND: Estimating the risk of antibiotic resistance is important in selecting empiric antibiotics. We asked how the timing, number of courses, and duration of antibiotic therapy in the previous 3 months affected antibiotic resistance in isolates causing invasive pneumococcal disease (IPD). METHODS: We conducted prospective surveillance for IPD in Toronto, Canada, from 2002 to 2011. Antimicrobial susceptibility was measured by broth microdilution. Clinical information, including prior antibiotic use, was collected by chart review and interview with patients and prescribers. RESULTS: Clinical information and antimicrobial susceptibility were available for 4062 (90%) episodes; 1193 (29%) of episodes were associated with receipt of 1782 antibiotic courses in the prior 3 months. Selection for antibiotic resistance was class specific. Time elapsed since most recent antibiotic was inversely associated with resistance (cephalosporins: adjusted odds ratio [OR] per day, 0.98; 95% confidence interval [CI], .96-1.00; P = .02; macrolides: OR, 0.98; 95% CI, .96-.99; P = .005; penicillins: OR [log(days)], 0.62; 95% CI, .44-.89; P = .009; fluoroquinolones: profile penalized-likelihood OR [log(days)], 0.62; 95% CI, .39-1.04; P = .07). Risk of resistance after exposure declined most rapidly for fluoroquinolones and penicillins and reached baseline in 2-3 months. The decline in resistance was slowest for macrolides, and in particular for azithromycin. There was no significant association between duration of therapy and resistance for any antibiotic class. Too few patients received multiple courses of the same antibiotic class to assess the significance of repeat courses. CONCLUSIONS: Time elapsed since last exposure to a class of antibiotics is the most important factor predicting antimicrobial resistance in pneumococci. The duration of effect is longer for macrolides than other classes.

Evolution of standardized clinical pathways: refining multidisciplinary care and process to improve outcomes of the surgical treatment of esophageal cancer.

BACKGROUND: The aim of this study is to determine the effect of the implementation and evolution of a multidisciplinary esophagectomy care pathway on postoperative outcomes over a 20-year experience. STUDY DESIGN: All patients undergoing esophagectomy for cancer between 1991 and 2012 were included. Patients were divided into four groups (Gp1 1991-1996, Gp2 1997-2002, Gp3 2003-2007, and Gp4 2008-2012). RESULTS: Five hundred and ninety-five patients were included (Gp1 92, Gp2 159, Gp3 161, and Gp4 183). Age remained consistent over time; however, a progressive significant increase was observed in BMI and Charlson comorbidity index. Increases were also noted in patients with clinical stage III cancers, in the use of neoadjuvant chemoradiotherapy, in salvage esophagectomy and in the utilization of pretreatment jejunostomy. We observed a significant reduction in estimated blood loss (EBL) and operative room IV fluid administration (ORFA) during the study period. Median ICU stay and length of hospital stay (LOS) (10 (5-50) to 8 (5-115) days) decreased over time. In-hospital mortality (0.3 %) and postoperative complications remained consistent over time. cumulative sum (CUSUM) analysis showed that EBL, ORFA, and LOS all declined during the study period, reaching mean values at case 120, 310, and 175, respectively. CONCLUSIONS: The results of this study show that process improvement within the pathway is likely more significant than the level of comorbidities, application of neoadjuvant chemoradiation, or technical approach in patients undergoing esophagectomy.

Vancomycin-variable Enterococcus faecium: in vivo emergence of vancomycin resistance in a vancomycin-susceptible isolate.

We report the emergence of vancomycin resistance in a patient colonized with a vanA-containing, vanRS-negative isolate of Enterococcus faecium which was initially vancomycin susceptible. This is a previously undescribed mechanism of drug resistance with diagnostic and therapeutic implications.

Neisseria gonorrhoeae treatment failure and susceptibility to cefixime in Toronto, Canada.

IMPORTANCE: Although cephalosporins are the cornerstone of treatment of Neisseria gonorrhoeae infections, cefixime is the only oral antimicrobial option. Increased minimum inhibitory concentrations (MICs) to cefixime have been identified worldwide and have been associated with reports of clinical failure. OBJECTIVE: To assess the risk of clinical treatment failure of N. gonorrhoeae infections associated with the use of cefixime. DESIGN, SETTING, AND POPULATION: A retrospective cohort study of culture-positive N. gonorrhoeae infections at a single sexual health clinic in Toronto, Canada, that routinely performs test of cure. The cohort comprised N. gonorrhoeae culture-positive individuals identified between May 1, 2010, and April 30, 2011, treated with cefixime as recommended by Public Health Agency of Canada guidelines. MAIN OUTCOME MEASURES: Cefixime treatment failure, defined as the repeat isolation of N. gonorrhoeae at the test-of-cure visit identical to the pretreatment isolate by molecular typing and explicit denial of reexposure. RESULTS: There were 291 N. gonorrhoeae culture-positive individuals identified. Of 133 who returned for test of cure, 13 were culture positive; 9 patients were determined to have experienced cefixime treatment failure, involving urethral (n = 4), pharyngeal (n = 2), and rectal (n = 3) sites. The overall rate of clinical treatment failure among those who had a test of cure was 6.77% (95% CI, 3.14%-12.45%; 9/133). The rate of clinical failure associated with a cefixime MIC of 0.12 µg/mL or greater was 25.0% (95% CI, 10.69%-44.87%; 7/28) compared with 1.90% (95% CI, 0.23%-6.71%; 2/105) of infections with cefixime MICs less than 0.12 µg/mL, with a relative risk of 13.13 (95% CI, 2.88-59.72; P < .001). CONCLUSION AND RELEVANCE: The rate of clinical failure following treatment of N. gonorrhoeae infections with cefixime was relatively high at a Toronto clinic and was associated with elevated MICs.

Toward an understanding of changes in diversity associated with fecal microbiome transplantation based on 16S rRNA gene deep sequencing.

Fecal microbiome transplantation by low-volume enema is an effective, safe, and inexpensive alternative to antibiotic therapy for patients with chronic relapsing Clostridium difficile infection (CDI). We explored the microbial diversity of pre- and posttransplant stool specimens from CDI patients (n = 6) using deep sequencing of the 16S rRNA gene. While interindividual variability in microbiota change occurs with fecal transplantation and vancomycin exposure, in this pilot study we note that clinical cure of CDI is associated with an increase in diversity and richness. Genus- and species-level analysis may reveal a cocktail of microorganisms or products thereof that will ultimately be used as a probiotic to treat CDI. IMPORTANCE Antibiotic-associated diarrhea (AAD) due to Clostridium difficile is a widespread phenomenon in hospitals today. Despite the use of antibiotics, up to 30% of patients are unable to clear the infection and suffer recurrent bouts of diarrheal disease. As a result, clinicians have resorted to fecal microbiome transplantation (FT). Donor stool for this type of therapy is typically obtained from a spouse or close relative and thoroughly tested for various pathogenic microorganisms prior to infusion. Anecdotal reports suggest a very high success rate of FT in patients who fail antibiotic treatment (>90%). We used deep-sequencing technology to explore the human microbial diversity in patients with Clostridium difficile infection (CDI) disease after FT. Genus- and species-level analysis revealed a cocktail of microorganisms in the Bacteroidetes and Firmicutes phyla that may ultimately be used as a probiotic to treat CDI.

Novel mutations in a patient isolate of Streptococcus agalactiae with reduced penicillin susceptibility emerging after long-term oral suppressive therapy.

Penicillin nonsusceptibility has been demonstrated in group B streptococci (GBS), but there is limited information regarding mechanisms of resistance. We report a case of GBS with reduced susceptibility to penicillin emerging after long-term suppressive oral penicillin therapy for a prosthetic joint infection. Molecular characterization of the isolate before and after long-term penicillin therapy revealed 5 mutations in the ligand-binding regions of PBP1a, -2a, and -2x not previously reported in GBS.

At the threshold: defining clinically meaningful resistance thresholds for antibiotic choice in community-acquired pneumonia.

BACKGROUND: Community-acquired pneumonia caused by Streptococcus pneumoniae is a major source of morbidity and mortality. Macrolide antibiotics are recommended as empirical first-line therapy for patients with community-acquired pneumonia. Guidelines suggest a 25% rate of high-level macrolide resistance in the community as the threshold beyond which macrolides should not be used. We evaluated the implications of this threshold for clinical failure rates. METHODS: We developed a theoretical model linking the prevalence of macrolide resistance to patient outcomes, based on the epidemiological concept of risk difference. We estimated the risk of clinical failure as a function of the likelihood and impact of discordant therapy and of the probability of clinical failure even in the presence of optimal therapy. The model was parameterized on the basis of the best available data derived from the published medical literature, and clinical failures were valued monetarily using an expected net benefit approach. RESULTS: Under the proposed 25% resistance threshold, the risk difference for such therapy would be 1.2% (95% credible interval, 0.5%-3.1%) for death, 1.6% (95% credible interval, 0.5%-3.2%) for bacteremia, and 3.3% (95% credible interval, 1.1%-5.7%) for prolonged clinical course; excess risks of death were valued at >$10,000 per empirical treatment of community-acquired pneumonia and were further elevated in high-risk populations. Excluding low-level resistance resulted in a 4-fold underestimation of projected risks. CONCLUSION: A 25% resistance threshold that fails to consider low-level resistance will result in high excess rates of morbidity and mortality because of discordant therapy. Whether projected failure rates are classified as unacceptable is an important health policy question, because risk of clinical failure needs to be weighed against other considerations.

A review of Streptococcus pneumoniae infection treatment failures associated with fluoroquinolone resistance.

We reviewed all of the published reports of cases of fluoroquinolone treatment failures for respiratory tract infection due to fluoroquinolone-resistant Streptococcus pneumoniae. There were 20 ciprofloxacin and levofloxacin treatment failures reported. Physicians should be aware, when treating pneumococcal respiratory tract infections in older patients with a fluoroquinolone, that clinical failures might occur, especially for patients with comorbid illnesses and a history of recent fluoroquinolone use.

Progressive and nonresolving pneumonia.

PURPOSE OF REVIEW: Patients with progressive and/or nonresolving community-acquired pneumonia are at risk for increased morbidity and mortality. It is critical to be able to identify patients at risk to institute early appropriate therapy. The purpose of this review is to summarise the most updated developments in this area. RECENT FINDINGS: This review will glean from the recent literature clinical, laboratory, and radiologic findings that help identify patients at risk for such complications of their pneumonia. New studies will be reviewed that have identified some of the causes for treatment failures including the type of pathogen and discordant antimicrobial therapy. It will also discuss newly recognised and emerging infectious diseases that may result in progressive or nonresponding pneumonia including severe acute respiratory syndrome, avian influenzae, severe group A streptococcal disease, and community-acquired methicillin-resistant Staphylococcus aureus. Promising treatments have been identified for patients with progressive pneumonia due to an overwhelming host immune response including activated protein C and intravenous immunoglobulin. SUMMARY: Both progressive and nonresolving pneumonia represent treatment failure as a result of inappropriate initial therapy, a noninfectious cause, or an overwhelming immune response. It is critical to be able to identify patients with nonresponding pneumonia and to identify patients at risk for progressive pneumonia to institute appropriate therapy.

Quinolone resistance among pneumococci: therapeutic and diagnostic implications.

Fluoroquinolones are widely recommended as empirical monotherapy for community-acquired pneumonia. Since 1999, case reports of failure of levofloxacin therapy due to levofloxacin-resistant strains of Streptococcus pneumoniae have started to appear. Most worrying is that, in some cases, levofloxacin resistance has been acquired by pneumococci within days of the initiation of therapy. Because use of current clinical antimicrobial resistance breakpoints fail to identify the majority of S. pneumoniae isolates with only first-step mutations, current treatment guidelines not only may have implications with regard to the ability of surveillance programs to detect emerging resistance but may have therapeutic implications as well.

Emergence of levofloxacin-resistant pneumococci in immunocompromised adults after therapy for community-acquired pneumonia.

We describe 4 patients infected with levofloxacin-resistant pneumococci after therapy for community-acquired pneumonia (CAP). The 4 patients had 15 episodes of CAP; Streptococcus pneumoniae was isolated from blood or sputum samples obtained during 14 of the episodes. The underlying medical condition was Bruton agammaglobulinemia in 3 patients and chronic lymphoid leukemia in the other. The initial episode of CAP in each patient was due to a levofloxacin-susceptible strain. One of 4 reinfections and 5 of 6 relapses were due to levofloxacin-resistant strains. All of these strains had amino acid substitutions in the quinolone-resistance-determining region of the genes parC and gyrA. The time between episodes of pneumonia varied from 1 to 4 months. In immunocompromised patients with suspected or proven pneumococcal infection, it may be prudent not to use fluoroquinolone monotherapy empirically when the patient has a history of fluoroquinolone therapy in at least the past 4 months.

The battle against emerging antibiotic resistance: should fluoroquinolones be used to treat children?

Inappropriate use of antibiotic drugs in humans and animals has led to widespread resistance among microbial pathogens. Resistance is the phenotypic expression corresponding to genetic changes caused by either mutation or acquisition of new genetic information. In some cases, multidrug resistance occurs. Streptococcus pneumoniae is one of the most important respiratory pathogens, playing a major role in both upper and lower respiratory tract infections. Pneumococcal resistance to antimicrobials may be acquired by means of horizontal transfer followed by homologous recombination of genetic material from the normal flora of the human oral cavity or by means of mutation. Resistance to penicillins and macrolides has been increasing for some time, but, recently, fluoroquinolone resistance has become an issue as well. We are concerned that, if fluoroquinolones are approved for use in children, their widespread use will result in rapid emergence of pneumococcal resistance, because children are more often colonized in the nasopharynx with high-density populations of pneumococci than are adults.