Breakthrough SARS-CoV-2 infections among recipients of tixagevimab-cilgavimab prophylaxis: A citywide real-world effectiveness study.

There are limited real-world data on the effectiveness of tixagevimab-cilgavimab as pre-exposure prophylaxis of COVID-19. We describe lessons learned when coordinating data collection and identifying breakthrough SARS-CoV-2 infections among patients across indications and institutions in a major US city. The Chicago Department of Public Health requested patient-level tixagevimab-cilgavimab administration data from all prescribing providers in Chicago, for treatments December 8, 2021 through June 30, 2022. Records were matched to COVID-19 vaccinations and laboratory-confirmed SARS-CoV-2 infections through December 31, 2022. Due to difficulty collecting data from all providers, targeted follow-up was conducted to improve completeness on key variables (demographics, vaccination status, clinical indication for prophylaxis). Over half of reported tixagevimab-cilgavimab administrations were to patients residing outside Chicago. Five hundred forty-four Chicago residents who received at least one dose of tixagevimab-cilgavimab were included in this analysis. Most were age 50 years or older (72%), Black non-Latinx (33%) or White non-Latinx (29%), and fully vaccinated (80%). Seventy-five patients (14%) had laboratory-confirmed COVID-19. Patients with and without breakthrough infections were demographically similar. Clinical indication was missing for >95% of cases, improved to 64% after follow-up; the most frequently specified was hematologic malignancy (10%). Severe outcomes were uncommon: 16% had documented COVID-19-related hospitalizations, one death was identified. Tixagevimab-cilgavimab recipients in Chicago had a lower rate of severe SARS-CoV-2 infection than reported among other untreated high-risk patients, including during predominance of non-neutralizing variants. Improving stakeholder collaboration is essential for generation of real-world effectiveness data, informing pandemic preparedness and optimizing use of medical countermeasures.

Scedosporium infection disseminated "from toe to head" in allogeneic stem cell transplant recipient: a case report.

BACKGROUND: Scedosporium is a lesser-known non-Aspergillus genus of mold that can present in unsuspecting ways. If overlooked, it may disseminate and cause high mortality in high-risk allogeneic stem cell transplant recipients. CASE PRESENTATION: This case report describes a 65-year-old patient with Acute Myeloid Leukemia who underwent an allogeneic hematopoietic stem cell transplant after a period of prolonged neutropenia with fluconazole prophylaxis. She suffered severe debility with altered mentation from a S. apiospermum infection which likely disseminated from a toe wound to the lung and central nervous system. She was successfully treated with liposomal amphotericin B and voriconazole, but faced a prolonged recovery from physical and neurologic sequela. CONCLUSIONS: The case highlights the importance of adequate anti-mold prophylaxis in high-risk patients, and the value of a thorough physical examination in this patient population, with particular attention to skin and soft tissue findings.

Shorter antibiotic courses in the immunocompromised: the impossible dream?

BACKGROUND: A growing number of studies have demonstrated similar outcomes with shorter courses of antibiotics for bacterial infections. Immunocompromised patients are frequently excluded from these studies despite anticipated benefits associated with shortening antibiotic courses (including lower risks of antibiotic toxicity, Clostridioides difficile infection, drug-resistant pathogens, and microbiome alterations). OBJECTIVES: To critically review the literature that assesses shorter antibiotic courses in immunocompromised patients, specifically among solid organ transplant recipients and neutropenic fever (NF) syndromes among patients on antineoplastic chemotherapy and undergoing haematopoietic cell transplant. SOURCES: References were identified through searches of PubMed, Embase, MEDLINE, and clinical guidelines documents. CONTENT: Among organ transplant recipients, the majority of studies assessing outcomes associated with shorter antibiotic courses have been retrospective but have demonstrated similar rates of clinically relevant endpoints. Patients with high- and low-risk NF have been well-studied, including enrolment in randomized studies, albeit with heterogeneous patient populations and outcomes assessed. Clinical improvement-guided adoption of shorter courses has been associated with fewer antibiotic days and similar rates of fever recurrence and mortality. IMPLICATIONS: Similar to studies demonstrating efficacy in immunocompetent patients, shorter antibiotic courses should be considered for immunocompromised hosts with presumed bacterial infections. Organ recipients and patients with NF syndromes should be prioritized for study in randomized controlled clinical trials assessing shorter course therapy.

Non-toxigenic Vibrio cholerae in an autologous stem cell and renal transplant recipient.

A patient with a renal transplant after an autologous stem cell transplant for multiple myeloma developed non-toxigenic Vibrio cholerae diarrhea after travel to Mexico. This is a rare cause of diarrhea in transplant recipients, and the patient had not had pre-travel counseling. This case reflects the lack of referral of transplant recipients for travel infectious disease review before overseas travel and the role of the live attenuated cholera vaccine.

Clinical Outcomes of Oral Suspension versus Delayed-Release Tablet Formulations of Posaconazole for Prophylaxis of Invasive Fungal Infections.

Posaconazole is used for prophylaxis for invasive fungal infections (IFIs) among patients with hematologic malignancies. We compared the incidence of breakthrough IFIs and early discontinuation between patients receiving delayed-release tablet and oral suspension formulations of posaconazole. This was a retrospective cohort study of patients receiving posaconazole between 1 January 2010 and 30 June 2016. We defined probable or proven breakthrough IFIs using the European Organization for Research and Treatment of Cancer (EORTC) criteria. Overall, 547 patients received 860 courses of posaconazole (53% received the oral suspension and 48% received the tablet); primary indications for prophylaxis were acute myeloid leukemia (69%), graft-versus-host disease (18%), and myelodysplastic syndrome (3%). There were no significant differences in demographics or indications between patients receiving the different formulations. The incidence and incidence rate of probable or proven IFIs were 1.6% and 3.2 per 10,000 posaconazole days, respectively. There was no significant difference in the rate of IFIs between suspension courses (2.8 per 10,000 posaconazole days) and tablet courses (3.7 per 10,000 posaconazole days) (rate ratio = 0.8, 95% confidence interval [CI] = 0.3 to 2.3). Of the 14 proven or probable cases of IFI, 8/14 had posaconazole serum concentrations measured, and the concentrations in 7/8 were above 0.7 µg/ml. Posaconazole was discontinued early in 15.5% of courses; however, the frequency of discontinuation was also not significantly different between the tablet (16.5%) and oral suspension (14.6%) formulations (95% CI for difference = -0.13 to 0.06). In conclusion, the incidence of breakthrough IFIs was low among patients receiving posaconazole prophylaxis and not significantly different between patients receiving the tablet formulation and those receiving the oral suspension formulation.

Disseminated, persistent, and fatal infection due to the vaccine strain of varicella-zoster virus in an adult following stem cell transplantation.

Live attenuated varicella vaccine is recommended for healthy individuals who are susceptible to varicella. Although the vaccine is safe, effective, and used worldwide, serious adverse events have been reported, mainly in immunocompromised patients who subsequently recovered. Here, we describe the fatality of an immunocompromised patient who received the varicella vaccine. His medical history provides a cautionary lens through which to view the decision of when vaccination is appropriate. A middle-aged man with non-Hodgkin lymphoma received chemotherapy and a stem cell transplant. He was vaccinated 4 years post-transplantation, despite diagnosis of a new low-grade lymphoma confined to the lymph nodes. Within 3 months of vaccination, he developed recurrent rashes with fever, malaise, weakness, hepatitis, weight loss, and renal failure. The syndrome was eventually determined to be associated with persistent disseminated zoster caused by the vaccine virus. This case illustrates a circumstance when a live viral vaccine should not be used.

Antimicrobial stewardship at a large tertiary care academic medical center: cost analysis before, during, and after a 7-year program.

BACKGROUND: An antimicrobial stewardship program was fully implemented at the University of Maryland Medical Center in July 2001 (beginning of fiscal year [FY] 2002). Essential to the program was an antimicrobial monitoring team (AMT) consisting of an infectious diseases-trained clinical pharmacist and a part-time infectious diseases physician that provided real-time monitoring of antimicrobial orders and active intervention and education when necessary. The program continued for 7 years and was terminated in order to use the resources to increase infectious diseases consults throughout the medical center as an alternative mode of stewardship. DESIGN: A descriptive cost analysis before, during, and after the program. PATIENTS/SETTING: A large tertiary care teaching medical center. METHODS: Monitoring the utilization (dispensing) costs of the antimicrobial agents quarterly for each FY. RESULTS: The utilization costs decreased from $44,181 per 1,000 patient-days at baseline prior to the full implementation of the program (FY 2001) to $23,933 (a 45.8% decrease) by the end of the program (FY 2008). There was a reduction of approximately $3 million within the first 3 years, much of which was the result of a decrease in the use of antifungal agents in the cancer center. After the program was discontinued at the end of FY 2008, antimicrobial costs increased from $23,933 to $31,653 per 1,000 patient-days, a 32.3% increase within 2 years that is equivalent to a $2 million increase for the medical center, mostly in the antibacterial category. CONCLUSIONS: The antimicrobial stewardship program, using an antimicrobial monitoring team, was extremely cost effective over this 7-year period.

Single center experience of a vancomycin resistant enterococcal endocarditis cohort.

OBJECTIVES: Vancomycin resistant enterococcus (VRE) infective endocarditis (IE) is an increasing nosocomial problem. We describe the clinical management and outcomes of a cohort of patients with VRE IE at a tertiary endocarditis referral center. METHODS: Retrospective review of all proven cases of VRE IE, from July 2000 through January 2008 was performed. Demographics, comorbidities and therapeutic details were collected and analyzed to assess for risk factors and clinical outcomes. RESULTS: Fifty cases of VRE IE were identified: 26 (52%) were Enterococcus faecium and 24 were Enterococcus faecalis. Vancomycin resistant E. faecalis IE was associated with the presence of a central venous line, liver transplantation, and mitral valve infection while VR E. faecium IE was significantly associated with tricuspid valve infection (p=0.03). The median duration of bacteremia was 14 days for E. faecium and 4 days for E. faecalis, respectively (p=0.002). Factors associated with mortality on bivariate analysis were hemodialysis via a catheter with VR E. faecium (OR=11.7. CI 1.1-122, p=0.02) and liver transplantation with both species. Combination antimicrobial therapy (OR=0.5 CI=0.06-3.2, p=0.1) and valve surgery (OR 1.3 CI 0.8-20, p=0.02) trended toward improved survival with E. faecalis on bivariate analysis. On multivariate analysis, none of the associations were significant. CONCLUSIONS: Hemodialysis and liver transplantation were factors associated with acquisition of VRE IE. There was a higher mortality and prolonged bacteremia with VR E. faecium IE than VR E. faecalis IE. Although not significant, combination antimicrobial therapy and surgical intervention trended toward improved survival.

Novel H1N1 influenza in hematopoietic stem cell transplantation recipients: two centers' experiences.

Respiratory virus infections, such as influenza A, cause significant morbidity in hematopoietic stem cell transplantation (HSCT) recipients. The clinical characteristics and impact of infection with the novel H1N1 virus in this patient population is not yet well defined, however. HSCT recipients diagnosed with proven or probable H1N1 during the 2009 pandemic were identified and charts were retrospectively reviewed with analysis of clinical descriptions, risk factors, diagnosis, treatments, and outcomes. Twenty-seven patients from two medical centers were identified. Fever and cough were the most common presenting symptoms. The incidence of influenza lower respiratory tract infection (LRTI) was 52% (14/27). Compared with patients with LRTI, those with influenza upper respiratory tract infection (URTI) were more likely to have a classic influenza-like syndrome. Compared to patients with URTI, those with LRTI were started on antiviral therapy significantly later after symptom onset (3.0 days vs 6.58 days after onset of symptoms; P = .03; 95% confidence interval [CI], 0.29-6.8). Overall influenza-related 30-day mortality was 22% (6/27), and that in patients with LRTI was 43% (6/14). Chronic steroid use (≥20 mg/day of prednisone equivalent) at the time of presentation was associated with LRTI (P = .006) and mortality (P = .003) on univariate analysis. Five cases were hospital-acquired. In this first season of the novel H1N1 pandemic, infection in HSCT often presented as an atypical severe illness with a high incidence of LRTI and high mortality.

Rifampin combination therapy for nonmycobacterial infections.

The increasing emergence of antimicrobial-resistant organisms, especially methicillin-resistant Staphylococcus aureus (MRSA), has resulted in the increased use of rifampin combination therapy. The data supporting rifampin combination therapy in nonmycobacterial infections are limited by a lack of significantly controlled clinical studies. Therefore, its current use is based upon in vitro or in vivo data or retrospective case series, all with major limitations. A prominent observation from this review is that rifampin combination therapy appears to have improved treatment outcomes in cases in which there is a low organism burden, such as biofilm infections, but is less effective when effective surgery to obtain source control is not performed. The clinical data support rifampin combination therapy for the treatment of prosthetic joint infections due to methicillin-sensitive S. aureus (MSSA) after extensive debridement and for the treatment of prosthetic heart valve infections due to coagulase-negative staphylococci. Importantly, rifampin-vancomycin combination therapy has not shown any benefit over vancomycin monotherapy against MRSA infections either clinically or experimentally. Rifampin combination therapy with daptomycin, fusidic acid, and linezolid needs further exploration for these severe MRSA infections. Lastly, an assessment of the risk-benefits is needed before the addition of rifampin to other antimicrobials is considered to avoid drug interactions or other drug toxicities.

Mitral valve infective endocarditis: benefit of early operation and aggressive use of repair.

BACKGROUND: In-hospital mortality rates for left-sided infective endocarditis (IE) exceed 20%. We investigated the outcomes of an aggressive approach to mitral valve IE that emphasizes early surgical intervention and preferential performance of mitral valve repair. METHODS: We reviewed 89 consecutive operations in 87 patients for native mitral valve IE at a single institution from 2002 to 2007. Operations occurred promptly after completion of preoperative studies. Independent risk factors for death were investigated using multivariable logistic regression. RESULTS: Mitral valve repair was accomplished in 56 of 89 patients (63%). Perioperative mortality was 4.4% (n = 4). Survival rates at 1 and 5 years were 89.9% (80 of 89) and 82.0% (73 of 90). There was a survival benefit for repair vs replacement at 1 (p = 0.03) and 5 years (p = 0.0017). Repair vs replacement (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.06 to 0.72), diabetes (OR, 4.43; 95% CI, 1.18 to 16.66), and renal failure (OR, 3.65; 95% CI, 1.3 to 12.91) were independent risk factors for late mortality. Among 59 patients with active IE, preoperative head computed tomography (CT) showed 29 (49%) had abnormalities, including 12 (41%) with intracerebral hemorrhage. The median interval was 4 days from admission to operation. The rate of permanent postoperative stroke was 1.1% (1 of 89). CONCLUSIONS: These results support early surgical therapy for mitral valve IE. Head CT abnormalities do not warrant delay of operation. Mitral valve repair was associated with a long-term survival advantage compared with valve replacement.

Risk factors for mortality from primary cryptococcosis in patients with HIV.

Cryptococcosis continues to have a high mortality rate in human immunodeficiency virus (HIV)-positive patients despite advances made in antifungal treatment, intracranial pressure management, and antiretroviral therapy. This retrospective chart review was conducted at the University of Maryland Medical Center and Baltimore VA Medical Center from 1993 to 2004. We reviewed all inpatient cases of cryptococcal infections to assess predictors of inpatient mortality among HIV-positive patients. Data collected included patient demographics, presenting symptoms and CD4 counts, lumbar puncture (LP) results including opening pressure (OP), cryptococcal antigen (CAg) levels, sites of infection, and drug therapy. Multivariate and survival analyses were performed. We identified 202 patients with primary cryptococcosis. The main sites of infection included blood (72%), central nervous system (85%), and lower respiratory tract (34%). Overall 30-day mortality was 14%. Predictors of mortality included syncope (P = 0.039; OR, 4.5), concomitant pneumonia (P = 0.001; OR, 3.5), respiratory failure (P < 0.001; OR, 10.5), and admission into the intensive care unit (P < 0.001; OR, 8). Amphotericin dose, OP > or = 250 mm H2O, and number of LPs were not found to be predictive of mortality. Mortality attributable to cryptococcosis remains high. Our study findings suggest that syncope, respiratory failure, pneumonia, and admission to the intensive care unit are independently associated with an increased risk of death within 30 days after cryptococcosis diagnosis.

Clinical experience with daptomycin for the treatment of patients with documented gram-positive septic arthritis.

BACKGROUND: Septic arthritis is considered a rheumatologic emergency that can lead to joint destruction and long-term impairment of joint function. Daptomycin is bactericidal in vitro against Staphylococcus aureus, the primary pathogen associated with septic arthritis. OBJECTIVE: To describe the use of daptomycin in patients with septic arthritis. METHODS: Data were collected as part of the Cubicin Outcomes Registry and Experience (CORE) program, a retrospective, observational, multicenter study, to describe the clinical use of daptomycin. Efficacy at the end of daptomycin therapy was determined by each center's investigator(s) as cure, improved, failure, or nonevaluable. Patients who had a diagnosis of septic arthritis, excluding concomitant osteomyelitis, as well as a positive culture by needle aspirate or deep tissue biopsy, were selected from the combined 2005 and 2006 CORE database. RESULTS: Twenty-two patients were included in this analysis. S. aureus was the most common pathogen isolated, with the majority resistant to methicillin. All patients received an antibiotic prior to daptomycin; in 7 patients, at least one of the prior antibiotics was continued with daptomycin. Almost two-thirds of patients received an antibiotic with daptomycin; rifampin was the most common. The median final dose and duration of daptomycin therapy were 5 mg/kg (range 3-6.3) and 22 days (range 3-52), respectively. Eighty-two percent of patients received daptomycin while admitted to a hospital; however, 68% received at least part of their daptomycin therapy as an outpatient. The outcomes of cure or improved were reported in 41% and 50% of the patients, respectively. Two adverse events were reported; neither was considered to be related to daptomycin. CONCLUSIONS: Daptomycin appeared to be effective when used as part of a treatment regimen for septic arthritis. These results require verification via a prospective clinical trial.

Polymyxin antibiotics for gram-negative infections.

PURPOSE: The role of polymyxin antibiotics in the treatment of multidrug-resistant gram-negative infections is reviewed. SUMMARY: Antimicrobial resistance is an increasing problem across hospitals worldwide, especially in intensive care settings, where nosocomial infections are 5-10 times more likely to occur than on the general wards. The polymyxins, a group of basic polypeptide antibiotics, were first isolated from Bacillus species in the late 1940s and appear to have a surface detergent effect, making them active against most gram-negative organisms. Early clinical reports suggested a high rate of toxicity associated with the polymyxins, specifically nephrotoxicity (20%) and neurotoxicity (7%); thus the polymyxins had largely fallen out of favor. However, recent studies have suggested that the toxicities associated with the polymyxins may be less severe and less frequent than earlier reports. The emergence of multidrug-resistant gram-negative organisms has led to a reemergence in the use of this antibiotic class. Various clinical trials that evaluated the polymyxins for the treatment of multidrug-resistant gram-negative organisms found that these antibiotics have acceptable effectiveness and may be used if necessary. CONCLUSION: The polymyxins have become a last resort for the treatment of infections caused by multidrug-resistant gram-negative organisms. Recent studies have suggested that the frequency of polymyxin-associated nephrotoxicity and neurotoxicity may not be as high as was once thought. The polymyxins seem to be effective in treating various infections caused by multidrug-resistant gram-negative organisms but should not be used as first-line therapy until more is known about this class of antibiotics.

Approaches to management of invasive fungal infections in patients with hematologic malignancies.

Invasive fungal infections have become increasingly common in patients with hematologic malignancies, especially in those at high risk with prolonged neutropenia and graft versus host disease after allogeneic stem cell transplantation, and are associated with significant morbidity, mortality, and cost. New diagnostic techniques and therapeutic agents have emerged recently to assist in the management of these infections. The galactomannan assay in association with routine clinical and radiologic screening may assist in the early diagnosis of invasive aspergillosis such that therapy may be initiated early. Also, several new antifungal agents have become available, allowing the practitioner more options in the prevention and treatment of fungal infections. New antifungal agents such as the lipid amphotericin B products, voriconazole, and the echinocandins appear to be safer to use than conventional amphotericin B. Voriconazole also has shown superiority to conventional amphotericin B in the treatment of invasive aspergillosis, and its well absorbed oral formulation makes it an excellent treatment to complete therapy as an outpatient. All these therapeutic options allow physicians to tailor antifungal therapy to the individual patient based on response and toxicity to prevent or treat invasive fungal infections. There are several new antifungal agents in development, and future studies will evaluate combination therapies to determine safety and efficacy.

Febrile neutropenia, colony-stimulating factors and therapy: time for a new methodology?

The utilization of granulocyte colony-stimulating factors (G-CSF) in febrile neutropenia has been controversial for many years. Berghmann et al.'s meta-analysis again demonstrates that G-CSF does not have an impact on mortality in febrile neutropenia, because the depth and duration of neutropenia in the trials are variable. Also, with mortality from febrile neutropenia less than 15%, any further study would require a vast number of patients to demonstrate a difference in mortality. The Elting and Cantor review provides a new paradigm to studies in patients with febrile neutropenia. These authors recognize that cost, quality of life, life-years gained and adverse events experienced with new therapies should be evaluated, in addition to the standard measures of infection resolution and related mortality. Therefore, for the evaluation of new therapeutic interventions, a consensus on stratified risk factors or the use of an already established model could provide end-points with comparable measurements.