Eggerthella lenta Bloodstream Infections Are Associated With Increased Mortality Following Empiric Piperacillin-Tazobactam (TZP) Monotherapy: A Population-based Cohort Study.

Background: Eggerthella lenta is a anaerobic gram-positive bacilli associated with polymicrobial intraabdominal infections. Recently, E. lenta was recognized as an important cause of anaerobic bloodstream infections (BSIs) associated with high mortality. Eggerthella lenta has been reported to have high minimal inhibitory concentrations (MICs) to piperacillin-tazobactam (TZP), a broad-spectrum antibiotic with anaerobic coverage commonly used in multiple centers for empiric treatment of abdominal sepsis. Methods: We describe a retrospective population-based analysis of invasive E. lenta infections from 2009 through 2015. A logistic regression analysis for 30-day mortality risk factors was conducted. Results: We identified 107 E. lenta infections, 95 (89%) were BSIs, 11 (10%) skin and soft tissue infections, and 1 intraabdominal abscess. Polymicrobial infections were found in 40%; 72% of isolates were from a gastrointestinal source, most commonly appendicitis (33%) of which two-thirds were perforated. TZP MIC50 and MIC90 for E. lenta isolates were 32 µg/mL and 64 µg/mL, respectively. The overall 30-day mortality for BSI was 23% and was independently associated with empiric TZP monotherapy (odds ratio [OR], 4.4; 95% confidence interval [CI], 1.2-16; P = .02) and intensive care unit stay (OR, 6.2; 95% CI, 1.4-27.3; P = .01). Thirty-day mortality rates were significantly influenced by the use of different TZP MIC breakpoints. Conclusions: Our results demonstrate the increased recognition of E. lenta as an anaerobic opportunistic pathogen and highlight the need for improved empiric antimicrobial guidelines and TZP MIC breakpoints with better correlation to clinical outcomes to guide appropriate management of invasive E. lenta infections.

Low Counts of B Cells, Natural Killer Cells, Monocytes, Dendritic Cells, Basophils, and Eosinophils are Associated with Postengraftment Infections after Allogeneic Hematopoietic Cell Transplantation.

Hematopoietic cell transplant (HCT) recipients are immunocompromised and thus predisposed to infections. We set out to determine the deficiency of which immune cell subset(s) may predispose to postengraftment infections. We determined day 28, 56, 84, and 180 blood counts of multiple immune cell subsets in 219 allogeneic transplant recipients conditioned with busulfan, fludarabine, and Thymoglobulin. Deficiency of a subset was considered to be associated with infections if the low subset count was significantly associated with subsequent high infection rate per multivariate analysis in both discovery and validation cohorts. Low counts of monocytes (total and inflammatory) and basophils, and low IgA levels were associated with viral infections. Low plasmacytoid dendritic cell (PDC) counts were associated with bacterial infections. Low inflammatory monocyte counts were associated with fungal infections. Low counts of total and naive B cells, total and CD56(high) natural killer (NK) cells, total and inflammatory monocytes, myeloid dendritic cells (MDCs), PDCs, basophils and eosinophils, and low levels of IgA were associated with any infections (due to any pathogen or presumed). In conclusion, deficiencies of B cells, NK cells, monocytes, MDCs, PDCs, basophils, eosinophils, and/or IgA plasma cells appear to predispose to postengraftment infections.

Immune cell subset counts associated with graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major transplantation complication. The purpose of this study was to measure immune cell subsets by flow cytometry early after transplantation (before median day of GVHD onset) to identify subsets that may play a role in GVHD pathogenesis. We also measured the subsets later after transplantation to determine which subsets may be influenced by GVHD or its treatment. We studied 219 patients. We found that acute GVHD (aGVHD) was preceded by high counts of CD4 T cells and CD8 T cells. It was followed by low counts of total and naive B cells, total and cytolytic NK cells, and myeloid and plasmacytoid dendritic cells. Chronic GVHD (cGVHD) was preceded by low counts of memory B cells. In conclusion, both CD4 and CD8 T cells appear to play a role in the pathogenesis of aGVHD. Generation of B cells, NK cells, and dendritic cells may be hampered by aGVHD and/or its treatment. Memory B cells may inhibit the development of cGVHD.

Genomic instability after allogeneic hematopoietic cell transplantation is frequent in oral mucosa, particularly in patients with a history of chronic graft-versus-host disease, and rare in nasal mucosa.

Genomic instability (GI) of cells may lead to their malignant transformation. Carcinoma after hematopoietic cell transplantation (HCT) frequently involves some (eg, oral) but not other (eg, nasal) epithelia. We examined GI in oral and nasal mucosal specimens from 105 subjects, including short-term (7-98 days, n = 32) and long-term (4-22 yrs, n = 25) allogeneic HCT survivors. Controls included autologous HCT survivors (n = 11), patients treated with chemotherapy without HCT (n = 9) and healthy controls (n = 27). GI was detected in 60% oral versus only 4% nasal specimens in long-term allogeneic HCT survivors (P < .001). None of the controls showed GI. In oral specimens, GI was significantly associated with history of oral chronic graft-versus-host disease (cGVHD). We conclude that GI after HCT is frequent in some (oral) but rare in other (nasal) epithelia. This may explain why some epithelia (especially those involved with cGVHD) are prone to develop cancer.

Low cytomegalovirus-specific T-cell counts at reactivation are associated with progression to high-level viremia or disease in seropositive recipients of hematopoietic cell grafts from seropositive but not seronegative donors.

BACKGROUND AIMS: Identifying patients who spontaneously resolve cytomegalovirus (CMV) reactivation could spare these patients from the toxicity of antiviral drugs such as ganciclovir. The role of CMV-specific T cells in clearing CMV viremia in patients who do not receive ganciclovir has not been evaluated. We assessed this in patients with CMV viremia between 50 and 50 000 genome copies/mL, because our threshold for initiating ganciclovir is 50 000 copies/mL. METHODS: We enumerated CMV-specific T cells in 39 CMV seropositive hematopoietic cell transplantation (HCT) recipients within 4 days of the first positive CMV polymerase chain reaction (PCR). CMV-specific T cells were defined as cells that upon stimulation with CMV lysate or pp65 overlapping peptides produced interferon (IFN)-γ, tumor necrosis factor (TNF)-α or interleukin (IL)-2, alone or in combination. RESULTS: Among Donor (D+), Recipient (R+) patients, unifunctional CMV-specific CD4 T-cells were higher in patients who spontaneously resolved CMV viremia (did not receive ganciclovir) versus those who progressed (received ganciclovir) (median 0.20 versus 0.02/µL lysate-stimulated cells, P < 0.05, and 0.26 versus 0.05/µL pp65 peptide-stimulated cells, P<0.05). Among D- R+ patients, there was no difference between patients with spontaneous resolution or progression; all subsets of CMV-specific T cells measured were barely detectable, in both patients with spontaneous resolution and those with progression. CONCLUSIONS: Among D+ R+ patients (but not D- R+ patients), high CMV-specific CD4 T-cell counts identify patients who can spontaneously resolve CMV reactivation. In D- R+ patients, immune mechanisms other than T cells may control the progression from reactivation to high-level viremia/disease.

Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation.

BACKGROUND AIMS: Anti-thymocyte globulin (ATG) is being used increasingly to prevent graft-versus-host disease (GvHD); however, its impact on immune reconstitution is relatively unknown. We (i) studied immune reconstitution after ATG-conditioned hematopoietic cell transplantation (HCT), (ii) determined the factors influencing the reconstitution, and (iii) compared it with non-ATG-conditioned HCT. METHODS: Immune cell subset counts were determined at 1-24 months post-transplant in 125 HCT recipients who received ATG during conditioning. Subset counts were also determined in 46 non-ATG-conditioned patients (similarly treated). RESULTS: (i) Reconstitution after ATG-conditioned HCT was fast for innate immune cells, intermediate for B cells and CD8 T cells, and very slow for CD4 T cells and invariant natural killer T (iNKT) (iNKT) cells. (ii) Faster reconstitution after ATG-conditioned HCT was associated with a higher number of cells of the same subset transferred with the graft in the case of memory B cells, naive CD4 T cells, naive CD8 T cells, iNKT cells and myeloid dendritic cells; lower recipient age in the case of naive CD4 T cells and naive CD8 T cells; cytomegalovirus recipient seropositivity in the case of memory/effector T cells; an absence of GvHD in the case of naive B cells; lower ATG serum levels in the case of most T-cell subsets, including iNKT cells; and higher ATG levels in the case of NK cells and B cells. (iii) Compared with non-ATG-conditioned HCT, reconstitution after ATG-conditioned HCT was slower for CD4 T cells, and faster for NK cells and B cells. CONCLUSIONS: ATG worsens the reconstitution of CD4 T cells but improves the reconstitution of NK and B cells.

Retrospective audit of a convenience cohort of individuals on HIV pre-exposure prophylaxis in Alberta, Canada.

BACKGROUND: We undertook an audit of a province-wide HIV pre-exposure prophylaxis (PrEP) program in Alberta (Canada). METHODS: A retrospective record review of individuals accessing PrEP in Alberta included demographics, PrEP indication(s), and reported non-prescription drug and alcohol use from March 2016 to June 2019. Hepatitis A, B, C, HIV and syphilis serology, serum creatinine, and nucleic acid amplification tests testing for chlamydia and gonorrhea were collected. Descriptive statistics, incidence, and prevalence were calculated. RESULTS: A total of 511 participants were seen at STI, sexual, and reproductive health clinics and private family practitioner (FP) offices; 98.4% (503) were men, median age was 34 years (IQR 28-43 years), and 89.8% (459) were gay or bisexual men who have sex with men. Non-prescription drug use was reported by 39.3% (201) and alcohol use by 55.4% (283). 94.3% (482) reported condomless anal sex in the past 6 months. Testing rates were high (>95%) for all tests except for chlamydia and gonorrhea at the first follow-up visit 89.6%; (3-4 months). There was one HIV seroconversion. The incidence of new bacterial STIs was high: chlamydia 17 cases per 100 person-years (95% CI 13.5% to 21.4%), gonorrhea 11.14 cases per 100 person-years (95% CI 8.3% to 15.0%), and syphilis 1.94 cases per 100 person-years (95% CI 0.73% to 5.12%). CONCLUSIONS: Following implementation of a provincial program for PrEP in Alberta, PrEP initiation and continuation was feasible in a range of settings and by both specialists and FPs.

HISTORIQUE: Les chercheurs ont entrepris une vérification du programme provincial de prophylaxie pré-exposition (PrEP) du VIH en Alberta, au Canada. MÉTHODOLOGIE: Les chercheurs ont procédé à une analyse rétrospective des dossiers des personnes qui ont eu accès à la PrEP en Alberta, y compris les données démographiques, les indications d'administrer une PrEP et la consommation déclarée de médicaments sans ordonnance et d'alcool entre mars 2016 et juin 2019. Ils ont recueilli la sérologie de l'hépatite A, B et C, du VIH et de la syphilis, la créatinine sérique et les tests d'amplification des acides nucléiques de la Chlamydia et de la gonorrhée. Ils ont également calculé les statistiques descriptives, l'incidence et la prévalence de ces maladies. RÉSULTATS: Au total, 511 participants ont été vus dans des cliniques d'ITS, de santé sexuelle et de santé reproductive ainsi qu'au cabinet de médecins de famille privés, soit 98,4 % d'hommes (503), d'un âge médian de 34 ans (ÉIQ : 28 à 43 ans) et 89,8 % (459) d'hommes gay ou bisexuels qui avaient des relations sexuelles avec d'autres hommes. Ainsi, 39,3 % (201) ont déclaré consommer des médicaments sans ordonnance et 55,4 % (283), de l'alcool. De plus, 94,3 % (482) ont indiqué avoir eu des relations sexuelles anales sans préservatif au cours des six mois précédents. Les taux de dépistage étaient élevés (>95 %) à l'égard de tous les tests au premier rendez-vous de suivi (au bout de trois à quatre mois), sauf ceux de la Chlamydia et de la gonorrhée, qui s'élevaient à 89,6 %. Un cas de séroconversion du VIH a été constaté. L'incidence de nouvelles ITS bactérienne était élevée : 17 cas de Chlamydia par 100 années-personnes (IC à 95 %, 13,5 % à 21,4 %), 11,14 cas de gonorrhée par 100 années-personnes (IC à 95 %, 8,3 % à 15,0 %) et 1,94 cas de syphilis par 100 années-personnes (IC à 95 %, 0,73 % à 5,12 %). CONCLUSIONS: Après la mise en œuvre d'un programme provincial de PrEP en Alberta, il a été établi qu'il était possible d'entreprendre et de poursuivre la PrEP dans divers milieux, à l'instigation de spécialistes tout autant que de médecins de famille.

Donor serostatus has an impact on cytomegalovirus-specific immunity, cytomegaloviral disease incidence, and survival in seropositive hematopoietic cell transplant recipients.

More cytomegalovirus (CMV)-specific T cells are transferred with grafts from CMV seropositive than seronegative donors. We hypothesized that seropositive recipients of grafts from seropositive donors (D+R+) have higher counts of CMV-specific T cells than seropositive recipients of grafts from seronegative donors (D-R+), and that this is clinically relevant in the setting of in vivo T cell depletion using rabbit-antihuman thymocyte globulin (ATG). We reviewed charts of 298 ATG-conditioned, seropositive recipients for CMV reactivation (pp65 antigenemia or CMV DNAemia above institutional threshold for preemptive therapy), recurrent CMV reactivation, CMV disease, and death. In 77 of these patients, we enumerated CMV-specific T cells. Median follow-up was 564 days. CMV-specific CD4+ and, to a lesser degree, CD8+ T cell counts were higher in D+R+ than D-R+ patients. D+R+ patients had lower cumulative incidence of CMV reactivation (21% versus 48%, P < .001), recurrent reactivation (4% versus 15%, P = .003), CMV disease (3% versus 13%, P = .005) and mortality (42% versus 56%, P = .006). We conclude that in the setting of in vivo T cell depletion using ATG, seropositive donors should be used for seropositive recipients. For scenarios where only seronegative donors are available, strategies to improve CMV-specific immunity (e.g., donor vaccination) should be explored.

High rabbit-antihuman thymocyte globulin levels are associated with low likelihood of graft-vs-host disease and high likelihood of posttransplant lymphoproliferative disorder.

Rabbit-antithymocyte globulin (ATG) given with conditioning has the potential to decrease the likelihood of graft-versus-host disease (GVHD) or graft failure and to increase the likelihood of relapse or infections. After a given ATG dose, serum ATG levels are variable. Here we determined ATG levels on days 7 and 28 in 153 patients whose conditioning included 4.5 mg/kg ATG (thymoglobulin). Median follow-up was 547 days (range: 14-1519, minimum for patients who have not died, relapsed, developed second malignancy, or had graft failure, 365). Both high day 7 levels and high day 28 levels were associated with low likelihoods of grade II-IV acute GVHD and chronic GVHD needing systemic immunosuppressive therapy, and a high likelihood of posttransplant lymphoproliferative disorder (PTLD). Patients with day 7 ATG levels above 0.803 mg/L had 0.52-fold risk of developing chronic GVHD needing systemic therapy (P = 0.012) and patients with day 7 ATG levels above 1.436 mg/L had 5.84-fold risk of developing PTLD (P = 0.001) compared to patients with lower ATG levels. There was no association of ATG levels with relapse, death, or non-PTLD infections. Association with graft failure could not be evaluated due to only 4 graft failures in the cohort. In conclusion, patients with slow clearance of ATG have a low risk of GVHD, but a high risk of PTLD. The clearance of this relatively low dose of ATG does not impact the likelihood of relapse, death, or non-PTLD infections.

A Novel Assay for Detection of Methicillin-Resistant Staphylococcus aureus Directly From Clinical Samples.

The timely detection of Methicillin-resistant Staphylococcus aureus (MRSA) is crucial for antimicrobial therapy and a key factor to limit the hospital spread of MRSA. Currently available commercial MRSA detection assays target the 3' end of the orfX gene and the right extremity of Staphylococcal Cassette Chromosome mec (SCCmec). These assays suffer from both false positive due to SCC-like elements that lack mecA and false negative results due to the inability to detect new or variant SCCmec cassettes with the existing primers. We developed a novel MRSA detection scheme, designed to circumvent issues present in the existing commercial assays. Our assay demonstrated specificity and accuracy, capable of detecting prototypic strains of SCCmec types I-XIII [C(t) values ranged 8.58-26.29]. Previous false positive isolates (N = 19) by Xpert MRSA nasal assay were accurately classified with our assay. Further validation with 218 randomly selected clinical isolates (73 MRSA, 75 MSSA, 43 MR-CoNS, and 27 MS-CoNS) confirmed its feasibility and practicality. Testing assay performance with 88 direct clinical swabs from 33 patients showed that the assay was 96.6% in agreement with clinical culture results. Our novel MRSA detection assay targets both the S. aureus specific sequence and the mecA/mecC genes simultaneously to overcome the false positive and false negative deficits of currently available commercial assays. The results validate our assay and confirmed its feasibility and practicality. The assay is not affected by SCCmec types and only needs modification if new mec homologs emerge and establishes a new platform for other emerging SCCmec types.

Multidrug-resistant Aeromonas hydrophila causing fatal bilateral necrotizing fasciitis in an immunocompromised patient: a case report.

BACKGROUND: Aeromonas hydrophila is a water-dwelling, gram-negative rod-shaped bacterium, associated with diarrheal illness and, less commonly, necrotizing skin and soft tissue infections, especially among immunocompromised patients. Necrotizing fasciitis is associated with a high mortality rate, especially when caused by Aeromonas spp. Our patient was infected with an extremely aggressive form of multidrug-resistant Aeromonas spp. that produced both an extended-spectrum ß-lactamase and an AmpC enzyme. Aeromonads are being recognized as important emerging pathogens because of their inherent antibiotic resistance profiles compounded by other virulence factors. These difficult-to-treat organisms can have significant implications in both clinical and public health settings. CASE PRESENTATION: A 37-year-old Caucasian male with immunosuppression due to aplastic anemia being treated with cyclosporine, presented to hospital with relapsed disease. While in hospital, he subsequently developed overwhelming sepsis secondary to bilateral lower extremity necrotizing fasciitis. The necrotizing fasciitis was caused by a multidrug-resistant strain of A. hydrophila. Despite broad-spectrum antibiotics and aggressive surgical debridement, he succumbed to this severe invasive infection. CONCLUSIONS: Necrotizing fasciitis caused by Aeromonas spp. is a rare infection that may have a poor clinical outcome, particularly if the diagnosis is delayed and/or the organism is highly virulent and multidrug resistant. Enhanced education of clinicians and microbiologists is required to prevent unnecessary complications and improve survival.

The epidemiology of Staphylococcus aureus carriage in patients attending inner city sexually transmitted infections and community clinics in Calgary, Canada.

BACKGROUND: Although the nares represent the most common carriage site for traditional hospital-associated strains of Staphylococcus aureus (SA), the predominant site of carriage of SA in the community is less certain. METHODS: We conducted a cross-sectional study in 285 patients attending sexually transmitted diseases and inner-city clinics to evaluate the prevalence, body site colonisation and risk factors associated with carriage of methicillin susceptible SA (MSSA). All isolates were characterized by pulsed field gel electrophoresis, staphylococcal cassette chromosome mec, staphylococcal protein A and multilocus sequence typing. RESULTS: The prevalence of colonisation with SA was 57.5% (164/285); 162 (56.8%) participants were colonized with MSSA, and 4 (1.4%) with methicillin-resistant SA (MRSA), 2 of them were co-colonised with both MRSA and MSSA. The most common sites of colonisation were the throat (73.1%), nares (65.2%) and interdigital web spaces of the hand (21.3%). Three out of 4 MRSA isolates were USA300-MRSA strains. Twelve MSSA isolates were closely related to the USA300 CA-MRSA. We identified sexual behaviours such as having more than 6 heterosexual sexual partners in the last 6 months and trimming pubic hair to be independently associated with MSSA colonisation, and more specifically practicing oral sex as a risk factor for throat colonisation. CONCLUSION: There is a high prevalence of MSSA carriage in this population, with a low prevalence of MRSA. The throat was the most common site of carriage and sexual behaviours were found to be risk factors for MSSA colonisation. Close strain relatedness of MSSA and USA300-MRSA isolates suggests either gain or loss of the SCCmec element, respectively.

[Fluoroquinolone prophylaxis utility during chemotherapy-induced severe neutropenia in patients with acute leukemia, with fluoroquinolone resistance high prevalence, in a reference hospital in Mexico City]. / Utilidad de la profilaxis con fluoroquinolonas durante la neutropenia grave inducida por quimioterapia en pacientes con leucemia aguda, en un hospital de referencia de la Ciudad de México con alta prevalencia de resistencia a fluoroquinolonas.

BACKGROUND: The use of fluoroquinolone prophylaxis in patients with cancer and neutropenia has failed to show a significant impact on mortality, despite its usefulness in reducing the incidence of gramnegative bacteremia. However, an increase in grampositive bacteremia and the emergence of resistant colonizing bacteria have consistently been noticed. OBJECTIVE: To determine the impact of prophylaxis with fluoroquinolones on the incidence of bacteremia and mortality in a hospital with high fluorquinolone resistance in Mexico City. PATIENTS: We conducted a retrospective and comparative study of patients with acute mieloid (AML) and hybrid (HL) leukemia who received or not prophylaxis with fluoroquinolones and who were attended from January 2000 to December 2003. We reviewed all pertinent clinical and laboratory data of the hematologic malignancies and the febrile episodes. RESULTS: A total of 108 febrile episodes of severe neutropenia occurred in 69 patients, with an incidence of 6.5 events/1000 day-patient with neutropenia. The median age was 35 +/- 18.3 years and 58% were men; 51 patients had AML (71.8%) and 20 (28.1%) HL. Prophylaxis had been given since the beginning of granulocytopenia in 46 (42.6%) febrile episodes (group 1), where as in 62 no prophylaxis was given (group 2). Of the 46 episodes with prophylaxis, 27 received ciprofloxacin 500 mg qd p.o. and 19, ciprofloxacin 500 mg qd po plus fluconazol 100 mg qd po. The median duration of prophylaxis was 8.5 days (range 1-90 days). Twenty-nine bacteremias (26.8%) were documented, with an incidence of 16.4 bacteremias/1000 day-patient with neutropenia, 12 (26%) in group 1 and 17 (27.5%) in group 2. Bacteremia was most frequently caused by gram negative organisms (18/29), being Escherichia coli (14) the most commonly isolated pathogen, with 7 episodes in each group. Eight (29.6%) of the 21 isolates in which fluoroquinolone susceptibility was tested were ciprofloxacin resistant, 3 in group 1 and 5 in group 2 (p = 0.58). Median survival of patients was 38 days in group 1 and 40 days in group 2. (p = 0.2); mortality was similar in both groups, 34% and 27%, respectively. CONCLUSIONS: In a hospital with a high prevalence of fluoroquinolone-resistance, prophylaxis in patients with acute leukemia and severe neutropenia did not prevent febrile episodes and did not have any impact on mortality. However, there was no increase in infections caused by resistant bacteria.

Lead Poisoning From a Ceramic Jug Presenting as Recurrent Abdominal Pain and Jaundice.

Lead poisoning may present with non-specific symptoms that may result in unnecessary investigations. We report a case of acute lead poisoning in a previously healthy 28-year-old man who presented with recurrent abdominal pain, jaundice, constipation, and weight loss. An extensive diagnostic work-up was completed with inconclusive results. A detailed history revealed an unusual source of lead exposure. Chelation therapy resulted in substantial clinical and biochemical improvement.

[Alveolar epithelial barrier in patients with acute respiratory distress syndrome (ARDS)]. / La barrera epitelial alveolar en el enfermo con síndrome de dificultad respiratoria aguda (SDRA).

The clearance of alveolar fluid depends on the anatomic and physiologic integrity of alveolar epithelial barrier. The vectorial transport of sodium begins at the apical surface in the type II cell through amiloride-sensitive sodium channel. Sodium is pumping by Na, K-ATPasa from the basolateral surface of type II cell to the interstice. Water passes through specialized channels in the type I cell membrane by the osmotic gradient created by sodium. The activity of the sodium transporters is regulated actively by genetics and depends on molecular processes that involve the hormonal stimulation. The damage to the epithelial membrane produces an increased of the permeability of great molecules, which favors generation of edema in the alveolar space, delay in the resolution and incapacity to regenerate epithelium. More clinic trials are required to demonstrate the paper of the transport of chloride and to clarify the true function of the specialized water channels in the regulation of the alveolar fluid clearance.