Clinical characteristics and genome epidemiology of Stenotrophomonas maltophilia in Japan.

BACKGROUND: Stenotrophomonas maltophilia is a carbapenem-resistant Gram-negative pathogen increasingly responsible for difficult-to-treat nosocomial infections. OBJECTIVES: To describe the contemporary clinical characteristics and genome epidemiology of patients colonized or infected by S. maltophilia in a multicentre, prospective cohort. METHODS: All patients with a clinical culture growing S. maltophilia were enrolled at six tertiary hospitals across Japan between April 2019 and March 2022. The clinical characteristics, outcomes, antimicrobial susceptibility and genomic epidemiology of cases with S. maltophilia were investigated. RESULTS: In total, 78 patients were included representing 34 infection and 44 colonization cases. The median age was 72.5 years (IQR, 61-78), and males accounted for 53 cases (68%). The most common comorbidity was localized solid malignancy (39%). Nearly half of the patients (44%) were immunosuppressed, with antineoplastic chemotherapy accounting for 31%. The respiratory tract was the most common site of colonization (86%), whereas bacteraemia accounted for most infection cases (56%). The 30 day all-cause mortality rate was 21%, which was significantly higher in infection cases than colonization cases (35% versus 9%; adjusted HR, 3.81; 95% CI, 1.22-11.96). Susceptibility rates to ceftazidime, levofloxacin, minocycline and sulfamethoxazole/trimethoprim were 14%, 65%, 87% and 100%, respectively. The percentage of infection ranged from 13% in the unclassified group to 86% in genomic group 6A. The percentage of non-susceptibility to ceftazidime ranged from 33% in genomic group C to 100% in genomic groups 6 and 7 and genomic group geniculate. CONCLUSIONS: In this contemporary multicentre cohort, S. maltophilia primarily colonized the respiratory tract, whereas patients with bacteraemia had the highest the mortality from this pathogen. Sulfamethoxazole/trimethoprim remained consistently active, but susceptibility to levofloxacin was relatively low. The proportions of cases representing infection and susceptibility to ceftazidime differed significantly based on genomic groups.

Infections Following Kidney Transplantation After Exposure to Immunosuppression for Treatment of Glomerulonephritis.

RATIONALE & OBJECTIVE: Kidney transplant patients with glomerulonephritis (GN) as their native disease commonly have received pretransplant immunosuppression (PTI). This may contribute to the immunosuppression burden potentially increasing the risk for infections after transplantation. STUDY DESIGN: Single-center, retrospective cohort study. SETTING & PARTICIPANTS: Recipients of a kidney transplant from January 2005 until May 2020 at a tertiary care university teaching hospital. EXPOSURE: Patients with GN as their native kidney disease who received PTI for treatment of GN (n=184) were compared with nondiabetic recipients of kidney transplants who did not receive PTI (n = 579). OUTCOME: First occurrence after transplantation of an infection outcome, either viral (BK or cytomegalovirus [CMV] infection) or bacterial. ANALYTICAL APPROACH: Cox regression analysis adjusted for age at transplant, sex, race, donor type, year of transplant surgery, dialysis vintage, receipt of T-cell depleting induction, and CMV transplant status. RESULTS: Over a median follow-up period of 5.7 years, patients with GN PTI were not at an increased risk for developing any first viral infection compared with controls (adjusted HR [AHR] 0.69 [95% CI, 0.52-0.91]) nor at increased risk for specific viral infections: BK infection 19.6% vs 26.3% (AHR 0.72 [95% CI, 0.50-1.05]) or CMV infection, 24.5% vs 29.0% (AHR, 0.76 [95% CI, 0.54-1.07]), respectively. There was also no increased risk of developing a first bacterial infection: 54.5% vs 57.5% (AHR, 0.90 [95% CI, 0.71-1.13]). These findings of no increased risk for infection were independent of the type of PTI used (cyclophosphamide, rituximab, mycophenolate mofetil, or calcineurin inhibitor) or the type of T-cell depleting induction therapy (alemtuzumab or antithymocyte globulin) administered. LIMITATIONS: Single-center study, no data on methylprednisone use for PTI, unmeasured confounding. CONCLUSIONS: Use of PTI for the treatment of GN was not associated with an increased risk of viral (BK or CMV) or bacterial infection after transplantation. Additional surveillance for infection after transplantation for patients who received PTI may not be necessary. PLAIN-LANGUAGE SUMMARY: Many kidney transplant patients have glomerular disease as the cause of kidney failure. These patients may be exposed to immunosuppression before transplantation, which could increase the risk for infections after receipt of a transplanted kidney. We identified kidney transplant recipients at a university teaching hospital who received immunosuppression before transplant for the treatment of glomerular kidney disease. We examined their risk for infection after transplantation by comparing it with the risk among transplant patients who were not exposed to immunosuppression before transplant. We observed no increased risk for infection after exposure to prior immunosuppression. Therefore, patients exposed to significant amounts of immunosuppression before transplantation may not require special surveillance or medication adjustment for fear of infection after their receipt of a kidney transplant.

Priorities and Progress in Gram-negative Bacterial Infection Research by the Antibacterial Resistance Leadership Group.

Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.

Utility of Urine Cultures During Febrile Neutropenia Workup in Hematopoietic Stem Cell Transplantation Recipients Without Urinary Symptoms.

The utility of obtaining screening urine cultures for febrile neutropenia (FN) during hematopoietic stem cell transplant (HCT) is unknown. In 667 adult HCT patients with FN, only 40 (6%) were found with bacteriuria. Antibiotics were modified in 3 patients (0.4%) based on urine cultures and none developed urinary-associated infectious complications.

Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease.

BACKGROUND: Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. METHODS: Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. RESULTS: No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. CONCLUSIONS: Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

Real-Life Use of Ceftolozane/Tazobactam for the Treatment of Bloodstream Infection Due to Pseudomonas aeruginosa in Neutropenic Hematologic Patients: a Matched Control Study (ZENITH Study).

We sought to assess the characteristics and outcomes of neutropenic hematologic patients with Pseudomonas aeruginosa (PA) bloodstream infection (BSI) treated with ceftolozane-tazobactam (C/T). We conducted a multicenter, international, matched-cohort study of PA BSI episodes in neutropenic hematologic patients who received C/T. Controls were patients with PA BSI treated with other antibiotics. Risk factors for overall 7-day and 30-day case fatality rates were analyzed. We compared 44 cases with 88 controls. Overall, 91% of episodes were caused by multidrug-resistant (MDR) strains. An endogenous source was the most frequent BSI origin (35.6%), followed by pneumonia (25.8%). There were no significant differences in patient characteristics between groups. C/T was given empirically in 11 patients and as definitive therapy in 41 patients. Treatment with C/T was associated with less need for mechanical ventilation (13.6% versus 33.3%; P = 0.021) and reduced 7-day (6.8% versus 34.1%; P = 0.001) and 30-day (22.7% versus 48.9%; P = 0.005) mortality. In the multivariate analysis, pneumonia, profound neutropenia, and persistent BSI were independent risk factors for 30-day mortality, whereas lower mortality was found among patients treated with C/T (adjusted OR [aOR] of 0.19; confidence interval [CI] 95% of 0.07 to 0.55; P = 0.002). Therapy with C/T was associated with less need for mechanical ventilation and reduced 7-day and 30-day case fatality rates compared to alternative agents in neutropenic hematologic patients with PA BSI. IMPORTANCE Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited. Our study is unique because it is focused on extremely immunosuppressed hematological patients with neutropenia and bloodstream infection (BSI) due to PA (mainly multidrug resistant [MDR]), a scenario which is often associated with very high mortality rates. In our study, we found that the use of C/T for the treatment of MDR PA BSI in hematological neutropenic patients was significantly associated with improved outcomes, and, in addition, it was found to be an independent risk factor associated with increased survival. To date, this is the largest series involving neutropenic hematologic patients with PA BSI treated with C/T.

Resistance in Enterobacterales Is Higher Among People Living With Human Immunodeficiency Virus.

BACKGROUND: Multidrug-resistant Enterobacterales (MDR-E) are important pathogens. People living with human immunodeficiency virus (HIV; PLWH) may be at greater risk for MDR-E infection given relatively high antibiotic exposure and burden of comorbidities. METHODS: We analyzed data from 36 521 patients in a healthcare system in North Carolina who had a clinical culture with growth of an Enterobacterales species from 2000 to 2018; 440 were PLWH. We used generalized linear models to estimate prevalence ratios and differences, contrasting PLWH and people not living with HIV (PNLWH) for resistance to individual antibiotic classes, as well as MDR-E. We assessed trends in prevalence over time by calculating the 5-year moving average and fitting restricted cubic spline models. RESULTS: The overall prevalence of MDR-E was higher among PLWH (21.5%; 95% confidence interval [CI], 18.2%-25.1%) vs PNLWH (16.5%; 95% CI, 16.2%-16.9%), with an adjusted prevalence ratio of 1.38 (95% CI, 1.14-1.65). PLWH had higher rates of antimicrobial resistance than PNLWH for all antibiotic classes analyzed, including penicillins, penicillin/beta lactamase inhibitor combinations, and sulfonamides. MDR-E prevalence was 3 to 10 percentage points higher among PLWH than PNLWH throughout the study period based on the 5-year moving average. CONCLUSIONS: In a large clinical study population in the southeastern United States from 2000 to 2018, the prevalence of antibacterial resistance among Enterobacterales was consistently higher among PLWH than PNLWH. These data highlight the importance of identifying and mitigating the factors that contribute to antimicrobial resistance in PLWH, given the potential clinical consequences of these resistant pathogens.

Cefiderocol for the Treatment of Adult and Pediatric Patients With Cystic Fibrosis and Achromobacter xylosoxidans Infections.

Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance.

Preventing infectious complications when treating non-malignant immune-mediated hematologic disorders.

Immunosuppressants, targeted antibody therapies, and surgical splenectomy are amongst the treatment choices for immune-mediated non-malignant hematologic disorders, with infection being the most common non-hematological adverse event from these therapies. Corticosteroids are associated with a length-of-treatment and dose-dependent risk for infection, including opportunistic infections. Screening and antimicrobial prophylaxis against tuberculosis, Strongyloides stercoralis, and Pneumocystis jirovecii pneumonia, are indicated in selected patients on steroids and with certain risk factors for infection. Rituximab is associated with hepatitis B virus reactivation. All patients planned to be started on rituximab should be screened for hepatitis B surface antigen and total core antibody, with antiviral prophylaxis given depending on test results. In eculizumab treated patients, immunization against meningococcal serogroups ACWY and B is recommended. In addition, some guidelines suggest antibiotic prophylaxis for the duration of eculizumab treatment. In splenectomized patients, counseling and immunization are cornerstones of infection prevention. Several federal and society guidelines about immunizations and prophylactic antimicrobial therapies for patients treated with various immunosuppressive agents exist and are summarized in this manuscript in a clinical-focused table. In addition, management suggestions are made where no formal guidelines exist.

Sex-Based Differences in Inpatient Burn Mortality.

BACKGROUND: Among burn patients, research is conflicted, but may suggest that females are at increased risk of mortality, despite the opposite being true in non-burn trauma. Our objective was to determine whether sex-based differences in burn mortality exist, and assess whether patient demographics, comorbid conditions, and injury characteristics explain said differences. METHODS: Adult patients admitted with burn injury-including inhalation injury only-between 2004 and 2013 were included. Inverse probability of treatment weights (IPTW) and inverse probability of censor weights (IPCW) were calculated using admit year, patient demographics, comorbid conditions, and injury characteristics to adjust for potential confounding and informative censoring. Standardized Kaplan-Meier survival curves, weighted by both IPTW and IPCW, were used to estimate the 30-day and 60-day risk of inpatient mortality across sex. RESULTS: Females were older (median age 44 vs. 41 years old, p < 0.0001) and more likely to be Black (32% vs. 25%, p < 0.0001), have diabetes (14% vs. 10%, p < 0.0001), pulmonary disease (14% vs. 7%, p < 0.0001), heart failure (4% vs. 2%, p = 0.001), scald burns (45% vs. 26%, p < 0.0001), and inhalational injuries (10% vs. 8%, p = 0.04). Even after weighting, females were still over twice as likely to die after 60 days (RR 2.87, 95% CI 1.09, 7.51). CONCLUSION: Female burn patients have a significantly higher risk of 60-day mortality, even after accounting for demographics, comorbid conditions, burn size, and inhalational injury. Future research efforts and treatments to attenuate mortality should account for these sex-based differences. The project was supported by the National Institutes of Health, Grant Number UL1TR001111.

Combined Medical and Surgical Management of Hepatic Mucormycosis in an Adult with Acute Myeloid Leukemia: Case Report and Review of the Literature.

Hepatic mucormycosis is a disease caused by a ubiquitous fungus which is especially important in patients with hematologic malignancies. We present a case of an adult patient with acute myeloid leukemia who developed the infection after undergoing chemotherapy. His successful management was an integrated approach of a minimally invasive surgical resection with anti-fungal therapy. We describe the management of this patient and a review of the literature.

Systems-based Practice in Burn Care: Prevention, Management, and Economic Impact of Health Care-associated Infections.

Health care-associated infections in burn patients, from ventilator-associated pneumonia to skin and soft tissue infections, can substantially compromise outcomes, because these complications are associated with longer lengths of stay, increased morbidity and mortality, and greater direct medical costs. Health care-associated infections are largely preventable, through surveillance, education, appropriate hand hygiene, and culture change, especially for device-related infections. Systems-based practice, which allows individuals and clinical microsystems to navigate and improve the macro health care system, may be one of the most powerful skill sets to effect change, permitting a shift in culture toward patient safety and quality improvement.

Life-threatening Skin Disorders Treated in the Burn Center: Impact of Health care-associated Infections on Length of Stay, Survival, and Hospital Charges.

This article reviews a single burn center experience with life-threatening skin disorders, over a 10-year period. It explores the incidence of health care-associated infections and the impact on length of stay, hospital charges, and mortality.

Even Better Than the Real Thing? Xenografting in Pediatric Patients with Scald Injury.

This article reviews a single burn center experience with porcine xenografts to treat pediatric scald injuries, over a 10-year period. The authors compare xenografting to autografting, as well as wound care only, and provide outcome data on length of stay, incidence of health care-associated infections, and need for reconstructive surgery.

NDM-5 and OXA-181 Beta-Lactamases, a Significant Threat Continues To Spread in the Americas.

Among Gram-negative bacteria, carbapenem-resistant infections pose a serious and life-threatening challenge. Here, the CRACKLE network reports a sentinel detection and characterization of a carbapenem-resistant Klebsiella pneumoniae ST147 isolate harboring blaNDM-5 and blaOXA-181 from a young man who underwent abdominal surgery in India. blaNDM-5 was located on an IncFII plasmid of ≈90 kb, whereas blaOXA-181 was chromosomally encoded. Resistome and genome analysis demonstrated multiple copies of the transposable element IS26 and a "hot-spot region" in the IncFII plasmid.

Clinical presentation and outcomes of norovirus infection in intestinal allograft compared to native intestine.

BACKGROUND: No data are available on clinical manifestations and course of norovirus gastroenteritis (NVE) in intestinal allograft (from intestinal and multivisceral transplant recipients, ITR) compared to native intestine (from other allograft recipients, nITR). METHODS: This was a retrospective study of solid organ transplant recipients with NVE at two centers from January 1, 2010 to April 1, 2014. Chi-square, t-test, linear and logistic regression analyses were done to compare NVE in ITR vs nITR patients. RESULTS: The ITR (45 patients) were compared to nITR (107 patients). ITR were younger (odds ratio [OR]=0.90; P<.0001), less likely to receive anti-lymphocyte induction therapy (OR=0.15; P<.0001), and had shorter time from transplant to NVE (OR=0.99; P=.008). On presentation ITR had less frequent nausea (OR=0.11; P<.0001) or vomiting (OR=0.36; P=.01), higher white blood cell count (OR=1.09; P=.001), and higher glomerular filtration rate (OR=1.02; P<.0001). ITR were less likely to receive anti-motility agents (OR=9.6; P<.0001). ITR were more likely to stay longer on intravenous (IV) fluids (OR=1.18; P<.0001); have recurrent NVE (OR=4.25; P<.0001); have longer hospital stay (OR=1.07; P<.0001); develop acute rejection (OR=5.1; P=.006); and have lower overall survival (OR=0.28; P=.006). CONCLUSIONS: Compared to nITR, the ITR with NVE were significantly younger, had less nausea and vomiting at presentation, received less anti-motility agents, required more IV fluids, and had longer hospital stay. A trend was seen for lower survival with NVE in ITR.

Increasing Rates of Fluoroquinolone Resistance in Escherichia coli Isolated From the Blood and Urine of Patients with Hematologic Malignancies and Stem Cell Transplant Recipients.

Fluoroquinolone (FQ) antibiotics have been shown to reduce mortality and the number of febrile episodes when used as prophylaxis during neutropenia. Prior studies suggest that prophylaxis may result in increasing rates of FQ resistance. Fluoroquinolone non-susceptibility trends in Escherichia coli isolated from blood and urine cultures were evaluated over a 16-year period during which prophylaxis was initiated in patients with hematologic malignancies and stem cell transplants. Non-susceptibility rates increased after the introduction of prophylaxis, with yearly non-susceptibility rates rising from 30%-33% to 40%-88% in blood isolates. The high rates of non-susceptibility now observed raise concerns about the continued efficacy of FQ prophylaxis. This concern exists particularly in those patients undergoing stem cell transplants where the total FQ non-susceptibility rates over the study period were 82.3%. Further evaluation of the effect of FQ prophylaxis on antibiotic resistance and its efficacy in the setting of increased rates of resistance is warranted.

Vancomycin-resistant Enterococcal Bloodstream Infections in Hematopoietic Stem Cell Transplant Recipients and Patients with Hematologic Malignancies: Impact of Daptomycin MICs of 3 to 4 mg/L.

PURPOSE: Case reports of treatment failure with standard-dose daptomycin (6 mg/kg) have recently surfaced in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) episodes with daptomycin MICs of 3 to 4 mg/L. The clinical implications of daptomycin MICs of 3 to 4 mg/L in VRE BSIs have not been elucidated. METHODS: We performed a single institutional retrospective analysis of adult stem cell transplant recipients and patients with hematologic malignancies diagnosed with VRE BSI from 2006 to 2014 and compared outcomes between those with daptomycin MICs of 3 to 4 mg/L those with 2 mg/L, as determined by Etest. FINDINGS: Forty-two daptomycin-treated VRE BSI episodes, all due to Enterococcus faecium were identified; 19 episodes with daptomycin MICs of 3 to 4 mg/L and 23 episodes with a daptomycin MIC of 2 mg/L. Patients in the higher daptomycin MIC group were more likely to be male, to be stem cell transplant recipients, and to have received high-dose daptomycin treatment (>6 mg/kg). In unadjusted analyses, microbiological failure in the daptomycin MICs 3 to 4 mg/L versus 2 mg/L groups (odds ratio = 1.79, 95% CI, 0.52-6.11; P = 0.35), the median duration of bacteremia (4 days in daptomycin MICs 3-4 mg/L vs 3 days in daptomycin MIC 2 mg/L; P = 0.18) and all-cause 30-day mortality (21% in daptomycin MICs 3-4 mg/L vs 35% in daptomycin MIC 2 mg/L group; P = 0.49) were not different. In adjusted analyses, the association between higher Pitt bacteremia scores and all-cause 30-day mortality was statistically significant (P = 0.0006), whereas the association between daptomycin MICs of 3 to 4 mg/L and all-cause 30-day mortality approached statistical significance (P = 0.06). IMPLICATIONS: Duration of bacteremia and microbiological failure rates did not differ by daptomycin MICs in VRE BSI episodes in our patients, composed of adult stem cell transplant recipients and patients with hematologic malignancies. There was a nonsignificant trend in multivariable analysis suggesting that all-cause 30-day mortality was lower in patients whose VRE bloodstream isolates were with daptomycin MICs of 3 to 4 mg/L.

Multidrug-Resistant Pseudomonas aeruginosa Infection in a Child with Cystic Fibrosis.

We describe a pediatric cystic fibrosis patient who developed a pulmonary exacerbation due to two multidrug-resistant (MDR) Pseudomonas aeruginosa isolates. In addition to these MDR organisms, the case was further complicated by ß-lactam allergy. Despite the MDR phenotype, both isolates were susceptible to an antimicrobial combination.