Considerations for the Use of Phage Therapy in Clinical Practice.

Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct to conventional antimicrobials. Expanded access and compassionate use cases have risen exponentially but have varied widely in approach, methodology, and clinical situations in which phage therapy might be considered. Large gaps in knowledge contribute to heterogeneity in approach and lack of consensus in many important clinical areas. The Antibacterial Resistance Leadership Group (ARLG) has convened a panel of experts in phage therapy, clinical microbiology, infectious diseases, and pharmacology, who worked with regulatory experts and a funding agency to identify questions based on a clinical framework and divided them into three themes: potential clinical situations in which phage therapy might be considered, laboratory testing, and pharmacokinetic considerations. Suggestions are provided as answers to a series of questions intended to inform clinicians considering experimental phage therapy for patients in their clinical practices.

Missing diagnoses of congenital cytomegalovirus infection in electronic health records for infants with laboratory-confirmed infection.

Congenital cytomegalovirus (CMV) is a leading cause of non-genetic sensorineural hearing loss and neurodevelopmental disabilities among US children. Studies using administrative healthcare databases have identified infants with congenital CMV using diagnostic codes from the International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification. Using Cerner Health Facts deidentified electronic health records, we assessed the sensitivity of CMV diagnostic codes among infants with laboratory confirmed congenital CMV infection (i.e. a positive CMV laboratory test - polymerase chain reaction, direct fluorescent antibody, or culture from urine, saliva, respiratory secretion or blood samples, or IgM serology - within 21 days of life). During 2010-2017, 668 congenital CMV cases were identified among 7,517,207 infants with encounters within 21 days of life, or 0.89 cases per 10,000 infants. The sensitivity of CMV diagnostic codes assigned within 21 and 90 days of life was 10.3% (95% CI: 8.2-12.9) and 11.1% (95% CI: 8.9-13.7), respectively.

Yearlong COVID-19 Infection Reveals Within-Host Evolution of SARS-CoV-2 in a Patient With B-Cell Depletion.

B-cell-depleting therapies may lead to prolonged disease and viral shedding in individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and this viral persistence raises concern for viral evolution. We report sequencing of early and late samples from a 335-day infection in an immunocompromised patient. The virus accumulated a unique deletion in the amino-terminal domain of the spike protein, and complete deletion of ORF7b and ORF8, the first report of its kind in an immunocompromised patient. Unique viral mutations found in this study highlight the importance of analyzing viral evolution in protracted SARS-CoV-2 infection, especially in immunosuppressed hosts.

Year-long COVID-19 infection reveals within-host evolution of SARS-CoV-2 in a patient with B cell depletion.

BACKGROUND: B-cell depleting therapies may lead to protracted disease and prolonged viral shedding in individuals infected with SARS-CoV-2. Viral persistence in the setting of immunosuppression raises concern for viral evolution. METHODS: Amplification of sub-genomic transcripts for the E gene (sgE) was done on nasopharyngeal samples over the course of 355 days in a patient infected with SARS-CoV-2 who had previously undergone CAR T cell therapy and had persistently positive SARS-CoV-2 nasopharyngeal swabs. Whole genome sequencing was performed on samples from the patient's original presentation and 10 months later. RESULTS: Over the course of almost a year, the virus accumulated a unique in-frame deletion in the amino-terminal domain of the spike protein, and complete deletion of ORF7b and ORF8, the first report of its kind in an immunocompromised patient. Also, minority variants that were identified in the early samples-reflecting the heterogeneity of the initial infection-were found to be fixed late in the infection. Remdesivir and high-titer convalescent plasma treatment were given, and the infection was eventually cleared after 335 days of infection. CONCLUSIONS: The unique viral mutations found in this study highlight the importance of analyzing viral evolution in protracted SARS-CoV-2 infection, especially in immunosuppressed hosts, and the implication of these mutations in the emergence of viral variants. SUMMARY: We report an immunocompromised patient with persistent symptomatic SARS-CoV-2 infection for 335 days. During this time, the virus accumulated a unique in-frame deletion in the spike, and a complete deletion of ORF7b and ORF8 which is the first report of its kind in an immunocompromised patient.

Infectious complications of CAR T-cell therapy across novel antigen targets in the first 30 days.

Infections are a known complication of chimeric antigen receptor (CAR) T-cell therapy with data largely emerging from CD19 CAR T-cell targeting. As CAR T-cell therapy continues to evolve, infection risks and management thereof will become increasingly important to optimize outcomes across the spectrum of antigens and disease targeted. We retrospectively characterized infectious complications occurring in 162 children and adults treated among 5 phase 1 CAR T-cell clinical trials. Trials included targeting of CD19, CD22, disialoganglioside (GD2) or B-cell maturation antigen (BCMA). Fifty-three patients (32.7%) had 76 infections between lymphocyte depleting (LD) chemotherapy and day 30 (D30); with the majority of infections (61, 80.3%) occurring between day 0 (D0) and D30. By trial, the highest proportion of infections was seen with CD22 CAR T cells (n = 23/53; 43.4%), followed by BCMA CAR T cells (n = 9/24; 37.5%). By disease, patients with multiple myeloma had the highest proportion of infections (9/24; 37.5%) followed by acute lymphoblastic leukemia (36/102; 35.3%). Grade 4 infections were rare (n = 4; 2.5%). Between D0 and D30, bacteremia and bacterial site infections were the most common infection type. In univariate analysis, increasing prior lines of therapy, recent infection within 100 days of LD chemotherapy, corticosteroid or tocilizumab use, and fever and neutropenia were associated with a higher risk of infection. In a multivariable analysis, only prior lines of therapy and recent infection were associated with higher risk of infection. In conclusion, we provide a broad overview of infection risk within the first 30 days post infusion across a host of multiple targets and diseases, elucidating both unique characteristics and commonalities highlighting aspects important to improving patient outcomes.

Consequences of hemophagocytic lymphohistiocytosis-like cytokine release syndrome toxicities and concurrent bacteremia.

Serious bacterial infections (SBI) can lead to devastating complications with CD19 CAR T cells and cytokine release syndrome (CRS). Little is known about consequences of and risk factors for SBI with novel CAR T-cell constructs or with CRS complicated by HLH-like toxicities. We report on three patients with B-cell acute lymphoblastic leukemia treated with CD22 CAR T cells who developed SBI and CRS-associated HLH. Serum cytokine profiling revealed sustained elevations well beyond CRS resolution, suggesting ongoing systemic inflammation. Heightened inflammatory states converging with SBI contribute to poor outcomes, and recognition and prevention of extended inflammation may be needed to improve outcomes.

Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells.

As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.

Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution.

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.

Variability in Diagnosis and Treatment of Ventilator-Associated Pneumonia in Neurocritical Care Patients.

BACKGROUND: Clinical approach to ventilator-associated pneumonia (VAP) in the neurocritical care unit (NCCU) varies widely among physicians despite training and validated criteria. METHODS: Prospective observational study of all mechanically ventilated patients with suspected VAP over 18 months in an academic NCCU. Patients meeting VAP criteria by a surveillance program (SurvVAP) were compared to treated patients who did not meet surveillance criteria (ClinVAPonly). We identified appropriate/potentially inappropriate antibiotic treatment and factors associated with excessive antibiotic days (EAD). RESULTS: Of 622 ventilated patients, 83 cases were treated as VAP. Of these, 26 (31.3 %) had VAP by CDC criteria (SurvVAP) (VAP rate = 7.3 cases/1,000 ventilator days). Clinical features significantly more prevalent in SurvVAP cases (vs. ClinVAPonly) were change in sputum character, tachypnea, oxygen desaturation, persistent infiltrate on chest X-ray and higher clinical pulmonary infection score, but not positive sputum culture. Treatment with pneumonia-targeted antibiotics for >8 days was significantly more common in ClinVAPonly versus SurvVAP patients (73.7 vs. 30.8 %, p < 0.001) even after excluding patients with other infections (p = 0.001). Based on current guidelines, the ClinVAPonly group contributed 225 EAD, including 38 vancomycin days, 70 piperacillin-tazobactam days and 85 cephalosporin days with cost figure over four times that of EAD in SurvVAP group. No pre-specified factors were associated with continued VAP treatment beyond 8 days. CONCLUSIONS: Incongruency between clinically and surveillance-defined VAP is common in acute neurological disease although outcomes did not differ between groups. Clinician behaviors rather than clinical factors may contribute to prolonged prescribing.

Ventilator-associated pneumonia: overdiagnosis and treatment are common in medical and surgical intensive care units.

OBJECTIVE: Diagnosing ventilator-associated pneumonia (VAP) is difficult, and misdiagnosis can lead to unnecessary and prolonged antibiotic treatment. We sought to quantify and characterize unjustified antimicrobial use for VAP and identify risk factors for continuation of antibiotics in patients without VAP after 3 days. METHODS: Patients suspected of having VAP were identified in 6 adult intensive care units (ICUs) over 1 year. A multidisciplinary adjudication committee determined whether the ICU team's VAP diagnosis and therapy were justified, using clinical, microbiologic, and radiographic data at diagnosis and on day 3. Outcomes included the proportion of VAP events misdiagnosed as and treated for VAP on days 1 and 3 and risk factors for the continuation of antibiotics in patients without VAP after day 3. RESULTS: Two hundred thirty-one events were identified as possible VAP by the ICUs. On day 1, 135 (58.4%) of them were determined to not have VAP by the committee. Antibiotics were continued for 120 (76%) of 158 events without VAP on day 3. After adjusting for acute physiology and chronic health evaluation II score and requiring vasopressors on day 1, sputum culture collection on day 3 was significantly associated with antibiotic continuation in patients without VAP. Patients without VAP or other infection received 1,183 excess days of antibiotics during the study. CONCLUSIONS: Overdiagnosis and treatment of VAP was common in this study and led to 1,183 excess days of antibiotics in patients with no indication for antibiotics. Clinical differences between non-VAP patients who had antibiotics continued or discontinued were minimal, suggesting that clinician preferences and behaviors contribute to unnecessary prescribing.

Short versus prolonged courses of antibiotic therapy for children with uncomplicated Gram-negative bacteraemia.

OBJECTIVES: The optimal duration of antibiotic therapy for uncomplicated Gram-negative bacteraemia remains undefined. Our objective was to compare clinical outcomes of receiving short (7-10 days) versus prolonged (>10 days) durations of antibiotic therapy for children with uncomplicated Gram-negative bacteraemia. METHODS: We conducted a retrospective cohort study of children with uncomplicated Gram-negative bacteraemia at The Johns Hopkins Hospital between 2002 and 2012. We estimated the risk of bacteraemic relapse among children who received short versus prolonged durations of antibiotic therapy using 1:1 nearest neighbour propensity score matching without replacement prior to performing regression analysis. RESULTS: There were 170 matched pairs that were well balanced on baseline covariates. The median duration of therapy in the short and prolonged courses was 10 days (IQR 10-10) and 14 days (IQR 14-17), respectively. The 30 day mortality was similar between the groups (OR 1.12; 95% CI 0.96-1.21). A prolonged duration of antibiotic therapy did not reduce the relapse risk compared with shorter durations (adjusted hazard ratio 0.67; 95% CI 0.35-1.27). Similarly, each additional day of antibiotic therapy was not protective against relapse risk (adjusted hazard ratio 0.99 per additional day; 95% CI 0.92-1.03). There was a trend towards an increased subsequent risk of candidaemia in children receiving longer treatment durations (hazard ratio 2.44; 95% CI 0.97-6.19). CONCLUSIONS: Antibiotic treatment for more than 10 days for uncomplicated bacteraemia in children does not reduce the risk of microbiological relapse compared with shorter-course therapy, but may be associated with an increased risk of candidaemia. Our findings need to be confirmed in a larger, prospective study.

Can matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) enhance antimicrobial stewardship efforts in the acute care setting?

We evaluated 222 hospitalized patients whose clinical isolates were tested using standard methods and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF). MALDI-TOF could have reduced time to appropriate therapy for 28.8% and 44.6% patients based on the treating physician's choices and stewardship team recommendations, respectively. Clinicians should be aware of scenarios in which MALDI-TOF can optimize antibiotic therapy.

What is the role of antimicrobial stewardship in improving outcomes of patients with CAP?

Community-acquired pneumonia (CAP) is one of the most common infectious diagnoses encountered in clinical practice and one of the leading causes of death in the United States. Adherence to antibiotic treatment guidelines is inconsistent and the erroneous diagnosis of CAP and misuse of antibiotics is prevalent in both inpatients and outpatients. This review summarizes interventions that may be promoted by antimicrobial stewardship programs to improve outcomes for patients with CAP.

Epidemiology, outcomes, and risk factors of invasive fungal infections in adult patients with acute myelogenous leukemia after induction chemotherapy.

This is a retrospective, single-center study of adult patients with newly diagnosed acute myelogenous leukemia (AML), who received intensive induction timed sequential chemotherapy from 1/2005 to 6/2010. Among 254 consecutive AML patients, 123 (48.4%) developed an invasive fungal infection (IFI): 14 (5.5%) patients with invasive candidiasis (IC) and 108 (42.5%) patients with invasive mould infections (IMI). Among 108 IMI identified, 4 (3.7%) were proven, 1 (0.9%) probable, and 103 (95.4%) were possible, using current definitions. Overall, 6-month mortality was 23.7% (27/114) and 20.6% (26/126) for patients with and without an IFI, respectively. Older age (≥50 years; hazard ratio [HR]: 2.5, P < 0.001), female gender (HR: 1.7, P = 0.006), and baseline renal and/or liver dysfunction (HR: 2.4, P < 0.001) were the strongest mortality predictors. We report relatively low rates of IC despite lack of routine primary antifungal prophylaxis, albeit associated with poor long-term survival. High rates of IMI, the vast majority with a possible diagnosis, were observed. Host-related variables (demographics and baseline organ dysfunction) were identified as the most significant risk factors for IFI and mortality predictors in this series.

Atrial flutter associated with carboplatin administration.

OBJECTIVE: To report a novel case of atrial flutter associated with carboplatin administration and review chemotherapy-related cardiac toxicities, focusing on platinum-containing compounds. CASE REPORT: A 69-year-old man with extensive small cell lung cancer and asymptomatic cardiovascular and cerebrovascular disease was inconsistently adherent to his medication regimen. While undergoing carboplatin infusion, he developed atrial flutter. He had no other immediate arrhythmogenic causes of atrial flutter and the arrhythmia spontaneously reverted to sinus rhythm after 24 hours. His condition remained stable until he died 8 days later. The cause of death was unknown and the family declined postmortem examination. DISCUSSION: Although this patient's cardiac history and nonadherence to his medications may have increased his susceptibility to develop atrial arrhythmias, the Naranjo probability scale reveals a possible relationship between atrial flutter and infusion of carboplatin. A literature search revealed other adverse cardiac events due to platinum compounds; however, to our knowledge, this case is the first to describe an association with atrial flutter. A definitive causal link cannot be determined, but this may have been the result of a direct arrhythmogenic effect of treatment or to a novel hypersensitivity reaction. Given the potential deleterious impact of drug-induced arrhythmias, we have reported this case to the Food and Drug Administration as a new adverse effect of carboplatin. CONCLUSIONS: Providers should consider cardiac monitoring during carboplatin infusion in patients with known cardiac disease or at high risk of cardiac complications.

High prevalence of unusual genotypes of Toxoplasma gondii infection in pork meat samples from Erechim, Southern Brazil.

Toxoplasmosis is the most common cause of infectious uveitis in Brazil, with a higher frequency in the South of the country. We have collected samples from porcine tongue and diaphragm obtained in both large and small abattoirs and used molecular biological technique to determine the prevalence of infection and RFLP analysis to type the parasites. Seventeen out of 50 (34%) samples from the diaphragm and 33 out of 50 (66%) samples from the tongue demonstrated a positive PCR reaction for T. gondii and restriction analysis of four of the positive samples revealed that all had a type I genotype at SAG2. However, when other unlinked loci were analyzed, these strains had a type III genotype at markers BTUB, SAG3, and GRA6. One of the strains (8T) had a type II allele at SAG3, indicating it has a combination of alleles normally seen in the clonal lineages. Our sampling indicates a high prevalence of infection and suggests that unusual genotypes of T. gondii are found in Brazil even among domesticated pigs.

High prevalence of unusual genotypes of Toxoplasma gondii infection in pork meat samples from Erechim, Southern Brazil

Toxoplasmosis is the most common cause of infectious uveitis in Brazil, with a higher frequency in the South of the country. We have collected samples from porcine tongue and diaphragm obtained in both large and small abattoirs and used molecular biological technique to determine the prevalence of infection and RFLP analysis to type the parasites. Seventeen out of 50 (34 percent) samples from the diaphragm and 33 out of 50 (66 percent) samples from the tongue demonstrated a positive PCR reaction for T. gondii and restriction analysis of four of the positive samples revealed that all had a type I genotype at SAG2. However, when other unlinked loci were analyzed, these strains had a type III genotype at markers BTUB, SAG3, and GRA6. One of the strains (8T) had a type II allele at SAG3, indicating it has a combination of alleles normally seen in the clonal lineages. Our sampling indicates a high prevalence of infection and suggests that unusual genotypes of T. gondii are found in Brazil even among domesticated pigs.

Toxoplasmose é a causa mais comum de uveíte infecciosa no Brasil, com maior freqüência no sul do país. Coletamos amostras de diafragma e língua de porcos em pequenos e grandes abatedouros e utilizamos biologia molecular para determinar a taxa de infecção e ''DNA genotyping'' para tipar os parasitas. Dezessete das 50 amostras de diafragma (34 por cento) e 33 das 50 amostras de língua (66 por cento) foram positivas na reação de PCR para T. gondii. A análise restritiva e o sequenciamento do DNA em quatro amostras revelaram que todas apresentam genótipo tipo I no SAG2. No entanto, quando outros loci não ligados foram analisados, estas mesmas amostras se mostraram como tipo III nos marcadores BTUB, SAG3 e GRA6. Uma das amostras (8T) mostrava-se como tipo II no SAG3, indicando um perfil misto. Estas amostras demonstraram não só uma alta taxa de infecção, mas também genótipos incomuns que não foram observados com freqüência em estudos prévios. Nosso trabalho sugere que genótipos incomuns de T. gondii podem ser encontrados no Brasil, até mesmo em porcos domesticados.

Immunodeficiency and intrinsic IFN resistance are associated with viral breakthrough to HCV therapy in HIV-coinfected patients.

Viral breakthroughs (VB), defined as having detectable HCV VL while on anti-HCV therapy after achieving maximal suppression, have not yet been characterized with the use of PEG-IFN in HIV/HCV-coinfected patients. We evaluated possible mechanisms for VB among HIV/HCV-coinfected patients receiving PEG-IFN/RBV. Thirty HIV/HCV coinfected patients were treated with PEG-IFN (1.5 mug/kg sc qwk) and RBV (1-1.2 g daily) for 48 weeks. Liver chemistry, HCV VL, genotyping, DNA microarray, and sequencing of HCV E-2 envelope were performed before and during treatment. VB had lower baseline HCV VL but higher ALT and AST than relapsers (ETR) (p < 0.05) and lower CD4+ T lymphocytes (%) than patients with sustained virological responses (SVR), but similar first and second phase HCV viral kinetics (vs. ETR and SVR; p > 0.05). HCV genotypes and envelope sequences were similar for patients with VB pretreatment and at break-through. VB had higher levels of interferon-induced gene (IFIG) expression pretreatment than patients with ETR (p < 0.01). HIV/HCV-coinfected patients have a high rate of VB on PEG-IFN/RBV therapy characterized by higher levels of IFIG expression, immunodeficiency, and hepatic inflammation. Novel strategies are required for the treatment of persons with VB.