Implementation of Bedaquiline, Pretomanid, and Linezolid in the United States: Experience Using a Novel All-Oral Treatment Regimen for Treatment of Rifampin-Resistant or Rifampin-Intolerant Tuberculosis Disease.

BACKGROUND: Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring. METHODS: Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring. RESULTS: Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. CONCLUSIONS: BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

Hypoalbuminemia is a risk factor for invasive fungal infections and poor outcomes in infected kidney transplant recipients.

INTRODUCTION: Invasive fungal infections (IFI), are estimated to occur in 2%-14% of kidney transplant recipients (KTRs) in the current era of immune suppression and are associated with high mortality rates. We hypothesized that hypoalbuminemia in KTRs is a risk factor for IFI and would be associated with poor outcomes. METHODS: In this study, using data from a prospective cohort registry, we describe the frequency of IFI due to Blastomycosis, Coccidioidomycosis, Histoplasmosis, Aspergillosis, and Cryptococcus in KTRs with serum albumin levels measured 3-6 months before diagnosis. Controls were selected based on incidence density sampling. KTRs were divided into three groups based on the pre-IFI serum albumin level: normal (≥4 g/dL), mild (3-4 g/dL), or severe (<3 g/dL) hypoalbuminemia. Outcomes of interest were uncensored graft failure after IFI and overall mortality. RESULTS: A total of 113 KTRs with IFI were compared with 348 controls. The incidence rate of IFI among individuals with normal, mild, and severe hypoalbuminemia was 3.6, 8.7, and 29.3 per 100 person-years, respectively. After adjustment for multiple variables, the trend for risk of uncensored graft failure following IFI was greater in KTRS with mild (HR = 2.1; 95% CI, .75-6.1) and severe (HR = 4.47; 95% CI, 1.56-12.8) hypoalbuminemia (P-trend < .001) compared to those with normal serum albumin. Similarly, mortality was higher in severe hypoalbuminemia (HR = 1.9; 95% CI, .67-5.6) compared to normal serum albumin (P-trend < .001). CONCLUSION: Hypoalbuminemia precedes the diagnosis of IFI in KTRs, and is associated with poor outcomes following IFI. Hypoalbuminemia may be a useful predictor of IFI in KTRs and could be incorporated into screening algorithms.

Cytomegalovirus nephritis in kidney transplant recipients: Epidemiology and outcomes of an uncommon diagnosis.

BACKGROUND: Data on epidemiology and outcomes of cytomegalovirus (CMV) nephritis in kidney transplant patients are limited due to the rarity of this condition. METHODS: A retrospective review of all kidney transplant recipients (KTR) (n = 6490) and biopsy-proven CMV nephritis between 1/1997 and 12/2020 was performed. RESULTS: The prevalence of CMV nephritis was low: 13/6490 (0.2%). The diagnosis was made at a median of 7.0 months (range 2.6-15.6 months) after transplant. 6 of 13 (46%) patients were CMV (D+/R-). Median CMV DNA load at biopsy was 376,000, IU/mL (range 87,000-6,460,000 IU/mL). Main biopsy features were CMV glomerulitis (n = 7/13, 54%) followed by CMV tubulointerstitial nephritis (6/13; 46%). Mean eGFR at biopsy (22.7 ± 12 mL/min/1.73 m2 ) was significantly decreased compared to baseline eGFR (38.7 ± 18.5 mL/min/1.73 m2 , p = 0.02). The vast majority, 11 of 13 (85%), experienced graft failure including 5 of 13 (38%) death-censored. 5 of 13 (38%) patients were diagnosed with acute rejection: three had concurrent acute rejection, and two had rejection within 3 months of index biopsy, respectively. Patients with tubulointerstitial CMV nephritis were significantly more likely to have rejection at the time of biopsy (50% vs. 0%, p < 0.05) compared to those with glomerular CMV nephritis. There were no significant differences between these groups in terms of eGFR at all time points, death, graft failure, immunosuppression changes or rejection after biopsy. CONCLUSION: CMV nephritis is rare but appears to be associated with poor patient/allograft outcomes. Early identification and timely treatment of CMV infection may prevent end-organ involvement and improve patient and allograft-related outcomes.

Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience.

Fecal microbiota transplant (FMT) is recommended for Clostridium difficile infection (CDI) treatment; however, use in solid organ transplantation (SOT) patients has theoretical safety concerns. This multicenter, retrospective study evaluated FMT safety, effectiveness, and risk factors for failure in SOT patients. Primary cure and overall cure were defined as resolution of diarrhea or negative C difficile stool test after a single FMT or after subsequent FMT(s) ± anti-CDI antibiotics, respectively. Ninety-four SOT patients underwent FMT, 78% for recurrent CDI and 22% for severe or fulminant CDI. FMT-related adverse events (AE) occurred in 22.3% of cases, mainly comprising self-limiting conditions including nausea, abdominal pain, and FMT-related diarrhea. Severe AEs occurred in 3.2% of cases, with no FMT-related bacteremia. After FMT, 25% of patients with underlying inflammatory bowel disease had worsening disease activity, while 14% of cytomegalovirus-seropositive patients had reactivation. At 3 months, primary cure was 58.7%, while overall cure was 91.3%. Predictors of failing a single FMT included inpatient status, severe and fulminant CDI, presence of pseudomembranous colitis, and use of non-CDI antibiotics at the time of FMT. These data suggest FMT is safe in SOT patients. However, repeated FMT(s) or additional antibiotics may be needed to optimize rates of cure with FMT.

Immunosuppression Does Not Affect Antibody Concentrations to Measles, Mumps, and Rubella in Patients with Inflammatory Bowel Disease.

BACKGROUND: The Advisory Committee on Immunization Practices (ACIP) recommends using the immunization record and not serologic testing to determine immunity against measles and rubella in the general population, due to potential false negatives. However, it is unknown whether the immune response is less durable among patients who are immunosuppressed. AIMS: The primary aim of this study was to evaluate sustained vaccine-induced measles, mumps, and rubella (MMR) antibody concentrations in immunosuppressed patients with inflammatory bowel disease (IBD). METHODS: We performed a cross-sectional study to compare antibody concentrations following the two-dose (MMR) vaccine among 46 patients with IBD and 20 healthy controls (HC). Three IBD groups stratified by the immunosuppressive regimen that preceded study entry for at least 3 months: (1) thiopurine monotherapy, (2) anti-TNF monotherapy, or (3) combination therapy (anti-TNF agent combined with an immunomodulator) were enrolled. RESULTS: All subjects had measurable antibody concentrations to the three vaccine viruses. Age and time since receipt of MMR series were similar in both groups. There were no difference in the antibody concentration of measles (IBD 667 mIU/ml vs HC 744 mIU/ml; p = 0.45), mumps (IBD 339 EU/ml vs HC 402 EU/ml; p = 0.62), or rubella (IBD 25 mIU/ml vs HC 62 mIU/ml; p = 0.11) among the groups. No differences in antibody concentrations were found among the IBD treatment groups. CONCLUSION: Immunosuppressed patients with IBD have sustained antibody concentrations comparable to healthy controls. Thus, gastroenterologist should follow the ACIP recommendations and use the immunization record when available to determine immunity to measles and rubella in patients with IBD. Clinical Trials Registry # NCT02434133.

Legionella: virulence factors and host response.

PURPOSE OF REVIEW: Legionella pneumophila is a facultative intracellular pathogen and an important cause of community-acquired and nosocomial pneumonia. This review focuses on the latest literature examining Legionella's virulence strategies and the mammalian host response. RECENT FINDINGS: Recent studies identify novel virulence strategies used by L. pneumophila and new aspects of the host immune response to this pathogen. Legionella prevents acidification of the phagosome by recruiting Rab1, a host protein. Legionella also blocks a conserved endoplasmic reticulum stress response. To access iron from host stores, L. pneumophila upregulates more regions allowing vacuolar colocalization N. In response to Legionella, the host cell may activate caspase-1, caspase-11 (mice) or caspase-4 (humans). Caspase-3 and apoptosis are activated by a secreted, bacterial effector. Infected cells send signals to their uninfected neighbors, allowing the elaboration of inflammatory cytokines in trans. Antibody subclasses provide robust protection against Legionella. SUMMARY: L. pneumophila is a significant human pathogen that lives in amoebae in the environment but may opportunistically infect the alveolar macrophage. To maintain its intracellular lifestyle, Legionella extracts essential iron from the cell, blocks inflammatory responses and manipulates trafficking to avoid fusion with the lysosome. The mammalian host has counter strategies, which include the release of proinflammatory cytokines, the activation of caspases and antibody-mediated immunity.

Clostridioides difficile Infection in the Stem Cell Transplant and Hematologic Malignancy Population.

Clostridioides difficile infection (CDI) is common in the stem cell transplant (SCT) and hematologic malignancy (HM) population and mostly occurs in the early posttransplant period. Treatment of CDI in SCT/HM is the same as for the general population, with the exception that fecal microbiota transplant (FMT) has not been widely adopted because of safety concerns. Several case reports, small series, and retrospective studies have shown that FMT is effective and safe. A randomized controlled trial of FMT for prophylaxis of CDI in SCT patients is underway. In addition, an abundance of novel therapeutics for CDI is currently in development.

Bacterial Infections in the Stem Cell Transplant Recipient and Hematologic Malignancy Patient.

Bacteremia (bloodstream infection) is frequent (20%-30% incidence) in the stem cell transplant and hematologic malignancy population and often occurs in the early post-transplant engraftment period. In most studies, Gram-positive bacteria occur at greater frequency than gram-negative bacteria, although some centers report that rates of gram-negative bloodstream infections have recently increased. In many centers, resistance rates among Enterococci and gram-negative bacteria, especially the Enterobacteriaceae, are extensive and associated with increased mortality. Better prediction tools, enhanced infection control, and new anti-infective agents hold promise for the treatment of highly resistant pathogens in this population.

Skin and Soft Tissue Infections Due to Nontuberculous Mycobacteria.

PURPOSE OF REVIEW: This review describes recent trends in the epidemiology of nontuberculous mycobacteria (NTM), emerging pathogens, new insights into NTM pathogenesis, and advances in diagnosis and treatment. RECENT FINDINGS: Emerging pathogens include Mycobacterium chimaera and drug-resistant subspecies of Mycobacterium abscessus. Important virulence mechanisms of pathogenic NTM include the ability to alter the macrophage's permissiveness to intracellular bacterial growth. New diagnostic tools consist of DNA probes, gene sequencing, and matrix-assisted laser desorption ionization-time of flight. These methods allow rapid speciation of NTM species, in some cases directly from patient samples. There are few novel agents available to treat NTM, although some repurposed drugs show excellent activity. The incidence of NTM infections appears to be increasing in a number of regions around the world. Molecular methods are now the diagnostic tools of choice. Discovery of novel effective agents and/or drug combinations with greater likelihood of cure, shorter treatment duration, and fewer side effects are research priorities.