Sequential Treatment Failure With Aztreonam-Ceftazidime-Avibactam Followed by Cefiderocol Due to Preexisting and Acquired Mechanisms in a New Delhi Metallo-ß-lactamase-Producing Escherichia coli Causing Fatal Bloodstream Infection.

We report a fatal case of New Delhi metallo-ß-lactamase (NDM)-producing Escherichia coli in a bacteremic patient with sequential failure of aztreonam plus ceftazidime-avibactam followed by cefiderocol. Acquired resistance was documented phenotypically and mediated through preexisting and acquired mutations. This case highlights the need to rethink optimal treatment for NDM-producing organisms.

Informing Building Strategies to Reduce Infectious Aerosol Transmission Risk by Integrating DNA Aerosol Tracers with Quantitative Microbial Risk Assessment.

Using aerosol-based tracers to estimate risk of infectious aerosol transmission aids in the design of buildings with adequate protection against aerosol transmissible pathogens, such as SARS-CoV-2 and influenza. We propose a method for scaling a SARS-CoV-2 bulk aerosol quantitative microbial risk assessment (QMRA) model for impulse emissions, coughing or sneezing, with aerosolized synthetic DNA tracer concentration measurements. With point-of-emission ratios describing relationships between tracer and respiratory aerosol emission characteristics (i.e., volume and RNA or DNA concentrations) and accounting for aerosolized pathogen loss of infectivity over time, we scale the inhaled pathogen dose and risk of infection with time-integrated tracer concentrations measured with a filter sampler. This tracer-scaled QMRA model is evaluated through scenario testing, comparing the impact of ventilation, occupancy, masking, and layering interventions on infection risk. We apply the tracer-scaled QMRA model to measurement data from an ambulatory care room to estimate the risk reduction resulting from HEPA air cleaner operation. Using DNA tracer measurements to scale a bulk aerosol QMRA model is a relatively simple method of estimating risk in buildings and can be applied to understand the impact of risk mitigation efforts.

Plasma Microbial Cell-free DNA Next-generation Sequencing in the Diagnosis and Management of Febrile Neutropenia.

BACKGROUND: Standard testing fails to identify a pathogen in most patients with febrile neutropenia (FN). We evaluated the ability of the Karius microbial cell-free DNA sequencing test (KT) to identify infectious etiologies of FN and its impact on antimicrobial management. METHODS: This prospective study (ClinicalTrials.gov; NCT02912117) enrolled and analyzed 55 patients with FN. Up to 5 blood samples were collected per subject within 24 hours of fever onset (T1) and every 2 to 3 days. KT results were compared with blood culture (BC) and standard microbiological testing (SMT) results. RESULTS: Positive agreement was defined as KT identification of ≥1 isolate also detected by BC. At T1, positive and negative agreement were 90% (9/10) and 31% (14/45), respectively; 61% of KT detections were polymicrobial. Clinical adjudication by 3 independent infectious diseases specialists categorized Karius results as: unlikely to cause FN (N = 0); definite (N = 12): KT identified ≥1 organism also found by SMT within 7 days; probable (N = 19): KT result was compatible with a clinical diagnosis; possible (N = 10): KT result was consistent with infection but not considered a common cause of FN. Definite, probable, and possible cases were deemed true positives. Following adjudication, KT sensitivity and specificity were 85% (41/48) and 100% (14/14), respectively. Calculated time to diagnosis was generally shorter with KT (87%). Adjudicators determined real-time KT results could have allowed early optimization of antimicrobials in 47% of patients, by addition of antibacterials (20%) (mostly against anaerobes [12.7%]), antivirals (14.5%), and/or antifungals (3.6%); and antimicrobial narrowing in 27.3% of cases. CLINICAL TRIALS REGISTRATION: NCT02912117. CONCLUSION: KT shows promise in the diagnosis and treatment optimization of FN.

Omadacycline: A Novel Tetracycline Derivative With Oral and Intravenous Formulations.

Omadacycline, an aminomethylcycline, is a novel member of the tetracycline class of antibiotics. It has received approval by the US Food and Drug Administration for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections, and is available in both oral and intravenous formulations. It is also being evaluated in clinical trials for the treatment of cystitis and pyelonephritis. The omadacycline molecule was designed to overcome tetracycline resistance and has broad-spectrum activity that includes gram-positive bacteria, gram-negative bacteria, anaerobes, atypicals, and other drug-resistant strains, like methicillin-resistant Staphylococcus aureus, as well as Yersinia pestis and Bacillus anthracis, organisms of biodefense interest. Omadacycline has minimal drug-drug pharmacokinetic interactions and a favorable safety profile, with the most common adverse events being gastrointestinal symptoms.

Coccidioidomycosis: What a long strange trip it's been.

The recorded history of coccidioidomycosis began in 1892 with the report of the illness of Domingo Escurra by Alejandro Posadas followed by a description of the first North American cases by Rixford and Gilchrist. Originally considered a protozoan, William Ophüls determined that Coccidioides was a fungus and that the lungs were the apparent initial site of infection. During the 1930s, both Gifford and Dickson determined that a self-limited illness, Valley Fever, was caused by the same fungus that caused the often fatal coccidioidal granuloma. Charles Smith, over a period of approximately 2 decades, comprehensively described the clinical and geographic epidemiology of coccidioidomycosis in California. Demosthenes Pappagianis continued this work after Smith's death. In 1957, one year before Marshall Fiese published his masterful monograph on coccidioidomycosis, the use of the first effective agent for the therapy of coccidioidomycosis, amphotericin B, was reported. This was followed by descriptions of its appropriate clinical use by William Winn and by Hans Einstein, among others. The development of the much less toxic azole antifungal agents greatly simplified therapy in many cases, but much of the management of patients with coccidioidomycosis still relies more on art than science. The search for the "Holy Grail" - a vaccine capable of preventing this disease-continues.

Diagnosis and treatment of histoplasmosis in solid organ transplant patients.

PURPOSE OF REVIEW: Unlike immunocompetent hosts, solid organ transplant (SOT) recipients with posttransplant histoplasmosis (PTH) often present with disseminated disease and have an attributable mortality of approximately 10%. In this review, we discuss currently available diagnostic tests and treatment strategies in PTH. RECENT FINDINGS: None of the available tests have a 100% diagnostic accuracy. Histoplasma antigen assays are the most sensitive commercially available tests. However, crossreactivity of histoplasma antigen with aspergillus galactomannan and false positive histoplasma antigen tests because of rabbit antithymocyte globulin may cause difficulty in interpreting positive test results in transplant recipients. Molecular assays such as amplification and sequencing of 'panfungal' portions of the 28S ribosomal RNA from clinical specimens appear to be promising.Lipid formulations of amphotericin B and itraconazole are the drugs of choice in the treatment of PTH. Other extended spectrum azoles also appear to be effective, but, like itraconazole, problems with drug interactions and prolongation of the QTc interval (except for isavuconazole, which shortens the QTc interval) remain. Mycophenolate therapy is associated with severe disease and should be stopped during active disease and, if feasible, calcineurin inhibitors and steroids should be reduced. SUMMARY: A combination of various tests (culture, antigen tests, nucleic amplification tests, etc.) should be used to optimize diagnostic yield. The role of unbiased next generation sequencing for early diagnosis and newer azoles in the treatment needs to be further explored.

Increasing Evidence of the Nephrotoxicity of Piperacillin/Tazobactam and Vancomycin Combination Therapy-What Is the Clinician to Do?

Early administration of appropriate empiric antibiotics is essential for achieving the best possible outcomes in sepsis. Yet the choice of antibiotic therapy has become more challenging due to recent reports of nephrotoxicity with the combination of vancomycin and piperacillin/tazobactam, the "workhorse" regimen at many institutions. In this article we assess the evidence for nephrotoxicity and its possible mechanisms, provide recommendations for risk mitigation, address the advantages and disadvantages of alternative antibiotic choices, and suggest areas for future research.

Real-Time Electronic Tracking of Diarrheal Episodes and Laxative Therapy Enables Verification of Clostridium difficile Clinical Testing Criteria and Reduction of Clostridium difficile Infection Rates.

Health care-onset health care facility-associated Clostridium difficile infection (HO-CDI) is overdiagnosed for several reasons, including the high prevalence of C. difficile colonization and the inability of hospitals to limit testing to patients with clinically significant diarrhea. We conducted a quasiexperimental study from 22 June 2015 to 30 June 2016 on consecutive inpatients with C. difficile test orders at an academic hospital. Real-time electronic patient data tracking was used by the laboratory to enforce testing criteria (defined as the presence of diarrhea [≥3 unformed stools in 24 h] and absence of laxative intake in the prior 48 h). Outcome measures included C. difficile test utilization, HO-CDI incidence, oral vancomycin utilization, and clinical complications. During the intervention, 7.1% (164) and 9.1% (211) of 2,321 C. difficile test orders were canceled due to absence of diarrhea and receipt of laxative therapy, respectively. C. difficile test utilization decreased upon implementation from an average of 208.8 tests to 143.0 tests per 10,000 patient-days (P < 0.001). HO-CDI incidence rate decreased from an average of 13.0 cases to 9.7 cases per 10,000 patient-days (P = 0.008). Oral vancomycin days of therapy decreased from an average of 13.8 days to 9.4 days per 1,000 patient-days (P = 0.009). Clinical complication rates were not significantly different in patients with 375 canceled orders compared with 869 episodes with diarrhea but negative C. difficile results. Real-time electronic clinical data tracking is an effective tool for verification of C. difficile clinical testing criteria and safe reduction of inflated HO-CDI rates.

Feasibility and applicability of antimicrobial stewardship in immunocompromised patients.

PURPOSE OF REVIEW: Antimicrobial stewardship is the primary intervention in the battle against antimicrobial resistance, but clinicians do not always apply many key antimicrobial stewardship principles to patients with significant immune defects due to lack of data and fear of bad outcomes. We review evidence regarding the application of stewardship principles to immunocompromised patients, with a focus on solid organ and hematopoietic stem cell transplant recipients. RECENT FINDINGS: Antimicrobial stewardship programs (ASPs), targeting immunocompromised patient populations such as oncology and transplant, are gaining traction. Emerging literature suggests that several stewardship interventions can be adapted to immunocompromised hosts and improve antimicrobial utilization, but data supporting improved outcomes is very limited. SUMMARY: The application of antimicrobial stewardship principles to immunocompromised patients is feasible, necessary, and urgent. As antimicrobial stewardship programs gain momentum across a diverse range of healthcare settings more immunocompromised patients will fall under their purview. It is imperative that centers applying antimicrobial stewardship principles share their experience and establish collaborative research efforts to advance our knowledge base in applying antimicrobial stewardship initiatives to immunocompromised host populations, both in terms of programmatic success and patient outcomes.

Histoplasmosis in transplant recipients.

Histoplasma capsulatum is a dimorphic fungus that most often causes asymptomatic infection in the immunocompetent population. In immunocompromised patients, including solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, however, it is likely to cause severe life-threatening infection. Post-transplant histoplasmosis (PTH) in SOT is uncommon with an incidence of ≤1% and is even rarer in HCT patients. The majority of PTH in SOT is diagnosed in the first 2 years following transplantation. Histoplasmosis may result from endogenous reactivation of latent infection, de novo post-transplant acquisition, and donor-derived infection. Disseminated infection is common. Fever is the most common symptom and clinical features are often nonspecific, but patients with disseminated infection may present with a septic picture. Other features, including pancytopenia and hepatosplenomegaly, may not be prominent early in the course of illness. Contemporary histoplasma antigen assays are the most sensitive tests but cross-reactivity with antigens of other fungi, including with Aspergillus galactomannan, is not uncommon. Treatment should be continued for at least a year. Histoplasma antigen levels have prognostic value and can be used to monitor the response to therapy. The attributable mortality is approximately 10%. Routine screening of donors and recipients is not currently recommended.

Leishmaniasis in solid organ and hematopoietic stem cell transplant recipients.

Leishmaniasis occurs in <1% of solid organ and hematopoietic stem cell transplant recipients in endemic countries in which transplants are performed. Visceral leishmaniasis (VL) makes up the bulk of reported cases. The onset generally occurs months after transplantation and the mode of acquisition is often impossible to determine, but de novo vector-borne infection and reactivation of inapparent infection are thought to be the principal means. The potential role of clinically inapparent donor infection is uncertain and screening is not currently recommended, nor is it recommended for recipients from endemic areas, some of whom may have detectable circulating protozoan nucleic acid. While transplant recipients with VL often present with the non-specific findings of fever and cytopenia, the additional presence of hepatosplenomegaly in patients from endemic areas should lead to a directed diagnostic evaluation with bone marrow examination and PCR testing of marrow and peripheral blood having a high yield. Management may often be complicated by the presence of concomitant infections. A lipid formulation of amphotericin B is the preferred treatment, especially for VL, but the relapse rate in transplant recipients is approximately 25%. PCR monitoring of blood for either secondary prophylaxis or preemptive therapy requires further study.

Norovirus.

Norovirus, an RNA virus of the family Caliciviridae, is a human enteric pathogen that causes substantial morbidity across both health care and community settings. Several factors enhance the transmissibility of norovirus, including the small inoculum required to produce infection (<100 viral particles), prolonged viral shedding, and its ability to survive in the environment. In this review, we describe the basic virology and immunology of noroviruses, the clinical disease resulting from infection and its diagnosis and management, as well as host and pathogen factors that complicate vaccine development. Additionally, we discuss overall epidemiology, infection control strategies, and global reporting efforts aimed at controlling this worldwide cause of acute gastroenteritis. Prompt implementation of infection control measures remains the mainstay of norovirus outbreak management.

When sepsis persists: a review of MRSA bacteraemia salvage therapy.

MRSA bacteraemia (MRSAB), including infective endocarditis, carries a high mortality rate, with up to 50% of patients failing initial therapy with vancomycin and requiring salvage therapy. Persistent MRSAB can be difficult to successfully eliminate, especially when source control is not possible due to an irremovable focus or the bacteraemia still persists despite surgical intervention. Although vancomycin and daptomycin are the only two antibiotics approved by the US FDA for the treatment of patients with MRSAB as monotherapy, the employment of novel strategies is required to effectively treat patients with persistent MRSAB and these may frequently involve combination drug therapy. Treatment strategies that are reviewed in this manuscript include vancomycin combined with a ß-lactam, daptomycin-based therapy, ceftaroline-based therapy, linezolid-based therapy, quinupristin/dalfopristin, telavancin, trimethoprim/sulfamethoxazole-based therapy and fosfomycin-based therapy. We recommend that combination antibiotic therapy be considered for use in MRSAB salvage treatment.

Mycotic Infections Acquired outside Areas of Known Endemicity, United States.

In the United States, endemic mycoses--blastomycosis, coccidioidomycosis, and histoplasmosis--pose considerable clinical and public health challenges. Although the causative fungi typically exist within broadly defined geographic areas or ecologic niches, some evidence suggests that cases have occurred in humans and animals not exposed to these areas. We describe cases acquired outside regions of traditionally defined endemicity. These patients often have severe disease, but diagnosis may be delayed because of a low index of suspicion for mycotic disease, and many more cases probably go entirely undetected. Increased awareness of these diseases, with a specific focus on their potential occurrence in unusual areas, is needed. Continued interdisciplinary efforts to reevaluate and better describe areas of true endemicity are warranted, along with a more nuanced view of the notion of endemicity. The term "nonendemic" should be used with care; mycoses in such regions might more accurately be considered "not known to be endemic."

First case of mesh infection due to Coccidioides spp. and literature review of fungal mesh infections after hernia repair.

Fungal mesh infections are a rare complication of hernia repairs with mesh. The first case of Coccidioides spp. mesh infection is described, and a systematic literature review of all known fungal mesh infections was performed. Nine cases of fungal mesh infection are reviewed. Female and male patients are equally represented, median age is 49.5 years, and critical illness and preinfection antibiotic use were common. Fungal mesh infections are rare, but potentially fatal, complications of hernias repaired with mesh.

First case of infectious endocarditis caused by Parvimonas micra.

P. micra is an anaerobic Gram-positive cocci, and a known commensal organism of the human oral cavity and gastrointestinal tract. Although it has been classically described in association with endodontic disease and peritonsillar infection, recent reports have highlighted the role of P. micra as the primary pathogen in the setting of invasive infections. In its most recent taxonomic classification, P. micra has never been reported causing infectious endocarditis in humans. Here, we describe a 71 year-old man who developed severe native valve endocarditis complicated by aortic valvular destruction and perivalvular abscess, requiring emergent surgical intervention. Molecular sequencing enabled identification of P. micra.