Multiplexed Gastrointestinal PCR panels for the Evaluation of Diarrhea in HCT Recipients.

BACKGROUND: Multiplexed gastrointestinal PCR panels (MGPP) are frequently employed as an aid in the diagnosis and management of diarrhea in HCT recipients. Many issues related to the optimal use of MGPP in HCT patients remain to be clarified. OBJECTIVE: To better define MGPP diagnostic and therapeutic stewardship in HCT recipients including indications and benefits of testing, optimal timing, and interpretation of results. STUDY DESIGN: We retrieved 463 consecutive MGPP ordered on 651 consecutive first HCT (312 allogeneic, 339 autologous) performed at our institution between June 2015 and June 2023. RESULTS: One hundred and sixteen (25%) of the 463 MGPP identified at least one and 12 (3%) more than one diarrheagenic pathogen. A positive result was more likely if the test was ordered within 48 hours of a hospital admission [32/78(41%)] or as an outpatient [46/111(41%)] as compared with evaluation of hospital onset diarrhea [38/274(14%)]. Among the positive results, the most frequent pathogens identified included C. difficile (64%), diarrheagenic E. coli (20%), norovirus (9%), and adenovirus 40/41 (5%). Thirty-eight percent of the positive C. difficile MGPP determinations were associated with a positive test for toxin. Among our allogeneic HCT cohort, 3% of MGPP for hospital onset diarrhea yielded an organism other than C. difficile. Fifty-six percent of positive and 14% of all submitted tests resulted in a change in treatment. For organisms other than C. difficile, only 1% of all tests and 5% of positive tests resulted in initiation of therapy. For patients at risk for acute graft vs. host disease (aGVHD), a positive or negative MGPP result was not predictive for a new diagnosis of aGVHD in proximity to diarrhea onset. CONCLUSIONS: MGPP testing is most useful when administered at hospital admission or as an outpatient. Since MGPP is sensitive and does not distinguish between colonization and causes of diarrhea, caution is needed in interpretation of results, especially for toxin negative C. difficile and diarrheagenic gram-negative organisms.

Validation of SeptiCyte RAPID to Discriminate Sepsis from Non-Infectious Systemic Inflammation.

(1) Background: SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and for estimating sepsis probabilities. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospectively banked and prospectively collected patient samples. (2) Methods: The cartridge-based SeptiCyte RAPID test accepts a PAXgene blood RNA sample and provides sample-to-answer processing in ~1 h. The test output (SeptiScore, range 0-15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (N = 356) and prospective (N = 63) samples were tested from adult patients in ICU who either had the systemic inflammatory response syndrome (SIRS), or were suspected of having/diagnosed with sepsis. Patients were clinically evaluated by a panel of three expert physicians blinded to the SeptiCyte test results. Results were interpreted under either the Sepsis-2 or Sepsis-3 framework. (3) Results: Under the Sepsis-2 framework, SeptiCyte RAPID performance for the combined retrospective and prospective cohorts had Areas Under the ROC Curve (AUCs) ranging from 0.82 to 0.85, a negative predictive value of 0.91 (sensitivity 0.94) for SeptiScore Band 1 (score range 0.1-5.0; lowest risk of sepsis), and a positive predictive value of 0.81 (specificity 0.90) for SeptiScore Band 4 (score range 7.4-15; highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86-0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in Bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. A comparable performance was obtained for the majority of patients reanalyzed under the Sepsis-3 definition, although a subgroup of 16 patients was identified that was called septic under Sepsis-2 but not under Sepsis-3. (4) Conclusions: This study validates SeptiCyte RAPID for estimating sepsis probability, under both the Sepsis-2 and Sepsis-3 frameworks, for hospitalized patients on their first day of ICU admission.

Syndromic Panel Testing Among Patients With Infectious Diarrhea: The Challenge of Interpreting Clostridioides difficile Positivity on a Multiplex Molecular Panel.

Background: Including Clostridioides difficile (CD) in gastrointestinal multiplex molecular panels (GIPCR) presents a diagnostic challenge. Incidental detection by polymerase chain reaction (PCR) without consideration of pretest probability (PTP) may inadvertently delay diagnoses of other treatable causes of diarrhea and lead to prescription of unnecessary antibiotics. Methods: We conducted a retrospective study to determine the frequency at which clinicians characterize PTP and disease severity in adult patients who test positive for CD by GIPCR. We organized subjects into cohorts based on the status of their CD PCR, glutamate dehydrogenase enzyme immunoassay (GDH), and toxin A/B detection, as well as by high, moderate, or low CD PTP. We used multivariable regression models to describe predictors of toxin positivity. Results: We identified 483 patients with positive CD PCR targets. Only 22% were positive for both GDH and CD toxin. Among patients with a low PTP for CDI, 11% demonstrated a positive CD toxin result compared to 63% of patients with a high PTP. A low clinician PTP for CD infection (CDI) correlated with a negative CD toxin result compared to cases of moderate-to-high PTP for CDI (odds ratio, 0.19 [95% confidence interval, .10-.36]). Up to 64% of patients with negative GDH and CD toxin received CD treatment. Only receipt of prior antibiotics, fever, and a moderate-to-high clinician PTP were statistically significant predictors of toxin positivity. Conclusions: Patients with a positive CD PCR were likely to receive treatment regardless of PTP or CD toxin results. We recommend that CD positivity on GIPCR be interpreted with caution, particularly in the setting of a low PTP.

An Algorithm Addressing the Problem of Overdiagnosis of Clostridioides difficile Infections in Hematopoietic Stem Cell Transplantation Recipients: Effects on C. difficile Infection Rates and Patient Outcomes.

Diarrhea of other causes and Clostridioides difficile colonization are common in patients hospitalized for hematopoietic stem cell transplantation (HSCT). It has been well recognized that these issues tend to decrease the specificity of stool testing for C. difficile infection (CDI). The best way to address this problem is uncertain. In September 2018, we initiated a project with the goal of addressing the apparent problem of overdiagnosis of CDIs in our HSCT population. Using the quality improvement tool Model for Improvement, we introduced a C. difficile stool testing and CDI diagnosis algorithm with the aim of decreasing unnecessary inpatient CDI diagnoses and treatments. In this study, we examined the effects of the algorithm. We reviewed all HSCT admissions for the 2 years before introduction of the algorithm and the subsequent 3 years, recording all stool submissions for C. difficile determination and CDI. At the close of the study, we recruited our advanced practice providers (APPs) to review all CDIs following algorithm initiation and provide feedback on the ease of use of the algorithm and potential improvements to the overall process. Stool submissions for C. difficile determination decreased from 38.0/1000 to 20.6/1000 inpatient days (P < .001) and CDI diagnoses decreased from 5.5/1000 to 2.4/1000 days (P = .007). Patients admitted for a first allogeneic HSCT, first autologous HSCT, or HSCT readmission showed similar proportionate reductions. No detrimental effects on hospital length of stay, overall survival, progression-free survival, rate of readmission post-HSCT, incidence of acute graft-versus-host disease, or incidence of recurrent CDI were noted following algorithm introduction. A strategy of education, monitoring/feedback, and ease of algorithm access proved effective in inducing provider compliance. APPs rated the algorithm high on ease of use. We conclude that the use of an algorithm defining criteria for C. difficile testing, diagnosis, and treatment was associated with significantly decreased CDI diagnoses on a HSCT inpatient unit without apparent adverse effects.

Extended spectrum cephalosporin resistant enterobacteriaceae carriage and infection in patients admitted with newly-diagnosed acute leukemia.

BACKGROUND: Current information is limited on the incidence, risk factors, and consequences of extended-spectrum cephalosporin resistant Enterobacteriaceae (ESCRE) carriage in patients undergoing therapy for newly-diagnosed acute leukemia. METHODS: We monitored 300 consecutive patients who submitted a first stool within the first week of initial hospitalization for initial and hospital acquired ESCRE carriage. Selected available isolates underwent DNA sequencing for determination of strain typing and resistance genes. RESULTS: 19 (6%) patients had ESCRE in their initial stool, and there was continued risk for new acquisition throughout their multiple hospitalizations. Patients with AML had more acquired carriage during their initial hospitalization. Increased hospitalizations and male sex were risk factors for detected acquired ESCRE carriage. ESCRE stool carriage was predictive for ESCRE BSI but not for overall survival. Sequencing revealed that E. coli ESCRE isolates contained primarily ESBL, while Enterobacter spp. and Citrobacter spp. showed primarily AmpC genes. The antibiotic sensitivity patterns for ESCRE BSI isolates reflected these genome findings. DISCUSSION/CONCLUSIONS: ESCRE carriage is common in patients with acute leukemia undergoing repeated hospitalizations and increases the risk for ESCRE BSI. ESCRE genera express differing resistance genes which may be predictive for empiric antibiotic efficacy.

Transfer of Extended Spectrum Cephalosporin Resistant Enterobacteriaceae Among Patients on an HSCT Unit and the Value of Surveillance and Contact Isolation.

The mechanism(s) of acquisition of extended-spectrum cephalosporin-resistant Enterobacteriaceae (ESCRE) on inpatient hospital units dedicated to hematopoietic stem cell transplantation (HSCT) is unclear. The objectives of this study were to determine whether ESCRE organisms are transmitted among patients housed on a HSCT unit, clarify the mechanisms involved, and determine whether routine surveillance for ESCRE carriage and contact isolation for ESCRE carriers is beneficial. The study was conducted on a 30-bed inpatient unit dedicated to the care of patients with hematologic malignancies and HSCT recipients. To investigate whether ESCRE organisms may be transmitted vertically to subsequent room occupants, presumably through contamination of room surfaces, we (1) cultured 6 high touch areas in 10 rooms before and 9 rooms after terminal cleaning that had been occupied by patients with ESCRE carriage, (2) determined the in vitro survivals of our most common clinical ESCRE species, and (3) followed the subsequent room occupants of 54 consecutive ESCRE colonized patients for the development of inpatient acquired ESCRE carriage. To investigate whether ESCRE organisms are transmitted horizontally among inpatients we (1) sequenced 60 available ESCRE Escherichia coli isolates obtained from unit inpatients and searched for identities using complete-genome multisequence locus typing (cgMLST) and (2) retrospectively tabulated the cumulative rates of acquired ESCRE carriage in 356 patients admitted for a first HSCT before (200 patients) or after (156 patients) institution of universal ESCRE stool surveillance and contact isolation for carriers. No ESCRE organisms were cultured from patient rooms before or after terminal cleaning. In vitro, few, if any, ESCRE organisms survived longer than 2 hours. Nine of the subsequent occupants of a room in which a patient with ESCRE carriage had resided were detected with ESCRE carriage, only 2 of whom carried the same species as that of the prior occupant. DNA sequencing and cgMLST determination of the 60 E. coli isolates showed 53 cgMLST strains. Seven of the 53 strains were shared by 2 patients. After institution of universal ESCRE surveillance/isolation there was a significant decline in acquired ESCRE carriage among HSCT recipients. We conclude that vertical transmission of ESCRE organisms through room contamination appears to be uncommon on modern HSCT units. Conversely, our results are consistent with the horizontal spread of ESCRE organisms, probably mediated by intermediate vectors such as personnel or shared equipment. Further studies are needed to better define the magnitude of and risk factors for ESCRE horizontal transfers and the benefits of ESCRE surveillance/isolation.

No Implementation Without Representation: Real-Time Pharmacist Intervention Optimizes Rapid Diagnostic Tests for Bacteremia at a Small Community Hospital.

Background: Rapid diagnostic tests (RDTs) for bacteremia allow for early antimicrobial therapy modification based on organism and resistance gene identification. Studies suggest patient outcomes are optimized when infectious disease (ID)-trained antimicrobial stewardship personnel intervene on RDT results. However, data are limited regarding RDT implementation at small community hospitals, which often lack access to on-site ID clinicians. Methods: This study evaluated the impact of RDTs with and without real-time pharmacist intervention (RTPI) at a small community hospital with local pharmacist training and asynchronous support from a remote ID Telehealth pharmacist. Time to targeted therapy (TTT) in patients with bacteremia was compared retrospectively across 3 different time periods: a control without RDT, RDT-only, and RDT with RTPI. Results: Median TTT was significantly faster in both the RDT with RTPI and RDT-only groups compared with the control group (2 vs 25 vs 51 hours respectively; P < .001). TTT was numerically faster for RDT with RTPI compared with RDT-only but did not reach statistical significance (P = .078). Median time to any de-escalation was significantly shorter for RDT with RTPI compared with both RDT-only (14 vs 33 hours; P = .012) and the control group (14 vs 45 hours; P < .001). Median length of stay was also significantly shorter in both RDT groups compared with the control group (4.0 vs 4.1 vs 5.5 hours; P = .013). Conclusion: This study supports RDT use for bacteremia in a small community hospital with ID Telehealth support, suggesting additional benefit with RTPI.

Evaluation of potential COVID-19 recurrence in patients with late repeat positive SARS-CoV-2 testing.

BACKGROUND: SARS-CoV-2 reinfection and reactivation has mostly been described in case reports. We therefore investigated the epidemiology of recurrent COVID-19 SARS-CoV-2. METHODS: Among patients testing positive for SARS-CoV-2 between March 11 and July 31, 2020 within an integrated healthcare system, we identified patients with a recurrent positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) assay ≥60 days after an initial positive test. To assign an overall likelihood of COVID-19 recurrence, we combined quantitative data from initial and recurrent positive RT-PCR cycle thresholds-a value inversely correlated with viral RNA burden- with a clinical recurrence likelihood assigned based on independent, standardized case review by two physicians. "Probable" or "possible" recurrence by clinical assessment was confirmed as the final recurrence likelihood only if a cycle threshold value obtained ≥60 days after initial testing was lower than its preceding cycle threshold or if the patient had an interval negative RT-PCR. RESULTS: Among 23,176 patients testing positive for SARS-CoV-2, 1,301 (5.6%) had at least one additional SARS-CoV-2 RT-PCRs assay ≥60 days later. Of 122 testing positive, 114 had sufficient data for evaluation. The median interval to the recurrent positive RT-PCR was 85.5 (IQR 74-107) days. After combining clinical and RT-PCR cycle threshold data, four patients (3.5%) met criteria for probable COVID-19 recurrence. All four exhibited symptoms at recurrence and three required a higher level of medical care compared to their initial diagnosis. After including six additional patients (5.3%) with possible recurrence, recurrence incidence was 4.3 (95% CI 2.1-7.9) cases per 10,000 COVID-19 patients. CONCLUSIONS: Only 0.04% of all COVID-19 patients in our health system experienced probable or possible recurrence; 90% of repeat positive SARS-CoV-2 RT-PCRs were not consistent with true recurrence. Our pragmatic approach combining clinical and quantitative RT-PCR data could aid assessment of COVID-19 reinfection or reactivation by clinicians and public health personnel.

Clinical evaluation of the acuitas® AMR gene panel for rapid detection of bacteria and genotypic antibiotic resistance determinants.

Urinary tract infections are leading causes of hospital admissions. Accurate and timely diagnosis is important due to increasing morbidity and mortality from antimicrobial resistance. We evaluated a polymerase chain reaction test (Acuitas AMR Gene Panel with the Acuitas Lighthouse Software) for detection of 5 common uropathogens (Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Enterococcus faecalis) and antibiotic resistance genes directly from urine for prediction of phenotypic resistance. Overall percent agreement was 97% for semiquantitative detection of uropathogens versus urine culture using a cut-off of 104 colony forming units per mL urine. Overall accuracy was 91% to 93% for genotypic prediction of common antibiotic resistance harbored by E. coli, K. pneumoniae, and P. mirabilis.

Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria.

BACKGROUND: Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH4 and BH4-dependent neurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM. METHODS: We prospectively enrolled Tanzanian children with CM and children with nonmalaria central nervous system conditions (NMCs). We measured CSF levels of BH4, neopterin, and BH4-dependent neurotransmitter metabolites, 3-O-methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using published reference ranges. RESULTS: Cerebrospinal fluid BH4 was elevated in CM (n = 49) compared with NMC (n = 51) (z-score 0.75 vs -0.08; P < .001). Neopterin was increased in CM (z-score 4.05 vs 0.09; P < .001), and a cutoff at the upper limit of normal (60 nmol/L) was 100% sensitive for CM. Neurotransmitter metabolite levels were overall preserved. A higher CSF BH4/BH2 ratio was associated with increased odds of survival (odds ratio, 2.94; 95% confidence interval, 1.03-8.33; P = .043). CONCLUSION: Despite low systemic BH4, CSF BH4 was elevated and associated with increased odds of survival in CM. Coma in malaria is not explained by deficiency of BH4-dependent neurotransmitters. Elevated CSF neopterin was 100% sensitive for CM diagnosis and warrants further assessment of its clinical utility for ruling out CM in malaria-endemic areas.

Are Clostridioides difficile infections being overdiagnosed in hematopoietic stem cell transplant recipients?

BACKGROUND: Because both diarrhea due to other causes and gastrointestinal colonization with toxigenic Clostridioides difficile are common in HSCT, there is a possibility of false-positive diagnoses of C difficile infections (CDI). METHODS: We estimated the probability of a patient being colonized by toxigenic C difficile by testing non-diarrheal surveillance stools from 223 HSCT recipients and the probability that a specimen submitted for C difficile testing was not CDI by determining the number of clinical tests that returned negative from this cohort. The number of expected false-positive CDI was estimated using these probabilities and compared with observed clinical test results. RESULTS: The expected false-positive and the observed numbers of positive clinical results were similar. The 20 patients diagnosed with CDI were also similar to 142 patients with diarrhea and C difficile-negative stools in number of stools on day of testing, associated symptoms, and the recorded number of days to formed stools. C difficile colonization was most commonly detected during the first week and CDI during the second. Retrospective analysis of 837 patients showed that 18 stools were submitted for each diagnosis of CDI. Ribotyping of the surveillance samples showed 17 ribotypes. CONCLUSIONS: Although several assumptions could impact the accuracy of our false-positive CDI estimates, it appears that many HSCT recipients diagnosed with CDI may actually represent colonized status and an alternative cause of diarrhea. Diagnostic stewardship, including limiting CDI diagnoses to patients with positive toxin and restricting stool submissions to patients with more severe symptoms, may decrease the number of false-positive diagnoses.

Antimicrobial Stewardship in a Hematological Malignancy Unit: Carbapenem Reduction and Decreased Vancomycin-Resistant Enterococcus Infection.

BACKGROUND: Antibiotic stewardship is challenging in hematological malignancy patients. METHODS: We performed a quasiexperimental implementation study of 2 antimicrobial stewardship interventions in a hematological malignancy unit: monthly antibiotic cycling for febrile neutropenia that included cefepime (± metronidazole) and piperacillin-tazobactam and a clinical prediction rule to guide anti-vancomycin-resistant Enterococcus faecium (VRE) therapy. We used interrupted time-series analysis to compare antibiotic use and logistic regression in order to adjust observed unit-level changes in resistant infections by background community rates. RESULTS: A total of 2434 admissions spanning 3 years pre- and 2 years postimplementation were included. Unadjusted carbapenem and daptomycin use decreased significantly. In interrupted time-series analysis, carbapenem use decreased by -230 days of therapy (DOT)/1000 patient-days (95% confidence interval [CI], -290 to -180; P < .001). Both VRE colonization (odds ratio [OR], 0.64; 95% CI, 0.51 to 0.81; P < .001) and infection (OR, 0.41; 95% CI, 0.2 to 0.9; P = .02) decreased after implementation. This shift may have had a greater effect on daptomycin prescribing (-160 DOT/1000 patient-days; 95% CI, -200 to -120; P < .001) than did the VRE clinical prediction score (-30 DOT/1000 patient-days; 95% CI, -50 to 0; P = .08). Also, 46.2% of Pseudomonas aeruginosa isolates were carbapenem-resistant preimplementation compared with 25.0% postimplementation (P = .32). Unit-level changes in methicillin-resistant Staphylococcus aureus and extended-spectrum beta lactamase (ESBL) incidence were explained by background community-level trends, while changes in AmpC ESBL and VRE appeared to be independent. The program was not associated with increased mortality. CONCLUSIONS: An antibiotic cycling-based strategy for febrile neutropenia effectively reduced carbapenem use, which may have resulted in decreased VRE colonization and infection and perhaps, in turn, decreased daptomycin prescribing.

Clostridioides difficile colonization and infection in patients admitted for a first autologous transplantation: Incidence, risk factors, and patient outcomes.

BACKGROUND: More data are needed regarding the incidence, risk factors, and outcomes for Clostridioides difficile infection (CDI) and colonization in patients undergoing an autologous hematopoietic stem cell transplantation (AHSCT). METHODS: We studied 472 consecutive patients admitted for a first AHSCT and conducted a prospective C difficile stool surveillance and ribotyping analysis in a subset of 94 patients. RESULTS: Clostridioides difficile infection was diagnosed in 7% of patients for an incidence of 3.4 CDI/1000 inpatient days, recurrent/reinfection CDI was rare. CDI was increased in patients who were colonized on admission, had required a recent pre-admission inpatient stay for fever and/or serious infection, or received empiric therapy with a carbapenem or extended-spectrum penicillin. CDI was associated with a longer length of stay and higher hospital costs. Twelve of 94 patients (13%) were found to have colonization on admission; CDI was diagnosed in 27% of these vs 1% in those with initial negative stools. Colonization in the hospital for those negative on admission was infrequent. C difficile ribotyping showed a predominance of 014/020. CONCLUSIONS: Clostridioides difficile infection is a significant infection in patients receiving a first AHSCT. The risk factors identified may be useful in designing preventive interventions.

Decrease in vancomycin-resistant Enterococcus colonization associated with a reduction in carbapenem use as empiric therapy for febrile neutropenia in patients with acute leukemia.

OBJECTIVE: To compare the effects of empiric carbapenems versus cycling cefepime and piperacillin/tazobactam on the rates of vancomycin-resistant Enterococcus (VRE) colonization, bloodstream infections, and outcomes of patients admitted with acute leukemia. DESIGN: Retrospective clinical study with VRE molecular strain typing and gastrointestinal microbiome comparison. SETTING: A regional referral center for acute leukemia. PATIENTS: 342 consecutive patients admitted with newly diagnosed acute leukemia. METHODS: In September 2015, we changed our empiric antibiotic of choice for neutropenic fever from a carbapenem to the cycling regimen. We studied 214 consecutive patients during the carbapenem period and 128 during the cycling period. Surveillance for VRE stool colonization was conducted weekly. Representative stool samples were analyzed for VRE MLST types and changes in the composition and diversity of the fecal microbiota. RESULTS: The change in empiric antibiotics was associated with a significant decrease in VRE colonization (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.27-0.66), a switch in the dominant VRE MLST types on the unit, and some modifications in the gastrointestinal microbiome. There were no differences in total gram-positive or gram-negative BSIs. During the carbapenem period, we observed higher absolute numbers of Candida spp and fewer ESBL BSIs, but these did not reach statistical significance. Patients during the carbapenem period had longer lengths of stay and durations of severe neutropenia and 10% higher hospital cost. CONCLUSIONS: Carbapenem-sparing empiric antibiotic regimens may have advantages related to VRE ecology, gastrointestinal dysbiosis, duration of neutropenia, cost and length of stay.

Physician agreement on the diagnosis of sepsis in the intensive care unit: estimation of concordance and analysis of underlying factors in a multicenter cohort.

BACKGROUND: Differentiating sepsis from the systemic inflammatory response syndrome (SIRS) in critical care patients is challenging, especially before serious organ damage is evident, and with variable clinical presentations of patients and variable training and experience of attending physicians. Our objective was to describe and quantify physician agreement in diagnosing SIRS or sepsis in critical care patients as a function of available clinical information, infection site, and hospital setting. METHODS: We conducted a post hoc analysis of previously collected data from a prospective, observational trial (N = 249 subjects) in intensive care units at seven US hospitals, in which physicians at different stages of patient care were asked to make diagnostic calls of either SIRS, sepsis, or indeterminate, based on varying amounts of available clinical information (clinicaltrials.gov identifier: NCT02127502). The overall percent agreement and the free-marginal, inter-observer agreement statistic kappa (κ free) were used to quantify agreement between evaluators (attending physicians, site investigators, external expert panelists). Logistic regression and machine learning techniques were used to search for significant variables that could explain heterogeneity within the indeterminate and SIRS patient subgroups. RESULTS: Free-marginal kappa decreased between the initial impression of the attending physician and (1) the initial impression of the site investigator (κ free 0.68), (2) the consensus discharge diagnosis of the site investigators (κ free 0.62), and (3) the consensus diagnosis of the external expert panel (κ free 0.58). In contrast, agreement was greatest between the consensus discharge impression of site investigators and the consensus diagnosis of the external expert panel (κ free 0.79). When stratified by infection site, κ free for agreement between initial and later diagnoses had a mean value + 0.24 (range - 0.29 to + 0.39) for respiratory infections, compared to + 0.70 (range + 0.42 to + 0.88) for abdominal + urinary + other infections. Bioinformatics analysis failed to clearly resolve the indeterminate diagnoses and also failed to explain why 60% of SIRS patients were treated with antibiotics. CONCLUSIONS: Considerable uncertainty surrounds the differential clinical diagnosis of sepsis vs. SIRS, especially before organ damage has become highly evident, and for patients presenting with respiratory clinical signs. Our findings underscore the need to provide physicians with accurate, timely diagnostic information in evaluating possible sepsis.

Predicting Antibiotic Resistance in Gram-Negative Bacilli from Resistance Genes.

We developed a rapid high-throughput PCR test and evaluated highly antibiotic-resistant clinical isolates of Escherichia coli (n = 2,919), Klebsiella pneumoniae (n = 1,974), Proteus mirabilis (n = 1,150), and Pseudomonas aeruginosa (n = 1,484) for several antibiotic resistance genes for comparison with phenotypic resistance across penicillins, cephalosporins, carbapenems, aminoglycosides, trimethoprim-sulfamethoxazole, fluoroquinolones, and macrolides. The isolates originated from hospitals in North America (34%), Europe (23%), Asia (13%), South America (12%), Africa (7%), or Oceania (1%) or were of unknown origin (9%). We developed statistical methods to predict phenotypic resistance from resistance genes for 49 antibiotic-organism combinations, including gentamicin, tobramycin, ciprofloxacin, levofloxacin, trimethoprim-sulfamethoxazole, ertapenem, imipenem, cefazolin, cefepime, cefotaxime, ceftazidime, ceftriaxone, ampicillin, and aztreonam. Average positive predictive values for genotypic prediction of phenotypic resistance were 91% for E. coli, 93% for K. pneumoniae, 87% for P. mirabilis, and 92% for P. aeruginosa across the various antibiotics for this highly resistant cohort of bacterial isolates.

Kinetic and Cross-Sectional Studies on the Genesis of Hypoargininemia in Severe Pediatric Plasmodium falciparum Malaria.

The low bioavailability of nitric oxide (NO) and its precursor, arginine, contributes to the microvascular pathophysiology of severe falciparum malaria. To better characterize the mechanisms underlying hypoargininemia in severe malaria, we measured the plasma concentrations of amino acids involved in de novo arginine synthesis in children with uncomplicated falciparum malaria (UM; n = 61), children with cerebral falciparum malaria (CM; n = 45), and healthy children (HC; n = 109). We also administered primed infusions of l-arginine uniformly labeled with 13C6 and 15N4 to 8 children with severe falciparum malaria (SM; age range, 4 to 9 years) and 7 healthy children (HC; age range, 4 to 8 years) to measure the metabolic flux of arginine, hypothesizing that arginine flux is increased in SM. Using two different tandem mass spectrometric methods, we measured the isotopic enrichment of arginine in plasma obtained at 0, 60, 90, 120, 150, and 180 min during the infusion. The plasma concentrations of glutamine, glutamate, proline, ornithine, citrulline, and arginine were significantly lower in UM and CM than in HC (P ≤ 0.04 for all pairwise comparisons). Of these, glutamine concentrations were the most markedly decreased: median, 457 µM (interquartile range [IQR], 400 to 508 µM) in HC, 300 µM (IQR, 256 to 365 µM) in UM, and 257 µM (IQR, 195 to 320 µM) in CM. Arginine flux during steady state was not significantly different in SM than in HC by the respective mass spectrometric methods: 93.2 µmol/h/kg of body weight (IQR, 84.4 to 129.3 µmol/h/kg) versus 88.0 µmol/h/kg (IQR, 73.0 to 102.2 µmol/h/kg) (P = 0.247) by the two mass spectrometric methods in SM and 93.7 µmol/h/kg (IQR, 79.1 to 117.8 µmol/h/kg) versus 81.0 µmol/h/kg (IQR, 75.9 to 88.6 µmol/h/kg) (P = 0.165) by the two mass spectrometric methods in HC. A limited supply of amino acid precursors for arginine synthesis likely contributes to the hypoargininemia and NO insufficiency in falciparum malaria in children.

Repurposing an Old Drug for a New Epidemic: Ursodeoxycholic Acid to Prevent Recurrent Clostridioides difficile Infection.

Recurrent Clostridioides difficile infection (rCDI) may be mediated in part by secondary bile acids. Here we report salvage therapy with ursodeoxycholic acid (UDCA) to prevent rCDI in 16 high-risk patients. Patients on UDCA had a low observed recurrence rate (12.5%). Controlled trials are needed to confirm these observations.

Clostridioides difficile colonization and infection in patients with newly diagnosed acute leukemia: Incidence, risk factors, and patient outcomes.

BACKGROUND: The frequency, risk factors, and outcomes for Clostridioides difficile infection (CDI) in patients with newly diagnosed acute leukemia (AL) admitted for induction therapy are unclear. METHODS: We studied 509 consecutive patients with AL admitted between 2006 and 2017 and conducted a prospective C difficile surveillance and ribotyping analysis in a subset of these. RESULTS: The incidence of CDI was 2.2/1,000 inpatient days during induction, and CDI was rare after discharge. CDI was highest in patients with acute myelogenous leukemia. A hospitalization shortly before admission and administration of a greater number of antibiotics increased the risk for CDI. No single class of antibiotics conveyed an increased risk. All cases were successfully treated, and CDI was not associated with an increase in length of stay, costs, or mortality. In a subgroup analysis, 16% of patients with acute myelogenous leukemia and 4% with other leukemia types were colonized on admission. Colonization was associated with a higher risk of CDI. Ribotyping of available isolates showed 27 different strain types with 014/020 and 027 being the most frequent. CONCLUSIONS: The number of antibiotics administered are a major risk factor for CDI in patients with AL. However, CDI appears to have minimal clinical impact in this population.