Anaerobic resistance: should we be worried? Purpose of review Anaerobic bacteria are implicated in a broad range of infections and can cause significant morbidity and mortality. As such, development of antimicrobial resistance (AMR) increases the risk of worse clinical outcomes and death. Recent findings Anaerobe AMR is highly variable according to region and species included in the survey. The overall trend is to increasing resistance, particularly in Europe and Asia, and in the Bacteroides fragilis group and Clostridium sp. Conversely, with the decline in RT027, resistance in Clostridiodes difficile is decreasing. Resistance to moxifloxacin and clindamycin has reached 30–50%, whereas prevalence of metronidazole and carbapenem resistance is generally low. Infections due to multidrug anaerobes have been increasingly reported, with clinical studies demonstrating adverse clinical outcomes, including higher mortality, with anaerobic resistance or inappropriate therapy. The role of antimicrobial stewardship in the setting of increasing anaerobe resistance is yet to be fully elucidated. Summary These findings highlight the importance of continuous surveillance in monitoring emerging trends in anaerobe AMR. Mean inhibitory concentrations should be reported due to variable susceptibility breakpoints and for detection of isolates with reduced susceptibility. At a local level, the clinical microbiology laboratory has a key role in identifying and undertaking susceptibility testing to inform individual patient management, develop local antibiograms and liaise with antimicrobial stewardship teams. A greater understanding of the clinical impact of anaerobic resistance and the role of antimicrobial stewardship in preventing resistance is required.

Primary immunodeficiencies and invasive fungal infection: when to suspect and how to diagnose and manage Purpose of review Invasive fungal infections (IFIs) most often occur secondary to acquired immunodeficiency states such as transplantation, AIDS or immune-modulatory treatment for neoplastic and autoimmune disorders. Apart from these acquired conditions, several primary immunodeficiency disorders (PIDs) can present with IFIs in the absence of iatrogenic immunosuppression. This review highlights recent advances in our understanding of PIDs that cause IFIs, which may help clinicians in the diagnosis and management of such infections. Recent findings A growing number of PIDs that cause varying combinations of invasive infections by commensal Candida, inhaled molds (primarily Aspergillus), Cryptococcus, Pneumocystis, endemic dimorphic fungi, dermatophytes, and/or agents of phaeohyphomycosis has uncovered the organ- and fungus-specific requirements for effective antifungal host defense in humans. Employing certain diagnostic algorithms tailored to the infecting fungus can facilitate the genetic diagnosis of the underlying PID, which has implications for the optimal management of affected patients. Summary Heightened clinical suspicion is required for the diagnosis of underlying genetic defects in patients who develop IFIs in the absence of acquired immunodeficiency. Early initiation of antifungal therapy followed by long-term secondary prophylaxis is typically needed to achieve remission, but hematopoietic stem-cell transplantation may sometimes be necessary to promote immune restoration and infection control.

Azole antifungals and new targeted therapies for hematological malignancy Purpose of review With the introduction of new targeted therapies for hematological malignancies comes the challenges of both assessing the risk of developing an IFD while being treated with these agents, as well as managing the drug--drug interactions between azole antifungals and the agents. Recent findings New targeted therapies for hematological malignancy include chimeric antigen receptor T cells (CAR T cells), Bi-specific T-cell Engager (BiTE) blinatumomab, and the antibody–drug conjugate (ADC) of calicheamicin inotuzumab ozogamicin for acute lymphoblasic leukemia (ALL) and lymphoma; the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and phosphatidylinositol 3-kinase (PI3Kδ) inhibitor idelalisib for lymphoma and graft-versus-host disease (GVHD); FMS-like tyrosine kinase 3 (FLT3) inhibitors, such as midostaurin, sorafenib and gilteritinib for acute myeloid leukemia (AML); and the BCL-2 inhibitor venetoclax for a range of hematological malignancies including lymphoma and leukemia. This review summarizes recommendations for IFD prophylaxis using these therapies and evidence for managing concomitant azole administration. Summary Whilst some evidence exists to guide IFD prophylaxis using new targeted therapies for hematological malignancies, there is an overall lack of descriptive, robust studies specifically describing IFD risk and management. With the emergence of novel agents, clinical judgment must be used to assess the risk of developing an IFD. Care must also be taken when administering azoles with drug--drug interactions, often requiring dose adjustment of the cancer therapies.

Rapid diagnosis of invasive candidiasis: ready for prime-time? Purpose of review We review the performance of culture-independent diagnostic tests (CIDTs), including β-D-glucan (BDG), polymerase chain reaction (PCR) and T2Candida, in diagnosing invasive candidiasis, their potential roles in patient management, and unintended consequences of testing. Recent findings In a recent multicenter trial, T2Candida was 90% sensitive and 98% specific for diagnosing candidemia. A new study provided the first data for T2Candida in diagnosing deep-seated candidiasis, demonstrating sensitivity/specificity of 45%/96%. Two studies showed that ongoing T2Candida-positivity is associated with poor prognosis. In several studies, serum BDG and T2Candida, targeted to patients at-risk for invasive candidiasis, were useful in guiding treatment decisions and antifungal stewardship. A randomized, multicenter trial of BDG-guided empiric antifungal treatment is underway among critically ill patients. PCR performance was highly variable for candidemia and deep-seated candidiasis in recent studies. CIDT results may overstate bloodstream infections, according to current National Healthcare Safety Network (NHSN) definitions. Summary BDG and T2Candida are nearing prime-time status in the clinic. To be useful, testing must be directed to carefully chosen patients and specific clinical questions. Candida PCR is limited by a need for standardized methodologies and commercial assays. NHSN definitions of bloodstream infections must be revised in the era of CIDTs.

Antibiotics and adverse events: the role of antimicrobial stewardship programs in ‘doing no harm’ Purpose of review Antimicrobial resistance (AMR) is a global threat worldwide, with deaths associated with AMR infections projected to exceed 10 million per year by the year 2050. The overuse and misuse of antibiotics is the primary driver of this resistance, with up to 50% of antibiotics prescribed in the hospital setting being either unnecessary or inappropriate. Antimicrobial stewardship (AMS) programs (ASPs) can mitigate some of this resistance, with the benefits well recognized; however, if we are to truly advance the state of AMS, the principles and practices should align with patient safety. Recent findings In a recent evaluation, among 1488 adult patients receiving systemic antibiotic therapy, 298 (20%) experienced at least one antibiotic-associated adverse drug event (ADE). Fifty-six (20%) nonclinically indicated antibiotic regimens were associated with an ADE. It is also well recognized that besides ADEs, the inappropriate use of antibiotics is associated the development of multidrug-resistant infections and Clostridium difficile infection. Summary Currently, there is a significant gap in ASPs correlating initiatives with patient safety goals, including reductions in antibiotic-associated ADEs and multidrug-resistant infections. Therefore, in this article, we provide the rationale for why ASPs are best suited to lead a collaborative effort to prevent antibiotic-associated ADEs and multidrug-resistant infections.

Candida auris: what have we learned so far? Purpose of review The increasing prevalence of fungal infections due to Candida species has been well described in critically ill patient populations, but in recent years a new species, Candida auris has received attention from the medical community worldwide. We aim to summarize the current knowledge related to C. auris, as new identification techniques, novel antifungal agents and more experience with outbreak management have been published in the past few years. Recent findings C. auris has been described in several countries, arising independently in separate clades. Its resistance to multiple antifungals and persistent colonization of patients and medical surfaces have become a therapeutic and infection control challenge. Recent elucidation of some of the molecular mechanisms related to pathogenicity and studies of in-vitro efficacy of novel antifungal agents can better guide therapy. Summary As C. auris continues to cause outbreaks worldwide, newer, and more efficient identification techniques, novel antifungals, and more knowledge in effective infection control techniques will allow better clinical outcomes in the management and control of invasive fungal disease.

Resistant or refractory cytomegalovirus infections after hematopoietic cell transplantation: diagnosis and management Purpose of review Refractory or resistant cytomegalovirus (CMV) infections are challenging complications after hematopoietic cell transplantation (HCT). Most refractory or resistant CMV infections are associated with poor outcomes and increased mortality. Prompt recognition of resistant or refractory CMV infections, understanding the resistance pathways, and the treatment options in HCT recipients are imperative. Recent findings New definitions for refractory and resistant CMV infections in HCT recipients have been introduced for future clinical trials. Interestingly, refractory CMV infections are more commonly encountered in HCT recipients when compared with resistant CMV infections. CMV terminase complex mutations in UL56, UL89, and UL51 could be associated with letermovir resistance; specific mutations in UL56 are the most commonly encountered in clinical practice. Finally, brincidofovir, maribavir, letermovir, and CMV-specific cytotoxic T-cell therapy expanded our treatment options for refractory or resistant CMV infections. Summary Many advances have been made to optimize future clinical trials for management of refractory or resistant CMV infections, and to better understand new resistance mechanisms to novel drugs. New drugs or strategies with limited toxicities are needed to improve outcomes of difficult to treat CMV infections in HCT recipients.

BK polyomavirus-specific antibody and T-cell responses in kidney transplantation: update Purpose of review BK polyomavirus (BKPyV) has emerged as a significant cause of premature graft failure after kidney transplantation. Without effective antiviral drugs, treatment is based on reducing immunosuppression to regain immune control over BKPyV replication. The paradigm of high-level viruria/decoy cells, BKPyV-DNAemia, and proven nephropathy permits early interventions. Here, we review recent findings about BKPyV-specific antibody and T-cell responses and their potential role in risk stratification, immune monitoring, and therapy. Recent finding Kidney transplant recipients having low or undetectable BKPyV-specific IgG immunoglobulin G (IgG) are higher risk for developing BKPyV-DNAemia if the donor has high BKPyV-specific IgG. This observation has been extended to neutralizing antibodies. Immunosuppression, impaired activation, proliferation, and exhaustion of BKPyV-specific T cells may increase the risk of developing BKPyV-DNAemia and nephropathy. Clearance of BKPyV-DNAemia was correlated with high CD8 T cell responses to human leukocyte antigen (HLA)-types presenting BKPyV-encoded immunodominant 9mers. For clinical translation, these data need to be assessed in appropriately designed clinical studies, as outlined in recent guidelines on BKPyV in kidney transplantation. Summary Evaluation of BKPyV-specific immune responses in recipient and donor may help to stratify the risk of BKPyV-DNAemia, nephropathy, and graft loss. Future efforts need to evaluate clinical translation, vaccines, and immunotherapy to control BKPyV replication.

Human herpesvirus 6 in transplant recipients: an update on diagnostic and treatment strategies Purpose of review The current review article focuses on recent advances in the approach to the diagnosis and treatment of human herpesvirus 6B (HHV-6B) in hematopoietic cell and solid organ transplant recipients. Recent findings Over the past few years, key studies have broadened our understanding of best practices for the prevention and treatment of HHV-6B encephalitis after transplantation. Moreover, important data have been reported that support a potential role of HHV-6B reactivation in the development of acute graft-versus-host disease and lower respiratory tract disease in transplant recipients. Finally, increasing recognition of inherited chromosomally integrated HHV-6 (iciHHV-6) and an expanding array of diagnostic tools have increased our understanding of the potential for complications related to viral reactivation originating from iciHHV-6 in donors or recipients. Summary Recent advances in diagnostic tools, disease associations, and potential treatments for HHV-6B present abundant opportunities for improving our understanding and management of this complex virus in transplant recipients.