Bacteroides and related species: The keystone taxa of the human gut microbiota.

Microbial communities play a significant role in maintaining ecosystems in a healthy homeostasis. Presently, in the human gastrointestinal tract, there are certain taxonomic groups of importance, though there is no single species that plays a keystone role. Bacteroides spp. are known to be major players in the maintenance of eubiosis in the human gastrointestinal tract. Here we review the critical role that Bacteroides play in the human gut, their potential pathogenic role outside of the gut, and their various methods of adapting to the environment, with a focus on data for B. fragilis and B. thetaiotaomicron. Bacteroides are anaerobic non-sporing Gram negative organisms that are also resistant to bile acids, generally thriving in the gut and having a beneficial relationship with the host. While they are generally commensal organisms, some Bacteroides spp. can be opportunistic pathogens in scenarios of GI disease, trauma, cancer, or GI surgery, and cause infection, most commonly intra-abdominal infection. B. fragilis can develop antimicrobial resistance through multiple mechanisms in large part due to its plasticity and fluid genome. Bacteroidota (formerly, Bacteroidetes) have a very broad metabolic potential in the GI microbiota and can rapidly adapt their carbohydrate metabolism to the available nutrients. Gastrointestinal Bacteroidota species produce short-chain fatty acids such as succinate, acetate, butyrate, and occasionally propionate, as the major end-products, which have wide-ranging and many beneficial influences on the host. Bacteroidota, via bile acid metabolism, also play a role in in colonization-resistance of other organisms, including Clostridioides difficile, and maintenance of gut integrity.

Fusobacteria behaving badly: Masquerading strains of strictly anaerobic Escherichiacoli misidentified due to the deletion of the hemB gene.

Three strictly anaerobic strains of Escherichia coli were misidentified as Fusobacterium mortiferum, due to a deletion of the hemB gene which is involved in anaerobic respiration. An unusual antimicrobial susceptibility pattern sparked the further diagnostic strategies that eventually identified these strains as true anaerobic E. coli This phenomenon is more common than appreciated and can have an impact on clinical practice including persistent and relapsing infections.

Enhanced Clostridioides difficile Infection Prevention With a Pharmacy-Controlled Policy That Adds a 3-Strain Lactobacillus Probiotic Concomitantly to Antibiotic Therapy.

When 70% of antibiotic users took a 3-strain Lactobacillus probiotic preparation the hospital-wide rate of healthcare-associated Clostridioides difficile infection improved significantly. The incidence of C. difficile infection for those taking the probiotic along with multiple antibiotics or a single high-risk antibiotic was decreased by at least half.

Efficacy of Bezlotoxumab in Trial Participants Infected With Clostridioides difficile Strain BI Associated With Poor Outcomes.

BACKGROUND: Bezlotoxumab reduced rates of recurrent Clostridioides difficile infection (rCDI) vs placebo in Monoclonal Antibodies for C. difficile Therapy (MODIFY) I/II trial participants receiving antibacterial drug treatment for CDI. A secondary objective of MODIFY I/II was to assess bezlotoxumab's efficacy against C. difficile strains associated with increased rates of morbidity and mortality. METHODS: In this post-hoc analysis of pooled MODIFY I/II data, efficacy endpoints were assessed in participants infected with restriction endonuclease analysis BI and non-BI strains of C. difficile at study entry. Treatment outcomes were compared between participants receiving bezlotoxumab (alone or with actoxumab [B, B+A]) and those receiving no bezlotoxumab (placebo or actoxumab [P, A]). RESULTS: From 2559 randomized participants, C. difficile was isolated from 1588 (67.2%) baseline stool samples. Participants with BI strains (n = 328) were older and had more risk factors for rCDI than non-BI strain participants (n = 1260). There were no differences in initial clinical cure rate between BI and non-BI strains in either group. The rCDI rate for BI strains treated with bezlotoxumab was lower than for the no bezlotoxumab group (B, B+A vs P, A: 23.6% vs 43.9%) and was also lower for the non-BI strains (B, B+A vs P, A: 21.4% vs 36.1%). Rates of 30-day CDI-associated rehospitalization were greater with BI vs non-BI strains in both groups. CONCLUSIONS: Infection with BI strains of C. difficile predicted poor outcomes in the MODIFY I/II trials. Bezlotoxumab (alone or with actoxumab) treatment was effective both in BI and non-BI subpopulations.

Bezlotoxumab for the Prevention of Recurrent Clostridioides difficile Infection: 12-Month Observational Data From the Randomized Phase III Trial, MODIFY II.

From Monoclonal Antibodies for C. difficile Therapy II, no participants (n = 0/69) with a sustained clinical cure through 12 weeks following bezlotoxumab infusion experienced recurrent Clostridioides difficile infection (rCDI) after 9 months (versus actoxumab + bezlotoxumab, n = 2/65; versus placebo, n = 1/34). Bezlotoxumab's efficacy appears to be due to prevention rather than delayed onset of rCDI. Clinical Trials Registration. NCT01513239.

In Vitro Activity of Tedizolid Compared to Linezolid and Five Other Antimicrobial Agents against 332 Anaerobic Isolates, Including Bacteroides fragilis Group, Prevotella, Porphyromonas, and Veillonella Species.

Tedizolid's anaerobic activity is unappreciated. In this study, it was active against all 332 anaerobic isolates tested at ≤2 µg/ml except Bilophila wadsworthia and was more active than linezolid against Bacteroides fragilis group species (MIC90, 1 µg/ml versus 2 to 4 µg/ml). Tedizolid was active against Gram-positive anaerobes (MIC90 for clostridia, 0.25 to 1 µg/ml; MIC90 for anaerobic cocci, ≤0.06 to 0.25 µg/ml). Our data coupled with clinical reports indicate that clinicians should consider its use in mixed infections where Staphylococcus aureus and anaerobes are involved.

Going for the Gold: A Description of the Centers of Excellence Designation by the Infectious Diseases Society of America.

Antimicrobial stewardship programs (ASPs) are recommended by the Centers for Disease Control and Prevention and World Health Organization and mandated by the Joint Commission to curb antimicrobial resistance. However, <50% of institutions have optimal ASPs in place. Building on its experience of antimicrobial stewardship (AMS) advocacy, the Infectious Diseases Society of America (IDSA) developed the AMS Centers of Excellence (CoE) program, which will serve as a conduit to share best practices and highlight the standards for other hospitals to achieve in order to advance the field of AMS. A designation of CoE signifies that these institutions deliver high-quality care consistently, serve as the "gold" standard for executing novel AMS principles, and demonstrate commitment to their ASP. Here, we describe the process and purpose of designating institutions as AMS CoEs, provide awareness to clinicians on opportunities available through IDSA with this CoE designation, and discuss the evolution of the program.

Whole-Genome Sequencing To Identify Drivers of Carbapenem-Resistant Klebsiella pneumoniae Transmission within and between Regional Long-Term Acute-Care Hospitals.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an antibiotic resistance threat of the highest priority. Given the limited treatment options for this multidrug-resistant organism (MDRO), there is an urgent need for targeted strategies to prevent transmission. Here, we applied whole-genome sequencing to a comprehensive collection of clinical isolates to reconstruct regional transmission pathways and analyzed this transmission network in the context of statewide patient transfer data and patient-level clinical data to identify drivers of regional transmission. We found that high regional CRKP burdens were due to a small number of regional introductions, with subsequent regional proliferation occurring via patient transfers among health care facilities. While CRKP was predicted to have been imported into each facility multiple times, there was substantial variation in the ratio of intrafacility transmission events per importation, indicating that amplification occurs unevenly across regional facilities. While myriad factors likely influence intrafacility transmission rates, an understudied one is the potential for clinical characteristics of colonized and infected patients to influence their propensity for transmission. Supporting the contribution of high-risk patients to elevated transmission rates, we observed that patients colonized and infected with CRKP in high-transmission facilities had higher rates of carbapenem use, malnutrition, and dialysis and were older. This report highlights the potential for regional infection prevention efforts that are grounded in genomic epidemiology to identify the patients and facilities that make the greatest contribution to regional MDRO prevalence, thereby facilitating the design of precision interventions of maximal impact.

Comparative In Vitro Activities of Relebactam, Imipenem, the Combination of the Two, and Six Comparator Antimicrobial Agents against 432 Strains of Anaerobic Organisms, Including Imipenem-Resistant Strains.

Relebactam is an important beta-lactamase inhibitor for certain aerobic organisms, but alone it has no antianaerobic activity, with most anaerobes having MICs of ≥32 µg/ml with the exception of a very few strains. There was no enhancement or antagonism of imipenem activity with the addition of relebactam, including activity against imipenem-resistant strains. The relebactam-imipenem combination had excellent overall activity against the anaerobes tested.

Comparative In Vitro Activity of Omadacycline against Dog and Cat Bite Wound Isolates.

Omadacycline was tested against 125 isolates recovered from infected cat and dog bites in humans. Its activity was similar to that of other compounds in the tetracycline class, and it was active against strains exhibiting tetracycline resistance. Against anaerobic isolates, resistance to tetracyclines was more prominent and omadacycline was the most active of the group. All isolates had omadacycline MICs of <1 µg/ml, with the exception of Eikenella corrodens, which showed reduced susceptibility to the entire tetracycline group.

In vitro activity of eravacycline and comparator antimicrobials against 143 recent strains of Bacteroides and Parabacteroides species.

Eravacycline, a novel fluorocycline antibiotic, has been evaluated against complicated mixed aerobic/anaerobic intra-abdominal infections but scant supporting in vitro data against anaerobes has been published. We found that eravacycline had good anaerobic in vitro activity with MICs of 4 µg/ml or less against all Bacteroides and Parabacteroides strains tested, except for two B. ovatus strains that had MICs of 8 µg/ml and one strain that had an MIC of 16 µg/ml. Eravacycline was four-to-eight fold more active than tigecycline.

In vitro stability of three oral vancomycin preparations stored at 2- 5 °C and ambient room temperature for up to 60 days against 100 Clostridioides (Clostridium) difficile and 51Staphylococcus aureus strains.

Oral vancomycin is used to treat Clostridioides (Clostridium) difficile infection. Several different preparations are available including reconstituted IV solutions, vancomycin capsules, and grape flavored vancomycin oral solution kit (CutisPharma). The shelf life for IV after reconstitution varies between 7 and 14 days under refrigeration, and a standard 30 days for vancomycin oral solution kit (CutisPharma). The impact of storage on the in vitro potency was determined in 3 different vancomycin preparations by measuring MICs for 100 strains of C. difficile and 25 strains of Staphylococcus aureus, at T0, 14, 30, and 60 days, stored at ambient (RT) and refrigerated (2-5 °C) temperatures. All vancomycin preparations showed potency over a period of 60 days regardless of storage conditions. However, the capsule preparation showed mold after 60 days at room temperature, but unlike vancomycin oral solution kit, which retained a clear appearance, the IV and capsule preps showed evidence of crystallization.

Molecular epidemiology of Clostridioides (Clostridium) difficile strains recovered from clinical trials in the US, Canada and Europe from 2006-2009 to 2012-2015.

The prevalence of C. difficile infection (CDI) and severe CDI are influenced by the prevalence of specific C. difficile strains, which are themselves influenced by antimicrobial susceptibility determinants as well as antimicrobial usage patterns. Restriction endonuclease analysis (REA) typing and antimicrobial susceptibility testing were used to characterize 1808 C. difficile isolates obtained from patients enrolled in four multicenter, multi-country, randomized CDI treatment trials conducted between 2006 and 2009 and between 2012 and 2015. By 2015, the epidemic REA group BI strain (RT027) had decreased in prevalence in North America (US: 43%-18%, Canada: 39%-24%, P < 0.001), but rates of moxifloxacin resistance remained high. In contrast, REA group Y (RT014/020) and DH (RT106) strains, both of which had low rates of moxifloxacin resistance, increased in prevalence (Y strain - US: 6%-17%, Canada: 11%-23%, P < 0.001; DH strain - US: 1%-11%, Canada: 0%-8%, P < 0.0001). In Europe, the BI strain (RT027) was highly prevalent in Eastern European countries in 2015, but was unchanged in other parts of Europe. As in North America, the Y strain (RT014/020) was prevalent in both time periods, but the DH strain was rarely identified. Continued international molecular surveillance of C. difficile will be important to track prevalence of known epidemic strains and detect emergence of new strains of potential epidemiologic significance.

Epidemiology of Carbapenem-Resistant Klebsiella pneumoniae in a Network of Long-Term Acute Care Hospitals.

BACKGROUND: The rapid emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a major public health threat, including in the long-term acute care hospital (LTACH) setting. Our objective in this study was to describe the epidemiologic characteristics of CRKP in a network of US LTACHs. METHODS: An observational study was performed among 64 LTACHs from January 2014 to March 2015. Clinical cultures were included, with the first CRKP isolate recovered from each patient per study quarter evaluated. LTACH and geographic area-based CRKP prevalence and clinical and microbiologic characteristics were described. RESULTS: A total of 3846 K. pneumoniae cultures were identified, with an overall carbapenem resistance rate of 24.6%. There were significant differences in CRKP rates across geographic regions, with the highest in the West (42.2%). Of 946 CRKP isolates, 507 (53.6%) were from a respiratory source, 350 (37.0%) from a urinary source, and 9 (9.4%) from blood. Among 821 unique patients with CRKP colonization or infection, the median age was 73 years. There was a high prevalence of respiratory failure (39.8%) and the presence of a central venous catheter (50.9%) or tracheostomy (64.8%). Resistance rates of CRKP isolates were high for amikacin (59.2%) and fluoroquinolones (>97%). The resistance rate to colistin/polymyxin B was 16.1%. CONCLUSIONS: Nearly 25% of K. pneumoniae clinical isolates in a US network of LTACHs were CRKP. Expansion of national surveillance efforts and improved communication among LTACHs and acute care hospitals will be critical for reducing the continued emergence of CRKP across the healthcare continuum.

In Vitro Activity of Pexiganan and 10 Comparator Antimicrobials against 234 Isolates, Including 93 Pasteurella Species and 50 Anaerobic Bacterial Isolates Recovered from Animal Bite Wounds.

Animal bite wounds affect more than 5 million Americans annually, resulting in 300,000 emergency department visits, 10,000 hospitalizations, and an untold number of physician office visits. Various forms of topical therapy are empirically self-employed by many patients prior to seeking medical attention. Pexiganan, a 22-amino-acid synthetic cationic analogue of the peptide magainin II, acts by selectively damaging bacterial cell membranes. We determined the MICs for pexiganan and other antimicrobial agents often used for treatment of bite wounds. Most isolates were from U.S. patients, and ∼10% were from European and Canadian patients. The comparator antimicrobials studied were penicillin, amoxicillin-clavulanate, piperacillin-tazobactam, meropenem, clindamycin, doxycycline, moxifloxacin, ceftriaxone, linezolid, and metronidazole. The MIC90s of pexiganan were 32 µg/ml (against Pasteurella multocida subsp. multocida), 16 µg/ml (P. multocida subsp. septica, Pasteurella canis, and Pasteurella dagmatis), 8 µg/ml (Pasteurella stomatis), 8 µg/ml (Eikenella corrodens), 2 µg/ml (Neisseria weaveri, Neisseria zoodegmatis, and Moraxella canis-Moraxella lacunata group), 16 µg/ml (Bergeyella zoohelcum), 64 µg/ml (Bacteroides pyogenes), 4 µg/ml (Fusobacterium russii), 32 µg/ml (Fusobacterium canifelinum), and 64 µg/ml (Prevotella heparinolytica). The concentration of pexiganan in the cream used was 8,000 µg/ml, more than 60 to 100 times the highest MIC obtained. Pexiganan exhibited a broad range of antimicrobial activity, showing potential for treating animal bite infections. A clinical trial seems warranted.

In Vitro Activities of Pexiganan and 10 Comparator Antimicrobials against 502 Anaerobic Isolates Recovered from Skin and Skin Structure Infections.

Pexiganan, a cationic peptide, exhibited a broad range of anti-anaerobic antimicrobial activity. The MIC90s of studied isolates were as follows: Bacteroides fragilis, 16 µg/ml; other B. fragilis group spp., 4 µg/ml; Prevotella and Fusobacterium spp., 32 µg/ml; Porphyromonas spp., 64 µg/ml; Propionibacterium acnes, 4 µg/ml; Eggerthella lenta and Peptostreptococcus anaerobius, 32 µg/ml; other Gram-positive rods and cocci, 4 µg/ml; Clostridium perfringens, 128 µg/ml; and other clostridia, 256 µg/ml. Pexiganan cream shows potential as adjunctive therapy for skin and skin structure infections (SSSIs) involving anaerobes.

Does moderate renal impairment affect clinical outcomes in complicated intra-abdominal and complicated urinary tract infections? Analysis of two randomized controlled trials with ceftolozane/tazobactam.

Objectives: For reasons not well understood, antibacterials can yield lower cure rates in renally impaired patients. We explored this subject for the novel antibacterial ceftolozane/tazobactam. Methods: ASPECT-complicated intra-abdominal infections (cIAIs) and ASPECT-complicated urinary tract infections (cUTIs) were randomized, double-blinded clinical trials. Analyses in moderate [creatinine clearance (CL CR ) 30-50 mL/min] and mild/no (CL CR > 50 mL/min) renal impairment (RI) patients were pre-specified as exploratory endpoints in the statistical analysis plans. We also explored variables potentially impacting outcomes in these subgroups. Clinicaltrials.gov NCT01445665/NCT01445678 and NCT01345929/NCT01345955. Results: At baseline, 4.5% (36/806) of cIAI patients and 7.3% (58/795) of cUTI patients had moderate RI. Moderate RI patients were older, had more comorbid conditions and had higher APACHE-II scores. In the cIAI microbiological intent-to-treat population, response rates were 48% and 69% in moderate RI patients receiving ceftolozane/tazobactam and meropenem, respectively; among moderate RI cIAI patients considered treatment failures, indeterminate responses were more frequent with ceftolozane/tazobactam (39%; 9/23) than meropenem (8%; 1/13). In the cUTI microbiological modified intent-to-treat population, response rates were 81% and 78% in moderate RI patients receiving ceftolozane/tazobactam and levofloxacin, respectively. In both studies, response rates in moderate RI patients were similar between treatment arms in microbiologically evaluable populations, which excluded indeterminate responses due to missing data/protocol deviations (cIAI: 72.7% ceftolozane/tazobactam versus 71.4% meropenem; cUTI: 87% ceftolozane/tazobactam versus 80% levofloxacin). Conclusions: Regardless of treatment, clinical cure rates in cIAI and cUTI were lower in moderate versus mild/no RI patients. In moderate RI cIAI patients, numerical differences in response rates between treatments were attributable to imbalances in the numerical patients deemed indeterminate.