Incubation period of Clostridioides difficile infection in hospitalized patients and long-term care facility residents: a prospective cohort study.

Background: The incubation period for Clostridioides difficile infection (CDI) is generally considered to be less than 1 week, but some recent studies suggest that prolonged carriage prior to disease onset may be common. Objective: To estimate the incubation period for patients developing CDI after initial negative cultures. Methods: In 3 tertiary care medical centers, we conducted a cohort study to identify hospitalized patients and long-term care facility residents with negative initial cultures for C. difficile followed by a diagnosis of CDI with or without prior detection of carriage. Cases were classified as healthcare facility-onset, community-onset, healthcare facility-associated, or community-associated and were further classified as probable, possible, or unlikely CDI. A parametric accelerated failure time model was used to estimate the distribution of the incubation period. Results: Of 4,179 patients with negative enrollment cultures and no prior CDI diagnosis within 56 days, 107 (2.6%) were diagnosed as having CDI, including 19 (17.8%) with and 88 (82.2%) without prior detection of carriage. When the data were censored to only include participants with negative cultures collected within 14 days, the estimated median incubation period was 6 days with 25% and 75% of estimated incubation periods occurring within 3 and 12 days, respectively. The observed estimated incubation period did not differ significantly for patients classified as probable, possible, or unlikely CDI. Conclusion: Our findings are consistent with the previous studies that suggested the incubation period for CDI is typically less than 1 week and is less than 2 weeks in most cases.

Outcomes of discordant HIV screening test results at a southern academic medical center.

OBJECTIVE: The aim of this study was to examine outcomes of follow-up for persons with discordant fourth-generation HIV screening test results. DESIGN: A retrospective chart review. METHODS: We analyzed the electronic health record at the Medical University of South Carolina for a 10-year period spanning 2012-2022 to identify instances of discordant HIV screening test results, wherein initial antigen/antibody screening was positive, but reflex confirmatory testing for HIV-1 and HIV-2 antibodies was negative. We reviewed individual records to evaluate clinical follow-up and determine if the discordant test represented an acute HIV infection, a false-positive result, or was unresolved. RESULTS: We identified 199 testing instances with discordant results. Most discordant results ( n  = 115) were subsequently determined to reflect a false-positive test, while 56 were unresolved without documented follow-up testing. Twenty-eight cases of acute HIV infection were identified of which 26 were linked to care within a month of initial testing. Two acute HIV cases were not identified in real time leading to delay in diagnosis and care. Testing done in the context of infectious symptoms and testing performed in the emergency department were associated with increased odds of a discordant test ultimately reflecting acute HIV infection. CONCLUSION: These results demonstrate the importance of appropriate and timely follow-up for discordant HIV screening test results.

Successful treatment of SARS-CoV-2 in an immunocompromised patient with persistent infection for 245 days: A case report.

Background: Immunocompromised patients receiving B-cell-depleting therapies are at increased risk of persistent SARS-CoV-2 infection, with many experiencing fatal outcomes. We report a successful outcome in a patient with rheumatoid arthritis (RA) on rituximab diagnosed with COVID-19 in July 2020 with persistent infection for over 245 days. Results: The patient received numerous treatment courses for persistent COVID-19 infection, including remdesivir, baricitinib, immunoglobulin and high doses of corticosteroids followed by a prolonged taper due to persistent respiratory symptoms and cryptogenic organizing pneumonia. Her clinical course was complicated by Pseudomonas aeruginosa sinusitis with secondary bacteremia, and cytomegalovirus (CMV) viremia and pneumonitis. SARS-CoV-2 positive RNA samples were extracted from two nasopharyngeal swabs and sequenced using targeted amplicon Next-Generation Sequencing which were analyzed for virus evolution over time. Viral sequencing indicated lineage B.1.585.3 SARS-CoV-2 accumulated Spike protein mutations associated with immune evasion and resistance to therapeutics. Upon slowly decreasing the patient's steroids, she had resolution of her symptoms and had a negative nasopharyngeal SARS-CoV-2 PCR and serum CMV PCR in March 2021. Conclusion: A patient with RA on B-cell depleting therapy developed persistent SARS-CoV-2 infection allowing for virus evolution and had numerous complications, including viral and bacterial co-infections with opportunistic pathogens. Despite intra-host evolution with a more immune evasive SARS-CoV-2 lineage, it was cleared after 245 days with reconstitution of the patient's immune system.

The hidden microbiome of hospital infection surveillance testing: biomarkers of health outcomes in MRSA and VRE colonization.

Background: Hospital-acquired infections present a major concern for healthcare systems in the U.S. and worldwide. Drug-resistant infections result in increased costs and prolonged hospital stays. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) are responsible for many drug-resistant infections in the U.S. We undertook two parallel studies aimed to investigate the differences in the microbial communities of individuals colonized with MRSA (or VRE) as compared to their respective non-colonized counterparts matched for age, sex, race, ethnicity, unit of admission, and diagnostic-related group, when available. Results: The VRE study showed considerably more Enterococcus genus communities in the VRE colonized samples. Our findings for both MRSA and VRE studies suggest a strong association between 16S rRNA gene alpha diversity, beta diversity, and colonization status. When we assessed the colonized microbial communities in isolation, the differences disappeared, suggesting that the colonized microbial communities drove the change. Isolating Staphylococcus, we saw significant differences expressed across colonization in specific sequence variants. Conclusions: The differences seen in the microbial communities from MRSA (or VRE) colonized samples as compared to non-colonized match-pairs are driven by the isolated communities of the Staphylococcus (or Enterococcus) genus, the removal of which results in the disappearance of any differences in the diversity observed across the match-pairs.

Natural History of Clostridioides difficile Colonization and Infection Following New Acquisition of Carriage in Healthcare Settings: A Prospective Cohort Study.

BACKGROUND: Limited information is available on the natural history of Clostridioides difficile colonization and infection in patients with new acquisition of C. difficile in healthcare settings. METHODS: In 3 hospitals and affiliated long-term care facilities, we collected serial perirectal cultures from patients with no diarrhea on enrollment to identify new acquisition of toxigenic C. difficile carriage and determined the duration and burden of carriage. Asymptomatic carriage was defined as transient if only 1 culture was positive, with negative cultures before and after, or persistent if 2 or more cultures were positive. Clearance of carriage was defined as 2 consecutive negative perirectal cultures. RESULTS: Of 1432 patients with negative initial cultures and at least 1 follow-up culture, 39 (2.7%) developed C. difficile infection (CDI) without prior detection of carriage and 142 (9.9%) acquired asymptomatic carriage, with 19 (13.4%) subsequently diagnosed with CDI. Of 82 patients analyzed for persistence of carriage, 50 (61.0%) had transient carriage and 32 (39.0%) had persistent carriage, with an estimated median of 77 days to clearance of colonization (range, 14-133 days). Most persistent carriers had a relatively high burden of carriage and maintained the same ribotype over time, whereas most transient carriers had a low burden of carriage detected only using broth enrichment cultures. CONCLUSIONS: In 3 healthcare facilities, 9.9% of patients acquired asymptomatic carriage of toxigenic C. difficile, and 13.4% were subsequently diagnosed with CDI. Most carriers had transient rather than persistent carriage and most patients developing CDI did not have prior detection of carriage.

Evaluation of Orthogonal Testing Algorithm for Detection of SARS-CoV-2 IgG Antibodies.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody testing is an important tool in assessment of pandemic progress, contact tracing, and identification of recovered coronavirus disease 2019 (COVID-19) patients. We evaluated an orthogonal testing algorithm (OTA) to improve test specificity in these use cases. METHODS: A two-step OTA was applied where individuals who initially tested positive were tested with a second test. The first-line test, detecting IgG antibodies to the viral nucleocapsid protein, was validated in 130 samples and the second-line test, detecting IgG antibodies to the viral spike protein in 148 samples. The OTA was evaluated in 4333 clinical patient specimens. The seropositivity rates relative to the SARS-CoV-2 PCR positivity rates were evaluated from our entire patient population data (n = 5102). RESULTS: The first-line test resulted in a clinical sensitivity of 96.4% (95% CI; 82.3% to 99.4%), and specificity of 99.0% (95% CI; 94.7% to 99.8%), whereas the second-line test had a sensitivity of 100% (95% CI; 87.1% to 100%) and specificity of 98.4% (95% CI; 94.2% to 99.5%). Using the OTA, 78/98 (80%) of initially positive SARS-CoV-2 IgG results were confirmed with a second-line test, while 11/42 (26%) of previously diagnosed COVID-19 patients had no detectable antibodies as long as 94 days post PCR diagnosis. CONCLUSION: Our results show that an OTA can be used to identify patients who require further follow-up due to potential SARS CoV-2 IgG false positive results. In addition, serological testing may not be sufficiently sensitive to reliably detect prior COVID-19 infection.

Potential for the current National Healthcare Safety Network (NHSN) >3 days after admission definition of laboratory-identified, healthcare-facility-onset, Clostridioides difficile infection (HO-CDI) to overestimate rates.

Healthcare-facility-onset C.difficile LabID events are defined as positive stool samples collected >3 days after hospitalization. Using a definition of >72 hours, we found that 84 of 1013 cases (8.3%) identified as C. difficile LabID events were collected between 48 and 72 hours after admission.

To Lump or To Split: Does Strain Lineage for Clostridioides difficile Matter?

Since 2001, numerous descriptive ecological studies of Clostridioides difficile infections (CDI) have identified a single lineage (BI/NAP1/027) associated with the epidemics of CDI, increased severity of CDI, and increased likelihood of incident CDI to become recurrent. Establishing causality between the clinical severity and outcomes for CDI and the lineages of the infecting strains, however, has proved elusive, with many conflicting results in previous observational studies. In this issue of the Journal of Clinical Microbiology, J. R. Garneau, C. N. Abou Chakra, L.-C. Fortier, A.-C. Labbé, et al. (J Clin Microbiol 57:e01724-18, 2019, https://doi.org/10.1128/JCM.01724-18) performed multilocus variable-number tandem-repeat analysis (MLVA) on 450 isolates from epidemic strain CDI arising in 10 Canadian centers during a previously well-described epidemic to assess the hypothesis that subpopulations of this lineage are associated with adverse clinical outcomes. The authors' key finding, however, was that MLVA genotyping grouped infections closely with associated hospital centers; CDI severity was not associated with any particular sublineage by MLVA. While the study does not support any causal inferences about strain-specific virulence of CDI, it does highlight the power of MLVA, a genotyping tool that remains valuable in tracking the geospatial transmission dynamics of CDI.

Oral Vancomycin for Secondary Prophylaxis of Clostridium difficile Infection.

OBJECTIVE: To summarize and critically appraise the evidence regarding oral vancomycin prophylaxis (OVP) to prevent recurrent Clostridium difficile infections (RCDIs), identify potential consequences of this emerging practice, and highlight future directions of study. DATA SOURCES: A MEDLINE literature search of English-language publications from 1947 through September 2018 was performed using the search terms vancomycin and C difficile and prophylaxis. Clinical trials were identified on the National Library of Medicine clinical trials registry. STUDY SELECTION AND DATA EXTRACTION: All clinical studies (n = 3) assessing oral vancomycin for secondary prophylaxis of C difficile infection (CDI) were evaluated by all authors. Other search results and references in selected publications were used for background and discussion. DATA SYNTHESIS: OVP reduced the risk of RCDI in high-risk patients taking systemic antibiotics. Variable dosing regimens and lack of safety data are limitations. OVP may have an adverse impact on the gastrointestinal microbiome, but this was not examined in the clinical studies. Relevance to Patient Care and Clinical Practice: Although current studies are limited by methodological concerns, clinicians can consider vancomycin 125 mg orally once or twice daily in high-risk patients receiving broad-spectrum antibacterial agents. Results of ongoing trials will define the most appropriate regimen and its impact on outcomes, including collateral damage. CONCLUSIONS: OVP reduces the risk of RCDIs and should be considered on a case-by-case basis. Caution is warranted before routine use is implemented because the impact on long-term outcomes has not been assessed and the optimal regimen has not been defined.

Transmission of Mycobacterium tuberculosis From Patients Who Are Nucleic Acid Amplification Test Negative.

Background: Among adults with signs and symptoms of pulmonary tuberculosis (TB), recognition of transmissible TB has implications for airborne infection isolation and public health activities. Sputum smear-negative TB patients account for around one-fifth of tuberculosis transmission. The tuberculosis transmission risk of TB patients with negative results on nucleic acid amplification test (NAAT) of respiratory specimens has not been established. We sought to estimate the tuberculosis transmission risk of NAAT-negative TB patients. Methods: We retrospectively reviewed Maryland TB program data collected from 2004 to 2009, during which time NAAT using the Mycobacterium Tuberculosis Direct Test (MTD) was performed routinely. Patients with sputum Mycobacterium tuberculosis (M.tb) isolates having matching genotypes were assigned to clusters. Transmission sequence was approximated by collection order of individuals' first culture-positive specimens. Minimum transmission risks of NAAT (MTD)-negative TB patients and of smear-negative TB patients were estimated based on individuals' positions within clusters. Results: Among 809 patients with culture-confirmed TB, M.tb genotypes were available for 782 (96.7%). For NAA-negative TB patients, the minimum transmission risk estimate was 5.1% (95% CI 0-11.4). For smear-negative TB patients, the minimum transmission risk estimate was 11.2% (95% CI 7.2-15.3). Conclusions: Minimum transmission risk of NAAT-negative TB patients was lower than that of smear-negative TB patients. However, transmission risk of NAA-negative TB patients appears to not be negligible.

Clostridium difficile.

Clostridium difficile infections (CDIs) have emerged as one of the principal threats to the health of hospitalized and immunocompromised patients. The importance of C difficile colonization is increasingly recognized not only as a source for false-positive clinical testing but also as a source of new infections within hospitals and other health care environments. In the last five years, several new treatment strategies that capitalize on the increasing understanding of the altered microbiome and host defenses in patients with CDI have completed clinical trials, including fecal microbiota transplantation. This article highlights the changing epidemiology, laboratory diagnostics, pathogenesis, and treatment of CDI.

Asymptomatic Clostridium difficile colonization as a reservoir for Clostridium difficile infection.

Clostridium difficile (CD) infection (CDI) is the leading cause of healthcare associated diarrhea despite intense hospital infection prevention programs. A substantial proportion of the population is asymptomatically colonized with CD, and evidence is mounting that these individuals serve as a reservoir for CDI. The purpose of this review is to discuss the mechanisms by which individuals may harbor toxigenic CD but remain asymptomatic, the evidence that asymptomatically colonized individuals serve as a source of CDI, and the implications of this potential CD reservoir for healthcare infection prevention.

Prevalence and duration of asymptomatic Clostridium difficile carriage among healthy subjects in Pittsburgh, Pennsylvania.

Previous studies suggested that 7 to 15% of healthy adults are colonized with toxigenic Clostridium difficile. To investigate the epidemiology, genetic diversity, and duration of C. difficile colonization in asymptomatic persons, we recruited healthy adults from the general population in Allegheny County, Pennsylvania. Participants provided epidemiological and dietary intake data and submitted stool specimens. The presence of C. difficile in stool specimens was determined by anaerobic culture. Stool specimens yielding C. difficile underwent nucleic acid testing of the tcdA gene segment with a commercial assay; tcdC genotyping was performed on C. difficile isolates. Subjects positive for C. difficile by toxigenic anaerobic culture were asked to submit additional specimens. One hundred six (81%) of 130 subjects submitted specimens, and 7 (6.6%) of those subjects were colonized with C. difficile. Seven distinct tcdC genotypes were observed among the 7 C. difficile-colonized individuals, including tcdC genotype 20, which has been found in uncooked ground pork in this region. Two (33%) out of 6 C. difficile-colonized subjects who submitted additional specimens tested positive for identical C. difficile strains on successive occasions, 1 month apart. The prevalence of C. difficile carriage in this healthy cohort is concordant with prior estimates. C. difficile-colonized individuals may be important reservoirs for C. difficile and may falsely test positive for infections due to C. difficile when evaluated for community-acquired diarrhea caused by other enteric pathogens.

Use of multilocus variable number of tandem repeats analysis genotyping to determine the role of asymptomatic carriers in Clostridium difficile transmission.

BACKGROUND: Previous studies have suggested that asymptomatic carriers of toxigenic Clostridium difficile are a source of hospital-associated (HA) infections. Multilocus variable number of tandem repeats analysis (MLVA) is a highly discriminatory molecular subtyping tool that helps to determine possible transmission sources. METHODS: Clostridium difficile isolates were recovered from perirectal swabs collected for vancomycin-resistant Enterococcus (VRE) surveillance as well as from clinical C. difficile toxin-positive stool samples from July to November 2009 at the University of Pittsburgh Medical Center Presbyterian (UPMC). MLVA was performed to determine the genetic relationships between isolates from asymptomatic carriers and patients with HA C. difficile infection (HA-CDI). Asymptomatic carriage and HA-CDI isolates were considered to be associated if the carriage isolate was collected before the HA-CDI isolate and if the MLVA genotypes had a summed tandem-repeat difference of ≤ 2. RESULTS: Of 3006 patients screened, 314 (10.4%) were positive for toxigenic C. difficile, of whom 226 (7.5%) were detected only by VRE surveillance cultures. Of 56 incident cases of CDI classified as HA at UPMC during the study with available isolates, 17 (30%) cases were associated with CDI patients, whereas 16 (29%) cases were associated with carriers. Transmission events from prior bed occupants with CDI (n = 2) or carriers (n = 2) were identified in 4 of 56 cases. CONCLUSIONS: In our hospital with an established infection control program designed to contain transmission from symptomatic CDI patients, asymptomatic carriers appear to have played an important role in transmission. Identification and isolation of carriers may be necessary to further reduce transmission of C. difficile in such settings.

Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.

Clostridium difficile infection (CDI) is a leading cause of hospital-associated gastrointestinal illness and places a high burden on our health-care system. Patients with CDI typically have extended lengths-of-stay in hospitals, and CDI is a frequent cause of large hospital outbreaks of disease. This guideline provides recommendations for the diagnosis and management of patients with CDI as well as for the prevention and control of outbreaks while supplementing previously published guidelines. New molecular diagnostic stool tests will likely replace current enzyme immunoassay tests. We suggest treatment of patients be stratified depending on whether they have mild-to-moderate, severe, or complicated disease. Therapy with metronidazole remains the choice for mild-to-moderate disease but may not be adequate for patients with severe or complicated disease. We propose a classification of disease severity to guide therapy that is useful for clinicians. We review current treatment options for patients with recurrent CDI and recommendations for the control and prevention of outbreaks of CDI.

Therapeutic approaches for Clostridium difficile infections.

Metronidazole and vancomycin remain the front-line therapies for most Clostridium difficile infections (CDI). However, recurrent CDI occurs in ∼ 25% of patients, causing significant morbidity and mortality and healthcare costs. For this population, traditional antibiotic therapies fail and new treatment options are greatly needed. The US Food and Drug Administration recently approved fidaxomicin for CDI treatment. This narrow-spectrum antibiotic preserves the normal gut microbiota and shows promise as a treatment for severe and recurrent CDI. Monoclonal antibodies and vaccines directed against toxin are currently in clinical trials and represent alternative, non-antibiotic therapies. Less traditional therapeutic interventions include bacteriotherapy with non-toxigenic C. difficile and fecal transplant. This commentary will provide an overview of current and forthcoming CDI therapies.

Association of relapse of Clostridium difficile disease with BI/NAP1/027.

Recurrent Clostridium difficile infection (CDI) occurs in up to 35% of patients. Recurrences can be due to either relapse with the same strain or reinfection with another strain. In this study, multilocus variable-number tandem-repeat analysis (MLVA) was performed on C. difficile isolates from patients with recurrent CDI to distinguish relapse from reinfection. In addition, univariate and multivariate analyses were performed to identify risk factors associated with relapse. Among patients with a single recurrence, relapse due to the original infecting strain was more prevalent than reinfection and the interval between episodes was shorter than among patients who had reinfections. Among patients with >1 recurrence, equal distributions of relapse and reinfection or a combination of the two episode types were observed. Initial infection with the BI/NAP1/027 epidemic clone was found to be a significant risk factor for relapse. This finding may have important implications for patient therapy. Classification of recurrent CDI episodes by MLVA can be utilized to make informed patient care decisions and to accurately define new CDI cases for infection control and reimbursement purposes.

Prevalence of Clostridium difficile in uncooked ground meat products from Pittsburgh, Pennsylvania.

The prevalence of Clostridium difficile in retail meat samples has varied widely. The food supply may be a source for C. difficile infections. A total of 102 ground meat and sausage samples from 3 grocers in Pittsburgh, PA, were cultured for C. difficile. Brand A pork sausages were resampled between May 2011 and January 2012. Two out of 102 (2.0%) meat products initially sampled were positive for C. difficile; both were pork sausage from brand A from the same processing facility (facility A). On subsequent sampling of brand A products, 10/19 samples from processing facility A and 1/10 samples from 3 other facilities were positive for C. difficile. The isolates recovered were inferred ribotype 078, comprising 6 genotypes. The prevalence of C. difficile in retail meat may not be as high as previously reported in North America. When contamination occurs, it may be related to events at processing facilities.