Michelle A. Barron

Zygomycosis in Solid Organ Transplant Recipients: A Prospective, Matched Case-Control Study to Assess Risks for Disease and Outcome

BACKGROUND Clinical characteristics, risks, and outcomes in solid organ transplant (SOT) recipients with zygomycosis in the era of modern immunosuppressive and newer antifungal agent use have not been defined. METHODS In a matched case-controlled study, SOT recipients with zygomycosis were prospectively studied. The primary outcome measure was success (complete or partial response) at 90 days. RESULTS Renal failure (odds ratio [OR], 3.17; P = .010), diabetes mellitus (OR, 8.11; P < .001), and prior voriconazole and/or caspofungin use (OR, 4.41; P = .033) were associated with a higher risk of zygomycosis, whereas tacrolimus (OR, 0.23; P = .002) was associated with a lower risk of zygomycosis. Liver transplant recipients were more likely to have disseminated disease (OR, 5.48; P = .021) and developed zygomycosis earlier after transplantation than did other SOT recipients (median, 0.8 vs 5.7 months; P < .001). Overall the treatment success rate was 60%. Renal failure (OR, 11.3; P = .023) and disseminated disease (OR, 14.6; P = .027) were independently predictive of treatment failure, whereas surgical resection was associated with treatment success (OR, 33.3; P = .003). The success rate with liposomal amphotericin B was 4-fold higher even when controlling for the aforementioned variables. CONCLUSIONS The risks identified for zygomycosis and for disseminated disease, including those that were previously unrecognized, have implications for further elucidating the biologic basis and for optimizing outcomes in SOT recipients with zygomycosis.

Administration of Spores of Nontoxigenic Clostridium difficile Strain M3 for Prevention of Recurrent C difficile Infection: A Randomized Clinical Trial

IMPORTANCE Clostridium difficile is the most common cause of health care-associated infection in US hospitals. Recurrence occurs in 25% to 30% of patients. OBJECTIVE To determine the safety, fecal colonization, recurrence rate, and optimal dosing schedule of nontoxigenic C. difficile strain M3 (VP20621; NTCD-M3) for prevention of recurrent C. difficile infection (CDI). DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from June 2011 to June 2013 among 173 patients aged 18 years or older who were diagnosed as having CDI (first episode or first recurrence) and had successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe. INTERVENTIONS Patients were randomly assigned to receive 1 of 4 treatments: oral liquid formulation of NTCD-M3, 10(4) spores/d for 7 days (n = 43), 10(7) spores/d for 7 days (n = 44), or 10(7) spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). MAIN OUTCOMES AND MEASURES The primary outcome was safety and tolerability of NTCD-M3 within 7 days of treatment. Exploratory secondary outcomes included fecal colonization with NTCD-M3 from end of study drug through week 6 and CDI recurrence from day 1 through week 6. RESULTS Among 168 patients who started treatment, 157 completed treatment. One or more treatment-emergent adverse events were reported in 78% of patients receiving NTCD-M3 and 86% of patients receiving placebo. Diarrhea and abdominal pain were reported in 46% and 17% of patients receiving NTCD-M3 and 60% and 33% of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7% of patients receiving placebo and 3% of all patients who received NTCD-M3. Headache was reported in 10% of patients receiving NTCD-M3 and 2% of placebo patients. Fecal colonization occurred in 69% of NTCD-M3 patients: 71% with 10(7) spores/d and 63% with 10(4) spores/d. Recurrence of CDI occurred in 13 (30%) of 43 placebo patients and 14 (11%) of 125 NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006); the lowest recurrence was in 2 (5%) of 43 patients receiving 10(7) spores/d for 7 days (OR, 0.1; 95% CI, 0.0-0.6; P = .01 vs placebo]). Recurrence occurred in 2 (2%) of 86 patients who were colonized vs 12 (31%) of 39 patients who received NTCD-M3 and were not colonized (OR, 0.01; 95% CI, 0.00-0.05; P < .001). CONCLUSIONS AND RELEVANCE Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe. Nontoxigenic C. difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01259726.

Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C difficile infection

IMPORTANCE Clostridium difficile is the most common cause of health care-associated infection in US hospitals. Recurrence occurs in 25% to 30% of patients. OBJECTIVE To determine the safety, fecal colonization, recurrence rate, and optimal dosing schedule of nontoxigenic C. difficile strain M3 (VP20621; NTCD-M3) for prevention of recurrent C. difficile infection (CDI). DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from June 2011 to June 2013 among 173 patients aged 18 years or older who were diagnosed as having CDI (first episode or first recurrence) and had successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe. INTERVENTIONS Patients were randomly assigned to receive 1 of 4 treatments: oral liquid formulation of NTCD-M3, 10(4) spores/d for 7 days (n = 43), 10(7) spores/d for 7 days (n = 44), or 10(7) spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). MAIN OUTCOMES AND MEASURES The primary outcome was safety and tolerability of NTCD-M3 within 7 days of treatment. Exploratory secondary outcomes included fecal colonization with NTCD-M3 from end of study drug through week 6 and CDI recurrence from day 1 through week 6. RESULTS Among 168 patients who started treatment, 157 completed treatment. One or more treatment-emergent adverse events were reported in 78% of patients receiving NTCD-M3 and 86% of patients receiving placebo. Diarrhea and abdominal pain were reported in 46% and 17% of patients receiving NTCD-M3 and 60% and 33% of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7% of patients receiving placebo and 3% of all patients who received NTCD-M3. Headache was reported in 10% of patients receiving NTCD-M3 and 2% of placebo patients. Fecal colonization occurred in 69% of NTCD-M3 patients: 71% with 10(7) spores/d and 63% with 10(4) spores/d. Recurrence of CDI occurred in 13 (30%) of 43 placebo patients and 14 (11%) of 125 NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006); the lowest recurrence was in 2 (5%) of 43 patients receiving 10(7) spores/d for 7 days (OR, 0.1; 95% CI, 0.0-0.6; P = .01 vs placebo]). Recurrence occurred in 2 (2%) of 86 patients who were colonized vs 12 (31%) of 39 patients who received NTCD-M3 and were not colonized (OR, 0.01; 95% CI, 0.00-0.05; P < .001). CONCLUSIONS AND RELEVANCE Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe. Nontoxigenic C. difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01259726.

Improvement of a clinical prediction rule for clinical trials on prophylaxis for invasive candidiasis in the intensive care unit

We created a clinical prediction rule to identify patients at risk of invasive candidiasis (IC) in the intensive care unit (ICU) (Eur J Clin Microbiol Infect Dis 2007; 26:271). The rule applies to <10% of patients in ICUs. We sought to create a more inclusive rule for clinical trials. Retrospective review of patients admitted to ICU ≥ 4 days, collecting risk factors and outcomes. Variations of the rule based on introduction of mechanical ventilation and risk factors were assessed. We reviewed 597 patients with a mean APACHE II score of 14.4, mean ICU stay of 12.5 days and mean ventilation time of 10.7 days. A variation of the rule requiring mechanical ventilation AND central venous catheter AND broad spectrum antibiotics on days 1–3 AND an additional risk factor applied to 18% of patients, maintaining the incidence of IC at 10%. Modification of our original rule resulted in a more inclusive rule for studies.

Epidemiology of Healthcare‐Associated Bloodstream Infection Caused by USA300 Strains of Methicillin‐Resistant Staphylococcus aureus in 3 Affiliated Hospitals

OBJECTIVE To describe the epidemiology of bloodstream infection caused by USA300 strains of methicillin-resistant Staphylococcus aureus (MRSA), which are traditionally associated with cases of community-acquired infection, in the healthcare setting. DESIGN Retrospective cohort study. SETTING Three academically affiliated hospitals in Denver, Colorado. METHODS Review of cases of S. aureus bloodstream infection during the period from 2003 through 2007. Polymerase chain reaction was used to identify MRSA USA300 isolates. RESULTS A total of 330 cases of MRSA bloodstream infection occurred during the study period, of which 286 (87%) were healthcare-associated. The rates of methicillin resistance among the S. aureus isolates recovered did not vary during the study period and were similar among the 3 hospitals. However, the percentages of cases of healthcare-associated MRSA bloodstream infection due to USA300 strains varied substantially among the 3 hospitals: 62%, 19%, and 36% (P<.001) for community-onset cases and 33%, 3%, and 33% (P=.005) for hospital-onset cases, in hospitals A, B, and C, respectively. In addition, the number of cases of healthcare-associated MRSA bloodstream infection caused by USA300 strains increased during the study period at 2 of the 3 hospitals. At each hospital, USA300 strains were most common among cases of community-associated infection and were least common among cases of hospital-onset infection. Admission to hospital A (a safety-net hospital), injection drug use, and human immunodeficiency virus infection were independent risk factors for healthcare-associated MRSA bloodstream infection due to USA300 strains. CONCLUSIONS The prevalence of USA300 strains among cases of healthcare-associated MRSA bloodstream infection varied dramatically among geographically clustered hospitals. USA300 strains are replacing traditional healthcare-related strains of MRSA in some healthcare settings. Our data suggest that the prevalence of USA300 strains in the community is the dominant factor affecting the prevalence of this strain type in the healthcare setting.

Pulmonary zygomycosis in solid organ transplant recipients in the current era.

Fifty‐eight solid organ transplant recipients with zygomycosis were studied to assess the presentation, radiographic characteristics, risks for extra‐pulmonary dissemination and mortality of pulmonary zygomycosis. Pulmonary zygomycosis was documented in 31 patients (53%) and developed a median of 5.5 months (interquartile range, 2–11 months) posttransplantation. In all, 74.2% (23/31) of the patients had zygomycosis limited to the lungs and 25.8% (8/31) had lung disease as part of disseminated zygomycosis; cutaneous/soft tissue (50%, 4/8) was the most common site of dissemination. Pulmonary disease presented most frequently as consolidation/mass lesions (29.0%), nodules (25.8%) and cavities (22.6%). Patients with disseminated disease were more likely to have Mycocladus corymbifer as the causative pathogen. The mortality rate at 90 days after the treatment was 45.2%. In summary, pulmonary zygomycosis is the most common manifestation in solid organ transplant recipients with zygomycosis, and disseminated disease often involves the cutaneous/soft tissue sites but not the brain.

Relationship of Reconstituted Adaptive and Innate Cytomegalovirus (CMV)-Specific Immune Responses with CMV Viremia in Hematopoietic Stem Cell Transplant Recipients

BACKGROUND Cytomegalovirus (CMV) is a major cause of morbidity in transplant recipients. An immunologic predictor of protection against CMV reactivation or disease is highly desirable. METHODS Thirty-eight allogeneic hematopoietic stem cell transplant recipients at risk of CMV disease were prospectively monitored using whole blood CMV-DNA polymerase chain reaction assay, lymphocyte proliferation assay (LPA), interferon gamma enzyme-linked immunospot assay (ELISPOT), and flow cytometric enumeration of CMV-specific CD69+interferon (IFN)gamma+CD4, CD8, natural killer cells, and gammadelta T cells. RESULTS Twenty-one subjects developed > or =1 episode of CMV viremia and 4 developed disease during 360 days of follow-up. Among CMV-seropositive recipients, positive CMV-LPA before transplantation correlated with higher risk of developing viremia after transplantation (P = .02). In contrast, after transplantation, reconstitution of CMV-LPA was significantly associated with absence of CMV viremia over 360 days of follow-up (P = .04) and with faster clearance of viremia during individual episodes of CMV reactivation (P = .03). Reconstitution of CMV-specific natural killer cells was also associated with absence of CMV viremia over 360 days of study (P = .04) but not with faster clearance of viremia. CMV-specific CD4, CD8, gammadelta T cells, and ELISPOT values were not significantly different in viremic subjects, compared with the corresponding values in nonviremic subjects, at any time point. CONCLUSIONS To our knowledge, this is the first study to prospectively compare multiple measures of innate and adaptive immune responses in hematopoietic stem cell transplant recipients with CMV viremia. The strongest immune correlates with protection against CMV viremia in hematopoietic stem cell transplant recipients are reconstitution of CMV-specific T cell memory responses (LPA) and recovery of natural killer cell function. In contrast, positive CMV-LPA before transplantation may be a marker of high risk of CMV reactivation after transplantation.

Invasive Mycotic Infections Caused by Chaetomium perlucidum, a New Agent of Cerebral Phaeohyphomycosis

ABSTRACT We report the first two cases of invasive human mycoses caused by the phaeoid ascomycete, Chaetomium perlucidum, and review the English literature regarding invasive Chaetomium infections. Fatal disseminated disease involving the brain, heart, lungs, and spleen is described in an acute myelogenous leukemia patient. A second patient with a history of asthma and chronic bronchiectasis experiencing right-middle-lobe syndrome grew C. perlucidum from lung tissue. This study adds C. perlucidum to the list of other known neurotropic Chaetomium species, C. atrobrunneum and C. strumarium, and also documents this organisms ability to disseminate beyond the central nervous system.

Severe influenza in 33 US hospitals, 2013–2014: Complications and risk factors for death in 507 patients

BACKGROUND Influenza A (H1N1) pdm09 became the predominant circulating strain in the United States during the 2013-2014 influenza season. Little is known about the epidemiology of severe influenza during this season. METHODS A retrospective cohort study of severely ill patients with influenza infection in intensive care units in 33 US hospitals from September 1, 2013, through April 1, 2014, was conducted to determine risk factors for mortality present on intensive care unit admission and to describe patient characteristics, spectrum of disease, management, and outcomes. RESULTS A total of 444 adults and 63 children were admitted to an intensive care unit in a study hospital; 93 adults (20.9%) and 4 children (6.3%) died. By logistic regression analysis, the following factors were significantly associated with mortality among adult patients: older age (>65 years, odds ratio, 3.1 [95% CI, 1.4-6.9], P=.006 and 50-64 years, 2.5 [1.3-4.9], P=.007; reference age 18-49 years), male sex (1.9 [1.1-3.3], P=.031), history of malignant tumor with chemotherapy administered within the prior 6 months (12.1 [3.9-37.0], P<.001), and a higher Sequential Organ Failure Assessment score (for each increase by 1 in score, 1.3 [1.2-1.4], P<.001). CONCLUSION Risk factors for death among US patients with severe influenza during the 2013-2014 season, when influenza A (H1N1) pdm09 was the predominant circulating strain type, shifted in the first postpandemic season in which it predominated toward those of a more typical epidemic influenza season.

Linezolid interaction with serotonin reuptake inhibitors: report of two cases and incidence assessment

Abstract Background: Prompted by the advent of potentially life-threatening neuromuscular symptoms following initiation of linezolid therapy in two patients receiving treatment with a serotonin reuptake inhibitor antidepressant, an evaluation was conducted to determine the incidence and characteristics of symptomatic serotonin toxicity among hospitalized patients receiving combined treatment with these medications. Methods: Patients admitted between January 1, 2006 and August 30, 2008 who received linezolid concurrently with citalopram or escitalopram were identified and their medical records were examined. Patients were judged to have serotonin toxicity if their records contained documentation of clinical evidence adequate to fulfill requisites of the Hunter Serotonin Toxicity Criteria. Severity of serotonin-related symptoms was graded according to previously established criteria. Results: During the period of observation, 24 patients received concurrent treatment with linezolid and citalopram or escitalopram. Of these, one patient (4%) treated with citalopram met evidentiary requirements for diagnosis of serotonin toxicity. The severity of symptoms in this patient was graded as mild. No evidence of serious harm related to a possible drug interaction was identified. Conclusions: Severe symptoms associated with serotonin toxicity were shown to be uncommon in patients receiving linezolid and selected serotonin reuptake inhibitors. Nonetheless, serious interaction-related toxicity has been observed at our institution and reported in detail by others. Accordingly, concurrent use of these medications is categorized as contraindicated. Alternative antimicrobial therapy should be instituted in most cases. If no suitable alternative is available, recipient patients should be hospitalized for expectant observation and rigorous monitoring.