Epidemiology, Timing, and Secondary Prophylaxis of Recurrent Nocardiosis.

Background: Nocardia tends to cause infection in immunocompromised patients or those with chronic pulmonary disease. Nocardia is known to recur, prompting the practice of secondary prophylaxis in patients perceived at high risk. However, few data exist regarding the epidemiology of recurrent nocardiosis or the effectiveness of secondary prophylaxis. Methods: We performed a multicenter, retrospective cohort study of adults diagnosed with nocardiosis from November 2011 to April 2022, including patients who completed primary treatment and had at least 30 days of posttreatment follow-up. Propensity score matching was used to analyze the effect of secondary prophylaxis on Nocardia recurrence. Results: Fifteen of 303 (5.0%) patients developed recurrent nocardiosis after primary treatment. Most recurrences were diagnosed either within 60 days (N = 6/15, 40.0%) or between 2 to 3 years (N = 4/15, 26.7%). Patients with primary disseminated infection tended to recur within 1 year, whereas later recurrences were often nondisseminated pulmonary infection. Seventy-eight (25.7%) patients were prescribed secondary prophylaxis, mostly trimethoprim-sulfamethoxazole (N = 67/78). After propensity-matching, secondary prophylaxis was not associated with reduced risk of recurrence (hazard ratio, 0.96; 95% confidence interval, .24-3.83), including in multiple subgroups. Eight (53.3%) patients with recurrent nocardiosis required hospitalization and no patients died from recurrent infection. Conclusions: Recurrent nocardiosis tends to occur either within months because of the same Nocardia species or after several years with a new species. Although we did not find evidence for the effectiveness of secondary prophylaxis, the confidence intervals were wide. However, outcomes of recurrent nocardiosis are generally favorable and may not justify long-term antibiotic prophylaxis for this indication alone.

An inconspicuous identification: Isolation and identification of a novel Pichia species presenting as fungemia following cardiac surgery.

Fungemia is common in critically ill patient populations, and is associated with a high rate of mortality, especially when caused by nonalbicans Candida species. Herein, we describe a fatal case of fungemia following cardiothoracic surgery in which the organism, initially identified as Candida inconspicua, represents a novel species: Pichia alaskaensis.

Temporal trends in antifungal susceptibility of Cryptococcus neoformans isolates from a reference laboratory in the United States, 2011-2021.

BACKGROUND: There are no established clinical breakpoints for antifungal agents against Cryptococcus species; however, epidemiological cut-off values can help distinguish wild-type (WT) isolates without any acquired resistance from non-WT strains, which may harbour resistance mechanisms. PATIENTS/METHODS: We describe the trends of antifungal MICs and percentages of WT C. neoformans species complex (CNSC) isolates processed in our reference laboratory from November 2011 to June 2021. There were only nine isolates in 2011, thus, we included them in the year 2012 for data analysis. Clinical data is also described when available. RESULTS: We identified 632 CNSC, the majority collected from blood (n = 301), cerebrospinal fluid (n = 230), and respiratory (n = 71) sources. The overall percentage of WT isolates for amphotericin B (AMB), 5-flucytosine, and fluconazole was 77%, 98%, and 91%, respectively. We noticed a statistically significant change in the percentage of AMB WT isolates over the years, with 98% of isolates being WT in 2012 compared to 79% in 2021 (p < .01). A similar change was not observed for other antifungal agents. Clinical data was available for 36 patients, primarily non-HIV immunocompromised patients with disseminated cryptococcosis. There were no statistically significant differences in the clinical characteristics and outcomes between patients with WT (58.3%) versus non-WT (41.7%) isolates, but we noticed higher mortality in patients infected with an AMB non-WT CNSC isolate. CONCLUSIONS: We observed an increase in the percentage of AMB non-WT CNSC isolates in the past decade. The clinical implications of this finding warrant further evaluation in larger studies.

Mortality After Nocardiosis: Risk Factors and Evaluation of Disseminated Infection.

Background: Nocardia primarily infects patients who are immunocompromised or those with chronic lung disease. Although disseminated infection is widely recognized as an important prognostic factor, studies have been mixed on its impact on outcomes of nocardiosis. Methods: We performed a retrospective cohort study of adults with culture-confirmed nocardiosis. Advanced infection was defined as disseminated infection, cavitary pulmonary infection, or pleural infection. The primary outcome was 1-year mortality, as analyzed by multivariable Cox regression. Results: Of 511 patients with culture growth of Nocardia, 374 (73.2%) who had clinical infection were included. The most common infection sites were pulmonary (82.6%), skin (17.9%), and central nervous system (14.2%). In total, 117 (31.3%) patients had advanced infection, including 74 (19.8%) with disseminated infection, 50 (13.4%) with cavitary infection, and 18 (4.8%) with pleural infection. Fifty-nine (15.8%) patients died within 1 year. In multivariable models, disseminated infection was not associated with mortality (hazard ratio, 1.16; 95% CI, .62-2.16; P = .650) while advanced infection was (hazard ratio, 2.48; 95% CI, 1.37-4.49; P = .003). N. farcinica, higher Charlson Comorbidity Index, and culture-confirmed pleural infection were also associated with mortality. Immunocompromised status and combination therapy were not associated with mortality. Conclusions: Advanced infection, rather than dissemination alone, predicted worse 1-year mortality after nocardiosis. N. farcinica was associated with mortality, even after adjusting for extent of infection. While patients who were immunocompromised had high rates of disseminated and advanced infection, immunocompromised status did not predict mortality after adjustment. Future studies should account for high-risk characteristics and specific infection sites rather than dissemination alone.

Antifungal Susceptibility Pattern of Candida glabrata from a Referral Center and Reference Laboratory: 2012-2022.

The prevalence of invasive candidiasis caused by non-Candida albicans has rapidly increased. Candida glabrata (Nakaseomyces glabrata) is an important pathogen associated with substantial mortality. Our study examined the antifungal temporal susceptibility of C. glabrata and cross-resistance/non-wild-type patterns with other azoles and echinocandins. Laboratory data of all adult patients with C. glabrata isolated from clinical specimens at the Mayo Clinic, Rochester, from 2012 to 2022 were collected. Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were used. We obtained 1046 C. glabrata isolates from 877 patients. Using CLSI and EUCAST breakpoints, 187 (17.9%) isolates and 256 (24.5%) isolates were fluconazole-resistant, respectively. Focusing on C. glabrata bloodstream infections, fluconazole-resistance ranged from 16 to 22%. Among those 187 fluconazole-resistant isolates, 187 (100%) and 184 (98.4%) isolates were also voriconazole and posaconazole non-wild-type, respectively, with 97 (51.9%) isolates deemed non-wild type for itraconazole. The fluconazole susceptibility pattern has not changed over the past decade. The proportion of fluconazole-resistant C. glabrata is relatively high, which could be due to the complexity of patients and fluconazole exposure. Itraconazole appears to be a compelling step-down therapy for fluconazole-resistant C. glabrata, given the high proportion of wild-type isolates. Further research to examine clinical outcomes is warranted.

Clinical characteristics of central nervous system phaeohyphomycosis: A brief report of 20 years' experience.

Central nervous system (CNS) phaeohyphomycosis is a rare and often fatal fungal infection. Our study reported a case series of eight CNS phaeohyphomycosis cases at our institution over the past 20 years. We did not observe the common pattern of risk factors, abscess location, or number of abscesses among them. Most patients were immunocompetent without classic risk factors for fungal infection. Early diagnosis and aggressive management with surgical intervention and prolonged antifungal therapy can lead to a favorable outcome. The study highlights the need for further research to better understand the pathogenesis and optimal management of this challenging rare infection.

Outcomes of transplant recipients with pretransplant Nocardia colonization or infection.

BACKGROUND: Specific pretransplant infections have been associated with poor posttransplant outcomes. However, the impact of pretransplant Nocardia isolation has not been studied. METHODS: We performed a retrospective study from three centers in Arizona, Florida, and Minnesota of patients with Nocardia infection or colonization who subsequently underwent solid organ or hematopoietic stem cell transplantation from November 2011 through April 2022. Outcomes included posttransplant Nocardia infection and mortality. RESULTS: Nine patients with pretransplant Nocardia were included. Two patients were deemed colonized with Nocardia, and the remaining seven had nocardiosis. These patients underwent bilateral lung (N = 5), heart (N = 1), heart-kidney (N = 1), liver-kidney (N = 1), and allogeneic stem cell transplantation (N = 1) at a median of 283 (interquartile range [IQR] 152-283) days after Nocardia isolation. Two (22.2%) patients had disseminated infection, and two were receiving active Nocardia treatment at the time of transplantation. One Nocardia isolate was resistant to trimethoprim-sulfamethoxazole (TMP-SMX) and all patients received TMP-SMX prophylaxis posttransplant, often for extended durations. No patients developed posttransplant nocardiosis during a median follow-up of 1.96 (IQR 0.90-6.33) years. Two patients died during follow-up, both without evidence of nocardiosis. CONCLUSIONS: This study did not identify any episodes of posttransplant nocardiosis among nine patients with pretransplant Nocardia isolation. As patients with the most severe infections may have been denied transplantation, further studies with larger sample sizes are needed to better analyze any impact of pretransplant Nocardia on posttransplant outcomes. However, among patients who receive posttransplant TMP-SMX prophylaxis, these data suggest pretransplant Nocardia isolation may not impart a heightened risk of posttransplant nocardiosis.

Emergence of Inducible Macrolide Resistance in Mycobacterium chelonae Due to Broad-Host-Range Plasmid and Chromosomal Variants of the Novel 23S rRNA Methylase Gene, erm(55).

Macrolides are a mainstay of therapy for infections due to nontuberculous mycobacteria (NTM). Among rapidly growing mycobacteria (RGM), inducible macrolide resistance is associated with four chromosomal 23S rRNA methylase (erm) genes. Beginning in 2018, we detected high-level inducible clarithromycin resistance (MICs of ≥16µg/mL) in clinical isolates of Mycobacterium chelonae, an RGM species not previously known to contain erm genes. Using whole-genome sequencing, we identified a novel plasmid-mediated erm gene. This gene, designated erm(55)P, exhibits <65% amino acid identity to previously described RGM erm genes. Two additional chromosomal erm(55) alleles, with sequence identities of 81% to 86% to erm(55)P, were also identified and designated erm(55)C and erm(55)T. The erm(55)T is part of a transposon. The erm(55)P allele variant is located on a putative 137-kb conjugative plasmid, pMchErm55. Evaluation of 133 consecutive isolates from 2020 to 2022 revealed 5 (3.8%) with erm(55). The erm(55)P gene was also identified in public data sets of two emerging pathogenic pigmented RGM species: Mycobacterium iranicum and Mycobacterium obuense, dating back to 2008. In both species, the gene appeared to be present on plasmids homologous to pMchErm55. Plasmid-mediated macrolide resistance, not described previously for any NTM species, appears to have spread to multiple RGM species. This has important implications for antimicrobial susceptibility guidelines and treatment of RGM infections. Further spread could present serious consequences for treatment of other macrolide-susceptible RGM. Additional studies are needed to determine the transmissibility of pMchErm55 and the distribution of erm(55) among other RGM species.

Clinical manifestations, treatment and outcomes of patients infected with Mycobacterium haemophilum with a focus on immune reconstitution inflammatory syndrome: a retrospective multi-site study.

BACKGROUND: Mycobacterium haemophilum is a nontuberculous mycobacterium with fastidious in vitro growth requirements and an increasingly reported cause of extrapulmonary disease. Timely diagnosis and management of M. haemophilum infections and the immune reconstitution inflammatory syndromes (IRIS) observed in a subset of patients during treatment remain challenging. METHODS: We conducted a retrospective chart review between January 1, 2010, and January 1, 2022 and identified 26 patients diagnosed with M. haemophilum infection at our institution. We describe their clinical presentation, diagnostic results, management, and outcomes. RESULTS: The majority of patients in our cohort had upper and/or lower extremity skin involvement, were immunosuppressed, and had generally favourable treatment outcomes. All tested M. haemophilum isolates were susceptible in vitro to clarithromycin and trimethoprim-sulfamethoxazole. Moreover, high rates of susceptibility were noted for ciprofloxacin (95%), linezolid (90%), and rifampin (85%). IRIS was identified in 31% of cases and should be considered in patients who develop worsening skin lesions or systemic symptoms following the initiation of effective antimicrobial therapy. Visualisation of acid-fast bacilli on initial tissue stains, a positive mycobacterial blood culture, and rapid de-escalation of tumour necrosis factor-α inhibitors and/or corticosteroids were more frequently encountered among patients in our cohort who developed IRIS. CONCLUSION: M. haemophilum infection should be considered among patients receiving immunomodulatory therapy who develop discoloured or nodular skin lesions involving the extremities, worsening focal arthritis, tenosynovitis, or isolated adenopathy. A heightened awareness of this pathogen's clinical and laboratory characteristics can lead to a timely diagnosis and favourable outcome.

Toto, we're not in Kansas anymore: First reported case of M. persicum septic arthritis.

In this report, we describe a case of septic arthritis caused by the newly described Mycobacterium persicum (formerly Mycobacterium kansasii complex). The patient's only significant exposure was home gardening. To our knowledge, this represents the first documented case of M. persicum infection in the United States and first septic arthritis.

Description, validation, and review of a decade of experience with a laboratory-developed PCR test for detection of Mycobacterium tuberculosis complex in pulmonary and extrapulmonary specimens.

Rapid detection of Mycobacterium tuberculosis complex directly from clinical specimens is critical for patient care. Mycobacterial culture requires days to weeks for results and therefore many laboratories employ rapid molecular methods for the diagnosis of tuberculosis. There are two FDA-cleared molecular assays for the detection of M. tuberculosis complex in the United States and both are cleared for testing of respiratory specimens only. The detection of M. tuberculosis complex in extrapulmonary specimens is often done using laboratory-developed PCR methods. In this work, the verification and subsequent validation of test performance over a decade is detailed for a laboratory-developed PCR assay (MTBRP) that detects M. tuberculosis complex from respiratory and non-respiratory specimens. The assay also provides information about potential isoniazid resistance. The performance of the MTBRP PCR assay was compared to the Cepheid Xpert MTB/RIF assay in acid-fast smear positive and smear negative specimens and mycobacterial culture for acid-fast smear positive specimens. The MTBRP assay demonstrated 99% correlation with the Xpert MTB/RIF assay using 499 respiratory specimens. The performance of the MTBRP PCR assay compared with mycobacterial culture for 867 AFB smear positive respiratory and non-respiratory specimens demonstrated a sensitivity of 100% and a specificity of 99.1%. This work provides longitudinal evidence using real-world clinical laboratory conditions and specimens to demonstrate that laboratory-developed PCR assays such as the MTBRP can provide a rapid and sensitive method for detection of pulmonary and extra-pulmonary tuberculosis from a wide-variety of smear positive specimen sources.

Targeted Metagenomic Sequencing-based Approach Applied to 2146 Tissue and Body Fluid Samples in Routine Clinical Practice.

BACKGROUND: The yield of next-generation sequencing (NGS) added to a Sanger sequencing-based 16S ribosomal RNA (rRNA) gene polymerase chain reaction (PCR) assay was evaluated in clinical practice for diagnosis of bacterial infection. METHODS: PCR targeting the V1 to V3 regions of the 16S rRNA gene was performed, with amplified DNA submitted to Sanger sequencing and/or NGS (Illumina MiSeq) or reported as negative, depending on the cycle threshold value. A total of 2146 normally sterile tissues or body fluids were tested between August 2020 and March 2021. Clinical sensitivity was assessed in 579 patients from whom clinical data were available. RESULTS: Compared with Sanger sequencing alone (400 positive tests), positivity increased by 87% by adding NGS (347 added positive tests). Clinical sensitivity of the assay that incorporated NGS was 53%, which was higher than culture (42%, P < .001), with an impact on clinical decision-making in 14% of infected cases. Clinical sensitivity in the subgroup that received antibiotics at sampling was 41% for culture and 63% for the sequencing assay (P < .001). CONCLUSIONS: Adding NGS to Sanger sequencing of the PCR-amplified 16S rRNA gene substantially improved test positivity. In the patient population studied, the assay was more sensitive than culture, especially in patients who had received antibiotic therapy.

Cardiovascular device infections due to rapidly growing Mycobacteria: A review of cases at a tertiary care hospital.

Cardiovascular device infection due to rapidly growing mycobacteria (RGM) is rarely encountered in clinical practice. Due to the increasing number of indications and use of cardiovascular devices in an aging population, optimized management of these infections is of great importance. We report seven cases of RGM cardiovascular device infection. Three patients had left-ventricular assist device (LVAD) infections; two patients had cardiovascular implantable device (CIED) infections; and one had an aortic vascular stent infection. Specific cardiac valvular infection was not detected among any of the patients. All patients had a high number of comorbidities which limited some patients from receiving optimal combination antimicrobial therapy. The prognosis of cardiovascular device infections with RGM is guarded with only four patients still alive; however, the treatment approach for each patient varied considerably and often based on concurrent medical conditions, overall adjustments to goals of care, and specific patient preferences. Further analysis of cardiovascular device infections with RGM is warranted to establish a more systematic approach in successful management.

Fungal and mycobacterial cultures should not be routinely obtained for diagnostic work-up of patients with suspected periprosthetic joint infections.

AIMS: Fungal and mycobacterial periprosthetic joint infections (PJI) are rare events. Clinicians are wary of missing these diagnoses, often leading to the routine ordering of fungal and mycobacterial cultures on periprosthetic specimens. Our goal was to examine the utility of these cultures and explore a modern bacterial culture technique using bacterial blood culture bottles (BCBs) as an alternative. METHODS: We performed a retrospective review of patients diagnosed with hip or knee PJI between 1 January 2010 and 31 December 2019, at the Mayo Clinic in Rochester, Minnesota, USA. We included patients aged 18 years or older who had fungal, mycobacterial, or both cultures performed together with bacterial cultures. Cases with positive fungal or mycobacterial cultures were reviewed using the electronic medical record to classify the microbiological findings as representing true infection or not. RESULTS: There were 2,067 episodes of PJI diagnosed within the study period. A total of 3,629 fungal cultures and 2,923 mycobacterial cultures were performed, with at least one of these performed in 56% of episodes (n = 1,157). Test positivity rates of fungal and mycobacterial cultures were 5% (n = 179) and 1.2% (n = 34), respectively. After a comprehensive review, there were 40 true fungal and eight true mycobacterial PJIs. BCB were 90% sensitive in diagnosing true fungal PJI and 100% sensitive in detecting rapidly growing mycobacteria (RGM). Fungal stains were performed in 27 true fungal PJI but were only positive in four episodes (14.8% sensitivity). None of the mycobacterial stains was positive. CONCLUSION: Routine fungal and mycobacterial stains and cultures should not be performed as they have little clinical utility in the diagnosis of PJI and are associated with significant costs. Candida species and RGM are readily recovered using BCB. More research is needed to predict rare non-Candida fungal and slowly growing mycobacterial PJI that warrant specialized cultures. Cite this article: Bone Joint J 2022;104-B(1):53-58.