Ciprofloxacin versus levofloxacin prophylaxis in hematopoietic stem cell transplantation: A randomized trial.

OBJECTIVES: We aimed to assess whether there is a difference between ciprofloxacin and levofloxacin as prophylaxis in hematopoietic stem cell transplant (SCT) recipients. METHODS: This is a prospective, randomized trial in patients receiving SCT at Henry Ford Health in the United States of America. We randomly assigned patients (1:1) to receive ciprofloxacin or levofloxacin. The primary outcome was incidence of bloodstream bacterial infections (BSI) up to day 60 after SCT. RESULTS: Between June 4, 2018, and May 23, 2022, we randomly assigned 308 consecutive patients to receive ciprofloxacin (154 patients) or levofloxacin (154 patients). BSI was similar in both the ciprofloxacin and levofloxacin groups (18 [11.7%] vs 18 [11.7%]). Pneumonia was more frequent in the ciprofloxacin group compared to the levofloxacin group (18 [18%] vs 7 [23%]; relative risk 2.57, 95% CI 1.11-5.98; p = 0.028). There were no differences in neutrophil engraftment, fever, Clostridium difficile infection, relapse incidence, overall survival, nonrelapse mortality, length of stay post-SCT, or intensive care unit admission. CONCLUSION: Although both prophylaxis regimens demonstrated the same efficacy in SCT recipients, levofloxacin prophylaxis led to less pneumonia in the first 60 days post-SCT. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov, NCT03850379.

Inflammatory endotype of odontogenic sinusitis.

BACKGROUND: Odontogenic sinusitis (ODS) is distinct from non-odontogenic rhinosinusitis with regard to clinical features as well as diagnostic and therapeutic approaches. While numerous studies have explored immune profiles of chronic rhinosinusitis, very few studies have explored the inflammatory endotype of ODS. METHODS: Odontogenic sinusitis was diagnosed by confirming infectious sinusitis adjacent to infectious maxillary odontogenic pathology. Maxillary sinus cultures and mucosal biopsies were obtained during endoscopic endonasal surgery in ODS and control patients. Controls were patients undergoing endoscopic skull base surgery with no sinus disease. Specimens were snap frozen in liquid nitrogen and stored at -80°C. Analysis was performed using a multiplex assay to measure Th-1 (TNFα, IFNγ, IL-2,12,18), Th-2 (IL-4,5,9,13), Th-17 (IL-17A,17F,22), and innate (CCL5,CXCL9,CXCL10, IL-6,8,10,12,23,27) immune pathways. Groups were compared via independent sample t-tests; if assumptions were violated, nonparametric Wilcoxon ranked sum tests were performed. RESULTS: Specimens from 22 ODS patients were compared to nine controls. ODS mucosal tissue was sampled in the setting of the following dental pathologies: post-dental extraction (n = 15), untreated apical periodontitis (n = 2), apical periodontitis after root canal therapy (n = 2), and maxillary sinus bone grafting with or without dental implantation (n = 3). The following cytokines were significantly elevated in ODS compared to controls: IFNγ, TNFα, IL-6, 8, 10, 27, and CXCL9. IL-17 levels were similar in both ODS and controls. Therefore, ODS demonstrated heightened innate and Th1 immune activity. CONCLUSION: ODS demonstrated both innate immune and Th1 inflammatory endotypes. Further studies are needed to explore ODS immunopathobiology and its potential impact on ODS management.

Utility of microbiologic testing in surveillance bronchoscopy following lung transplantation: A retrospective cohort study.

BACKGROUND: The utility of surveillance bronchoscopy (SB) for the clinical management of lung transplant recipients (LTRs) is undefined. This study evaluates the role of SB in the monitoring and care of LTRs. METHODS: We retrospectively analyzed all LTRs who had SB at Henry Ford Hospital in Detroit, Michigan between August 2014 and August 2019. Bronchoscopies performed for clinical symptoms, new radiographic abnormalities, and to assess stents or acute rejection were excluded. A total of 107 LTRs and 449 bronchoscopies were analyzed. The primary outcome was the rate of change in clinical care based on microbiologic and pathologic test results. Secondary outcomes were rates of microbiologic and pathologic test positivity and rates of adverse effects. RESULTS: The most common microbiologic tests performed on bronchoalveolar lavage were bacterial (96.9%), fungal (95.3%), and acid-fast bacillus (95.1%) stains and cultures. Of 2560 microbiologic tests, 22.0% were positive and resulted in therapy changes for 2.9%. Positive galactomannan, acid-fast bacillus tests, and Pneumocystis jirovecii antigen/polymerase chain reaction did not result in therapy changes. Of the 370 transbronchial biopsies performed, 82.2% were negative for acute rejection and 13% were positive for A1/A2 rejection. Immunosuppressive therapy changes occurred after 15.8% with reduction in immunosuppression due to positive microbiologic tests in 16.9%. Adverse events occurred in 8.0% of patients. CONCLUSION: Diagnostic stewardship is warranted when performing SB in LTRs.

Systematic review and meta-analysis of effectiveness of treatment options against SARS-CoV-2 infection.

Treatment options for severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) are limited with no clarity on efficacy and safety profiles. We performed a systematic review and meta-analysis of studies on patients ≥18 years reporting data on therapeutic interventions in SARS-CoV-2. Primary outcome was all-cause mortality and secondary outcomes were rates of mechanical ventilation, viral clearance, adverse events, discharge, and progression to severe disease. Pooled rates and odds ratios (OR) were calculated. Twenty-nine studies with 5207 patients were included. Pooled all-cause mortality in intervention arm was 12.8% (95% confidence interval [CI]: 8.1%-17.4%). Mortality was significantly higher for studies using hydroxychloroquine (HCQ) for intervention (OR: 1.36; 95% CI: 0.97-1.89). Adverse events were also higher in HCQ subgroup (OR: 3.88; 95% CI: 1.60-9.45). There was no difference in other secondary outcomes. There is a need for well-designed randomized clinical trials for further investigation of every therapeutic intervention for further insight into different therapeutic options.

Clinical characteristics and predictors of survival in adults with coronavirus disease 2019 receiving tocilizumab.

Coronavirus disease 2019 (COVID-19) can progress to cytokine storm that is associated with organ dysfunction and death. The purpose of the present study is to determine clinical characteristics associated with 28 day in-hospital survival in patients with coronavirus disease 2019 (COVID-19) that received tocilizumab. This was a retrospective observational cohort study conducted at a five hospital health system in Michigan, United States. Adult patients with confirmed COVID-19 that were admitted to the hospital and received tocilizumab for cytokine storm from March 1, 2020 through April 3, 2020 were included. Patients were grouped into survivors and non-survivors based on 28 day in-hospital mortality. Study day 0 was defined as the day tocilizumab was administered. Factors independently associated with in-hospital survival at 28 days after tocilizumab administration were assessed. Epidemiologic, demographic, laboratory, prognostic scores, treatment, and outcome data were collected and analyzed. Clinical response was collected and defined as a decline of two levels on a six-point ordinal scale of clinical status or discharged alive from the hospital. Of the 81 patients included, the median age was 64 (58-71) years and 56 (69.1%) were male. The 28 day in-hospital mortality was 43.2%. There were 46 (56.8%) patients in the survivors and 35 (43.2%) in the non-survivors group. On study day 0 no differences were noted in demographics, clinical characteristics, severity of illness scores, or treatments received between survivors and non-survivors. C-reactive protein was significantly higher in the non-survivors compared to survivors. Compared to non-survivors, recipients of tocilizumab within 12 days of symptom onset was independently associated with survival (adjusted OR: 0.296, 95% CI: 0.098-0.889). SOFA score ≥8 on day 0 was independently associated with mortality (adjusted OR: 2.842, 95% CI: 1.042-7.753). Clinical response occurred more commonly in survivors than non-survivors (80.4% vs. 5.7%; p < 0.001). Improvements in the six-point ordinal scale and SOFA score were observed in survivors after tocilizumab. Early receipt of tocilizumab in patients with severe COVID-19 was an independent predictor for in-hospital survival at 28 days.

Proceeding report of the Second Symposium on Hidradenitis Suppurativa Advances (SHSA) 2017.

The 2nd Annual Symposium on Hidradenitis Suppurativa Advances (SHSA) took place on 03-05 November 2017 in Detroit, Michigan, USA. This symposium was a joint meeting of the Hidradenitis Suppurativa Foundation (HSF Inc.) founded in the USA, and the Canadian Hidradenitis Suppurativa Foundation (CHSF). This was the second annual meeting of the SHSA with experts from different disciplines arriving from North America, Europe and Australia, in a joint aim to discuss most recent innovations, practical challenges and potential solutions to issues related in the management and care of Hidradenitis Suppurativa patients. The last session involved clinicians, patients and their families in an effort to educate them more about the disease.

Ertapenem - a potent treatment for clinical and quality of life improvement in patients with hidradenitis suppurativa.

BACKGROUND: A paucity of knowledge exists regarding the use of ertapenem in hidradenitis suppurativa. Our retrospective chart review and telephone interview aims to investigate the utility of intravenous ertapenem in severe, refractory hidradenitis suppurativa. METHODS: This retrospective chart review and telephone interview included patients with severe, refractory hidradenitis suppurativa treated with intravenous ertapenem between March 2013 and December 2016. Data were obtained from medical charts. During the telephone interview, patients were asked questions relating to satisfaction, quality of life changes, and disease state changes with ertapenem therapy. RESULTS: A total of 36 patients including 22 females and 14 males with Hurley stage II or III hidradenitis suppurativa were included. Thirty-five patients (97.2%), demonstrated improvements in hidradenitis suppurativa with ertapenem treatment. In total, 28 patients participated in our telephone interview. Twenty patients (71.4%) were very satisfied (n = 12) or satisfied (n = 8). Quality of life improved in 85.7% of patients (n = 24). CONCLUSION: Following ertapenem therapy, patients reported improvements in quality of life. This treatment appears promising as an adjunct to biologics or as a bridge to surgery in the treatment of severe, refractory hidradenitis suppurativa.

Characterization of BK Polyomaviruses from Kidney Transplant Recipients Suggests a Role for APOBEC3 in Driving In-Host Virus Evolution.

BK polyomavirus (BKV) frequently causes nephropathy (BKVN) in kidney transplant recipients (KTRs). BKV has also been implicated in the etiology of bladder and kidney cancers. We characterized BKV variants from two KTRs who developed BKVN followed by renal carcinoma. Both patients showed a swarm of BKV sequence variants encoding non-silent mutations in surface loops of the viral major capsid protein. The temporal appearance and disappearance of these mutations highlights the intra-patient evolution of BKV. Some of the observed mutations conferred resistance to antibody-mediated neutralization. The mutations also modified the spectrum of receptor glycans engaged by BKV during host cell entry. Intriguingly, all observed mutations were consistent with DNA damage caused by antiviral APOBEC3 cytosine deaminases. Moreover, APOBEC3 expression was evident upon immunohistochemical analysis of renal biopsies from KTRs. These results provide a snapshot of in-host BKV evolution and suggest that APOBEC3 may drive BKV mutagenesis in vivo.

Brincidofovir as Salvage Therapy for Adenovirus Disease in Intestinal Transplant Recipients.

BACKGROUND: Adenoviruses are double-stranded DNA viruses that typically cause mild self-limiting respiratory, ocular, and gastrointestinal infections. In immunocompromised patients, especially transplant recipients, the infection can be severe, with dissemination and multiorgan failure. In intestinal transplant recipients, the incidence is as high as 57%. To our knowledge, no standardized guidelines or U.S. Food and Drug Administration-approved medications exist for the treatment of adenovirus disease. AIMS: We describe two isolated intestinal transplant recipients who developed adenovirus disease (viremia with viral enteritis) that was managed with a new experimental drug, brincidofovir (an oral lipid conjugate prodrug of cidofovir), as salvage therapy. RESULTS: The first patient was a 44-year-old woman who developed adenoviral enteritis 1 month after transplantation, which resolved with ribavirin therapy. Two weeks later, the infection recurred, and brincidofovir was initiated. While receiving this therapy for 3 months, she developed severe acute rejection, which was managed with rabbit antithymocyte globulin followed by infliximab. Eventually, complete resolution of the rejection and adenoviral enteritis was achieved. At 12 months posttransplantation, the patient was healthy and tolerating enteral feeding. The second patient was a 28-year-old man who had undergone isolated intestinal transplantation 6 years before he presented with generalized weakness and an increased ostomy output; he was diagnosed with adenoviral enteritis. Maintenance immunosuppression was reduced, and brincidofovir was started. The infection resolved with a month of therapy. Six months after the infection, he was healthy and tolerating enteral feeding. CONCLUSION: This is the first publication, to our knowledge, to describe two cases in which brincidofovir was used to successfully treat adenovirus infection in intestinal transplant recipients. Thus, these cases demonstrate that brincidofovir appears to be a safe and effective option in the management of adenoviral enteritis in these patients.

Mycobacterium marinum remains an unrecognized cause of indolent skin infections.

We identified 5 patients who had cutaneous lesions with cultures that yielded Mycobacterium marinum. It was discovered that all 5 patients had a home aquarium, and infection was preceded by trauma to the hand. However, the association between the development of the infection and exposure of the trauma site to the aquarium was not initially established until repeated questioning was performed. Skin biopsies or incision and drainage were performed for all patients, and the diagnosis was established by culture of the specimens. The mean time from initial presentation to diagnosis and initiation of appropriate treatment was 91 days (range, 21-245 days). Prolonged therapy for 2 to 6 months was necessary for resolution of the infection.

Predictors of fecal transplant failure.

BACKGROUND: Clostridium difficile infection (CDI) is a significant healthcare burden, with increased morbidity and mortality. Traditional treatment regimens using antibiotics for recurrent CDI are significantly less successful compared with 80-90% with fecal microbiota transplantation (FMT). There is a paucity of data on failure rates and mortality after FMT in CDI. This study aims to identify the rates of failure, relapse, and mortality associated with FMT as well as the risk factors for FMT failure. METHODS: A large retrospective cohort study was carried out including all patients who underwent FMT from December 2012 through May 2014. Patient factors (demographics, comorbidities, immune-suppression, transplant history, antibiotics used, hospitalization, and surgeries), disease factors (number of episodes of CDI, treatments, and severity), and transplant factors (route and number of FMT) were examined. Failure of treatment was defined as no resolution of diarrhea in patients who had been treated with one or more fecal microbiota transplantation within 90 days of FMT. RESULTS: A total of 201 patients (age 66.6±18.3 years, 62.2% women) were included. The overall failure rate was 12.4%. Patients with failed fecal transplant had increased number of FMTs compared with those who responded (mean 1.92±0.997 vs. 1.29±0.615; P=0.004). No colectomies or death related to CDI were found in our patient population. Significant predictors of failure were female sex (P=0.016), previous hospitalization (P=0.006), and surgery before FMT (P=0.005). The overall mortality rate was 9.0% and failure of FMT was associated with an increased risk of death (odds ratio=5.833, confidence interval 2.01-16.925; P<0.05). CONCLUSION: FMT is a suitable alterative to antibiotic use for recurrent CDIs, with a high success rate. The results indicate that hospital-acquired CDI may be a predictor of failure of FMT.

Performance of lateral flow device and galactomannan for the detection of Aspergillus species in bronchoalveolar fluid of patients at risk for invasive pulmonary aspergillosis.

Early diagnosis of invasive pulmonary aspergillosis (IPA) remains difficult due to the variable performance of the tests used. We compared the performance characteristics of Aspergillus lateral flow device (LFD) in bronchoalveolar lavage (BAL) vs. BAL-galactomannan (GM), for the diagnosis of IPA. 311 BAL specimens were prospectively collected from patients who underwent bronchoscopy from January to May 2013. Patients at risk for IPA were divided into haematological malignancy (HEM) and non-HEM groups: solid organ transplants (SOT) (lung transplant (LT) and non-LT SOT); chronic steroid use (CSU); solid tumour (STU) and others. We identified 96 patients at risk for IPA; 89 patients (93%) were in the non-HEM groups: SOT 57 (LT, 46, non-LT SOT, 11); CSU 21; STU 6, other 5. Only three patients met criteria for IA (two probable; one possible). Overall sensitivity (SS) was 66% for both and specificity (SP) was 94% vs. 52% for LFD and GM respectively. LFD and GM performance was similar in the HEM group (SS 100% for both and SP 83% vs. 100% respectively). LFD performance was better than GM among non-HEM SOT patients (P = 0.02). Most false-positive GM results occurred in the SOT group (50.8%), especially among LT patients (56.5%). LFD performance was superior with an overall SP of 95.6% in SOT (P < 0.002) and 97% in LT patients (P = 0.0008). LFD is a rapid and simple test that can be performed on BAL to rule out IPA.

Intestinal microbiota transplantation, a simple and effective treatment for severe and refractory Clostridium difficile infection.

BACKGROUND: Restoring normal fecal flora through intestinal microbiota transplantation (IMT) was successful in curing recurrent Clostridium difficile infection (CDI). However, only a few cases have been reported of IMT being utilized for the treatment of severe or fulminant CDI. AIM: Is IMT a simple and effective treatment for severe and recurrent CDI? METHODS: In this retrospective study, we report 14 patients with severe CDI refractory to conventional medical therapy, who underwent IMT. Fresh donor stool specimen was manually homogenized with warm tap water, filtered through gauze and then instilled through nasogastric tube (NGT). The primary outcome was clinical cure, defined as less than 3 loose bowel movements a day on day 7 after IMT and no need for further CDI therapy. The secondary outcomes were recurrence of CDI within 100 days of IMT and 30-day mortality after IMT. Descriptive statistics were done. RESULTS: Fourteen patients with severe and refractory CDI received IMT. Mean age was 73.4 ± 11.9 years (range 52-92). IMT was given via NGT in 13 of the 14 patients. Eleven patients (79 %) achieved cure after IMT. No recurrence was seen in the patients who responded to IMT and were alive within the 100 day follow-up period. IMT was well tolerated. The 30-day all-cause mortality was 29 %, all 4 patients died as a result of their underlying cancer. No patients died as a result of CDI or IMT. CONCLUSIONS: IMT performed at the bedside via NGT is effective and safe for the treatment of severe and refractory CDI, and prevents recurrence.

Targeting cytomegalovirus-infected cells using T cells armed with anti-CD3 × anti-CMV bispecific antibody.

Human cytomegalovirus (CMV) reactivation and infection can lead to poor outcomes after allogeneic stem cell transplantation. We hypothesized that anti-CD3 activated T cells (ATCs) armed with chemically heteroconjugated anti-CD3 × polyclonal anti-CMV bispecific antibody (CMVBi) will target and eliminate CMV-infected cells. Arming doses of CMVBi as low as 0.01 ng/10(6) ATCs was able to mediate specific cytotoxicity (SC) directed at CMV-infected target cells significant above unarmed ATCs at mutiplicities of infection (MOI) between 0.01 and 1. At effector-to-target ratios (E:T) of 25:1, 12.5:1, 6.25:1, and 3.125:1, armed ATCs significantly enhanced killing of CMV-infected targets compared with unarmed ATCs. At an MOI of 1.0, the mean % SC directed at CMV-infected targets cells for CMVBi-armed ATCs at E:T of 3.12, 6.25, and 12.5 were 79%, 81%, and 82%, respectively; whereas the mean % SC for unarmed ATCs at the same E:T were all <20%. ATCs, Cytogam(®), or CMVBi alone did not lyse uninfected or CMV-infected targets. Co-cultures of CMVBi-armed ATCs with CMV-infected targets induced cytokine and chemokine release from armed ATCs. This nonmajor histocompatibility complex restricted strategy for targeting CMV could be used to prevent or treat CMV infections after allogeneic stem cell transplantation or organ transplantation.

A comparative study of the post-antifungal effect (PAFE) of amphotericin B, triazoles and echinocandins on Aspergillus fumigatus and Candida albicans.

OBJECTIVES: To study the post-antifungal effect (PAFE) of antifungal drugs on Aspergillus fumigatus by a radiometric assay and compare the results with those obtained for Candida albicans. METHODS: A. fumigatus cultures pregrown for 48 h in 96-well microtitre plate were exposed to various concentrations of the antifungal drug for 2 h. The drug-treated mycelia were washed, incubated in RPMI 1640 containing (14)C-labelled amino acids and the accumulation of radioactivity in the mycelia at different time intervals was determined. The PAFE was determined by plotting the amount of radioactivity associated with the mycelia against post-treatment incubation time. The PAFE of antifungal drug on C. albicans was examined by determining the multiplication (cfu/mL) of drug-pretreated cells at different time intervals for 24 h in drug-free medium. RESULTS: Amphotericin B produced a prolonged PAFE (7.5 +/- 0.70 h) against A. fumigatus whereas itraconazole (0.5 +/- 0.0 h), voriconazole (0.5 +/- 0.0 h), posaconazole (0.75 +/- 0.35 h), ravuconazole (0.38 +/- 0.17 h) and the echinocandins caspofungin (< or =0.5 h) and micafungin (< or =0.5 h) produced short PAFE. Short exposure (1 h) of C. albicans to low concentrations (0.125-1 mg/L) of amphotericin B (5.3 +/- 1.15 h), caspofungin (5.6 +/- 0.57 h) and micafungin (5 +/- 1.0 h) produced prolonged PAFE whereas the triazoles produced a short (< or =0.5 h) PAFE. CONCLUSIONS: Determination of (14)C-labelled amino acid accumulation in antifungal drug-pretreated mycelia is a suitable method for studying PAFE in A. fumigatus. Antifungal drugs with fungicidal activity tend to possess longer PAFE compared to fungistatic drugs.