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Purpose of review Recently, fungal meningitis outbreaks have occurred in association with neuraxial and epidural anesthesia in immunocompetent patients. Herein, we describe the course of those outbreaks, their diagnosis, treatment, prognosis, and lessons learned. Recent findings Two outbreaks of Fusarium solani meningitis during 2022–2023 were associated with epidural anesthesia in two distant cities in Mexico (Durango and Matamoros). The initial etiological agent identification was delayed due to insensitivity of cultures. A Fusarium solani qPCR was validated and positive in 38% cerebrospinal fluid (CSF) samples from Durango, while BD-Glucan allowed early diagnosis of the index case in Matamoros. Antifungal treatment with voriconazole and liposomal amphotericin B (L-AmB) was recommended. Overall mortality was 51%. Once the cause was confirmed, some patients received fosmanogepix. Summary Fungal meningitis outbreaks due to filamentous fungi are usually associated with direct epidural inoculation. They result in severe presentations and high mortality. Early diagnosis should be suspected, BD-Glucan CSF testing screening is recommended. Aggressive antifungal treatment based on antifungal susceptibility testing should be administered as early as possible. The advent of molecular diagnostic methods and new antifungal drugs may allow for timely diagnosis and treatment, increasing the chances of survival.

Purpose of review Given the high mortality and morbidity associated with invasive fungal diseases (IFDs), the use of combination antifungal therapies is often considered despite the dearth of data. This review aims to summarize the current state of literature of combination antifungal therapies, discussing the potential roles of newer antifungal combinations and key considerations for their clinical use. Recent findings In infections other than cryptococcal meningitis or in the setting of empirical treatment for suspected azole-resistant Aspergillus infections, the utility of the combination antifungal approaches remains controversial given the paucity of well designed randomized controlled trials. Data on potential combined antifungal treatments have been primarily limited to in-vitro studies, animal models, case reports and/or observational studies. With availability of novel antifungal agents (e.g. ibrexafungerp, fosmanogepix), combination therapy to treat mould infections should be re-visited. A phase 2 clinical trial of ibrexafungerp combined with voriconazole to treat invasive pulmonary aspergillosis is on-going. Summary There is a need to investigate the use of combination antifungal agents. This includes delineating the indication of these combined antifungal therapies and determining how to use them most appropriately in the clinical setting.

Purpose of review This review describes the current status of diagnosing invasive mould disease and Pneumocystis pneumonia using nonconventional diagnostics methods. Recent findings There has been significant development in the range of nonculture mycological tests. Lateral flow tests (LFTs) for diagnosing aspergillosis complement galactomannan ELISA testing, and LFTs for other fungal diseases are in development. Rapid and low through-put B-D-Glucan assays increase access to testing and there has been significant progress in the standardization/development of molecular tests. Despite this, no single perfect test exists and combining tests (e.g., antigen and molecular testing) is likely required for the optimal diagnosis of most fungal diseases. Summary Based on established clinical performance few mycological tests can be used alone for optimal diagnosis of fungal disease (FD) and combining tests, including classical approaches is the preferred route for confirming and excluding disease. Next-generation sequencing will likely play an increasing role in how we diagnose disease, but optimization, standardization and validation of the entire molecular process is needed and we must consider how host biomarkers can stratify risk. Given the burden of FD in low- and medium-income countries, improved access to novel but more so existing diagnostic testing is critical along with simplification of testing processes.

Purpose of review We review the clinical presentations of invasive fungal infections in a selection of inborn errors of immunity. In addition, we review the particularities of their management, including antifungal therapy, prophylaxis, and immunomodulatory treatments. Recent findings Patients with chronic granulomatous disease and with signal transducer and activator of transcription 3 (STAT3) deficiency are particularly prone to aspergillosis. Mold-active antifungal prophylaxis should be prescribed to all patients with chronic granulomatous disease, and in patients with STAT3 deficiency and underlying parenchymal lung disease. Invasive fungal infections are rare in patients with STAT1 gain-of-function mutations, while the clinical phenotype of caspase-associated recruitment domain-containing protein 9 deficiency encompasses a wide range of superficial and invasive fungal infections. Most patients with inborn errors of immunity and invasive fungal infections require prolonged durations of antifungals. Hematopoietic stem cell transplantation should be considered early for patients with chronic granulomatous disease, but results have been more mixed for other inborn errors of immunity with active invasive fungal infections. Summary Inborn errors of immunity can confer increased susceptibility to a variety of invasive fungal infections, which can present with specific clinical and radiological features. Management of fungal infections in these patients is often challenging, and relies on a combination of antimicrobial prophylaxis, antifungal treatments, and immunomodulation.

Purpose of review This review aims to highlight the multifaceted nature of brucellosis, emphasizing the latest advancements in its diagnosis and management. Given the global prevalence and potential complications of brucellosis, understanding recent advancements in diagnostic techniques and treatment strategies is crucial for clinicians. Recent findings Recent literature reveals significant progress in diagnostic methods, including the application of fluorescence polarization immunoassay and time-resolved fluorescence resonance energy transfer technologies as well as the invention of artificial Brucella antigens, which offer enhanced sensitivity and specificity. Advances in molecular diagnostics and serological tests have improved early detection rates, however their interpretation remains challenging. Evolving treatment regimens such as the use of hydroxychloroquine as part of triple therapy and the use of nano-delivery systems in therapies have shown promise, in hopes of reducing relapse rates and managing chronic cases. Summary The findings underscore the necessity for clinicians to adopt a comprehensive approach to diagnosing and managing brucellosis. Integrating advanced diagnostic tools with tailored therapeutic strategies can significantly improve patient outcomes. Future research should focus on optimizing these diagnostic techniques and exploring novel therapeutic agents.

Purpose of review We describe the epidemiology of the recent global surge in invasive group A streptococcal (GAS) disease and consider its proximate and distal causes. We highlight important knowledge gaps regarding clinical management and discuss potential strategies for prevention. Recent findings Rates of invasive GAS (iGAS) disease were increasing globally prior to the COVID-19 pandemic. Since mid-2022, following the worst years of the pandemic in 2020 and 2021, many countries with systems to monitor GAS syndromes have reported surges in cases of iGAS concurrent with increased scarlet fever, pharyngitis, and viral co-infections. The emergence of the hypervirulent M1UK strain as a cause of iGAS, particularly in high income countries, is concerning. New data are emerging on the transmission dynamics of GAS. GAS remains universally susceptible to penicillin but there are increasing reports of macrolide and lincosamide resistance, particularly in invasive isolates, with uncertain clinical consequences. Intravenous immunoglobulin is used widely for streptococcal toxic shock syndrome and necrotizing soft tissue infections, although there is limited clinical evidence, and none from a completed randomized controlled trial. Intensive and expensive efforts at population-level control of GAS infections and postinfectious autoimmune complications have been only partially successful. The great hope for control of GAS diseases remains vaccine development. However, all modern vaccine candidates remain in the early development stage. Summary In many countries, iGAS rates surged from mid-2022 in the aftermath of pandemic control measures and physical distancing. The emergence of a dominant hypervirulent strain is an important but incomplete explanation for this phenomenon. Clinical management of iGAS remains highly empirical and new data has not emerged. A vaccine remains the most likely means of achieving a sustainable reduction in the burden of iGAS.

Purpose of review Congenital cytomegalovirus infection (cCMV) is the leading infectious cause of sensorineural hearing loss and lifelong neurodevelopmental disabilities. Studies suggest antiviral therapy can prevent fetal infection after maternal primary infection, as well as halt the progression of hearing loss and neurodevelopmental disabilities in newborns with symptomatic cCMV. With growing worldwide momentum on early detection and diagnosis of cCMV, this review describes the exciting recent advances in antiviral therapies in CMV infected pregnant mothers and babies, as well as emerging evidence on anti-CMV vaccines. Recent findings New opportunities for prenatal and neonatal interventions have driven a rising interest in screening and identification of asymptomatic CMV infection. Routine screening of pregnant women to identify primary infection in first trimester is now advocated in Western Europe but has yet to be examined from a public health perspective in other regions. Evidence is emerging for maternal valaciclovir therapy to prevent fetal infection after a maternal primary CMV infection in the first trimester of pregnancy. For those infants who are born with symptomatic cCMV, a 6-month course of valganciclovir, started within the first 4 weeks of life, and possibly up to 13 weeks of life, is the current recommended therapy. However, there is unclear evidence for the benefit of treatment for asymptomatic cCMV and cCMV with isolated hearing loss. Research to identify more effective antivirals and an effective CMV vaccine continues. Summary More research is needed to determine the region-specific applicability of the new European recommendations for routine CMV screening in pregnancy. Areas of uncertainty in postnatal management include timing of initiation, duration of treatment and identifying pediatric subgroups that benefit from modification of the standard treatment recommendations.

Purpose of review The purpose of this review is to report the available evidence regarding the use of combination regimens of antivirals and/or antibody-based therapy in the treatment of SARS-CoV-2 in immunocompromised patients. Recent findings Literature search identified 24 articles, excluding single case reports, which included mainly patients with hematological malignancies and/or B-cell depletion. Data were divided based on the timing and reason for administration of combination treatment, that is, early treatment to prevent progression to severe COVID-19 and treatment of prolonged or relapsed infection. We described the treated populations, treatment duration and composition of combination treatment. We briefly addressed new treatment options and we proposed an algorithm for the management of COVID-19 infection in patients affected by hematological malignancies. Summary Combination treatment seems an effective (73–100%) and well tolerated (…

Purpose of review The aim of this study was to summarize the current knowledge of therapeutic options for mpox (formerly known as monkeypox) in the context of recent outbreaks and the ongoing evolution of the virus. Recent findings Multiple therapeutic agents, including tecovirimat, cidofovir, brincidofovir, and vaccinia immune globulin, have been used during the multicountry outbreak of mpox caused by Clade 2b monkeypox virus that began in 2022. Tecovirimat has been most extensively used, based on efficacy against mpox lethal challenge in animal models, and human safety data. Real-world observational evidence has further supported safety with minimal adverse events in large cohorts and mixed reports of reductions in time to lesion resolution. Several prospective randomized controlled trials using tecovirimat are underway with headline results from a study in the Democratic Republic of the Congo showing no difference in lesion resolution compared to placebo. Other studies including in outpatient settings are underway in Europe and the Americas. Cidofovir and brincidofovir, limited by adverse event profiles, have been less extensively studied. Vaccinia immune globulin has been used predominantly in salvage therapy for severe mpox, with no large observational series available. Summary The 2022 multicountry outbreak of mpox marked a public health emergency. Agents approved for smallpox management were widely used for mpox, supported by animal and in-vitro evidence, and human safety data. The large number of human cases has allowed retrospective observational study of these agents and facilitated recruitment in prospective trials. The ongoing evolution of the virus may pose challenges for therapeutic interventions, necessitating rigorous randomized controlled trials to guide clinical use.

Purpose of review Infections are the leading cause of non-relapse mortality following chimeric antigen receptor (CAR)-T-cell therapy, with viral infections being frequent both in the early and late phases post-infusion. We review the epidemiology of viral infections and discuss critical approaches to prevention and management strategies in this setting. Recent findings Herpesviruses dominate the early period. herpes simplex virus and varicella zoster virus infections are rare due to widespread antiviral prophylaxis, but cytomegalovirus (CMV) reactivation is increasingly observed, particularly in high-risk groups including B cell maturation antigen (BCMA)-CAR-T-cell therapy recipients and patients receiving corticosteroids. While CMV end-organ disease is rare, CMV is associated with increased mortality, emphasizing the need to evaluate the broader impact of CMV on long-term hematological, infection, and survival outcomes. Human herpesvirus-6 (HHV-6) has also emerged as a concern, with its diagnosis complicated by overlapping symptoms with neurotoxicity, underscoring the importance of considering viral encephalitis in differential diagnoses. Respiratory viruses are the most common late infections with a higher incidence after BCMA CAR-T-cell therapy. Vaccination remains a critical preventive measure against respiratory viruses but may be less immunogenic following CAR-T-cell therapy. The optimal timing, type of vaccine, and dosing schedule require further investigation. Summary A better understanding of viral epidemiology and preventive trials are needed to improve infection prevention practices and outcomes following CAR-T-cell therapies.

Purpose of review Cytomegalovirus (CMV) infection is associated with severe clinical disease and high morbidity in immunocompromised hosts. Letermovir and maribavir, are two recently developed antiviral drugs used in the prevention and treatment of resistant and refractory CMV. Following the publication of landmark randomized trials and increased use, both clinical trial data and real-world experience has reported the development of antiviral drug resistance. The aim of this review was to comprehensively review the published literature on letermovir and maribavir drug resistance and to describe the clinical scenarios in which they may emerge. Recent findings For letermovir, the most frequently detected resistance mutations occur in the UL56 gene (C325Y/W/F) and confer total resistance. Maribavir resistance mutations most often occur in the UL97 gene and resistance-associated variants (RAVs) T409M, H411Y, C480F have all been detected. The clinical context in which letermovir and maribavir resistance occurs include high viral loads at initiation, intensified immunosuppression, subtherapeutic drug exposure because of poor adherence, drug interactions, and inadequate central nervous system (CNS) penetration. Emergence of resistance mutations generally occurs within the first 3 months of initiation. Summary The detection of letermovir and maribavir resistance mutations highlights an ongoing clinical challenge in the management of CMV.

Purpose of review Infections caused by multidrug-resistant Acinetobacter baumannii present a significant global health challenge. Available treatment options are limited and frequently constrained by unfavourable safety and pharmacokinetic profiles. Sulbactam-durlobactam is a novel β-lactamase inhibitors combination specifically developed to target A. baumannii, including carbapenem-resistant strains. The purpose of this review is to assess the current evidence supporting the role of sulbactam-durlobactam in the management of A. baumannii infections. Recent findings We summarize the available evidence regarding the pharmacokinetic and pharmacodynamic profiles of sulbactam-durlobactam from key in-vitro and in-vivo studies. Additionally, efficacy results from the Phase III randomized controlled trial and real-world data on sulbactam-durlobactam\'s use against severe A. baumannii infections are also discussed. Summary Sulbactam-durlobactam is a promising addition to the treatment options for carbapenem-resistant A. baumannii infections. Ongoing research and vigilance are essential to monitor the development of in-vivo resistance, assess effectiveness across diverse patient populations, and explore potential synergistic combinations with other antimicrobials. Careful stewardship and comprehensive clinician education will be crucial to optimizing the clinical use of sulbactam-durlobactam.

Purpose of review To discuss the therapeutic options available for the management of difficult-to-treat strains of Stenotrophomonas maltophilia (Sma), namely those resistant to trimethoprim-sulfamethoxazole and fluoroquinolones. Recent findings Recent pharmacological studies have highlighted the fact that current breakpoints for first-line antibiotics against Sma are too high. In light of these data, it is likely that the prevalence of difficult-to-treat (DTR) Sma is underestimated worldwide. Two promising alternatives for treating DTR strains are cefiderocol and the combination of aztreonam and an L2 inhibitor. However, clinical trials are currently very limited for these antibiotics and no comparative studies have been carried out to date. It is important to note that the clinical efficacy of cefiderocol appears to be inferior to that initially anticipated from in-vitro and animal studies. Consequently, minocycline and ceftazidime may remain viable options if they are used against strains with a low minimum inhibitory concentration. We advise against the use of intravenous polymyxins and tigecycline. Finally, recent literature does not support the systematic use of combination therapy or long-course treatments. In the coming years, phage therapy may become a promising approach against DTR Sma infections. Summary Overall, clinical comparative studies focused on DTR strains are required in order to provide more accurate and actionable information for therapeutic decisions.

Purpose of review We aim to review the rationale, methods, and experiences with diagnostic stewardship targeted at urinary tract infection (UTI) and related urinary syndromes. Recent findings In the last 18 months, several articles have demonstrated the impact of diagnostic stewardship interventions at limiting inappropriate diagnosis of UTIs or inappropriate antibiotic-prescribing, targeting the urinary tract. Antimicrobial stewardship programs may create and implement interventions at the point of urine test ordering, urine test resulting, or at the point of prescribing antibiotics after results have returned. Specific design and implementation of stewardship interventions depends on context. To maximize their impact, interventions should be accompanied by education and garner buy-in from providers. Summary Diagnostic stewardship can decrease unnecessary antibiotics and inappropriate diagnosis of UTI with multifaceted interventions most likely to be effective. Remaining questions include how to reduce ASB treatment in new populations, such as those with immune compromise, and persistent unknowns regarding UTI diagnosis and diagnostics.

Purpose of review Infections caused by nonprimarily pathogenic Gram-negative bacilli (GNB) have been increasingly reported from the second half of the 20th century to the present. This phenomenon has expanded during the antibiotic era and in the presence of immunodeficiency. Before the discovery of sulphonamides and penicillin G, infections caused by GNB were rare compared to Gram-positive infections. The advent of anticancer therapy, the expansion of surgical procedures, the use of corticosteroids, and the implantation of prosthetic materials, along with better control of Gram-positive infections, have promoted the current increase in GNB infections. GNB have similar antimicrobial targets to Gram-positive bacteria. However, only antibiotics that can penetrate the double membrane of GNB and remain in them for a sufficient duration have antibacterial activity against them. Recent findings Sulphonamides and early penicillins had limited activity against GNB. Ampicillin and subsequent beta-lactams expanded their spectrum to treat GNB. Aminoglycosides may re-surge with less toxic drugs, as highly resistant to beta-lactams GNB rise. Polymyxins, tetracyclines, and fluoroquinolones are also used for GNB. Combinations with other agents may be needed in specific cases, such as in the central nervous system and prostate, where beta-lactams may have difficulty reaching the infection site. Alternatives to current treatments must be sought in the discovery of new drug families and therapies such as phage therapy combined with antibiotics. Summary Narrower-spectrum immunosuppressive therapies and antibiotics, antimicrobials that minimally intervene with the human microbiota, and instant diagnostic methods are necessary to imagine a future where currently dominant bacteria in infectious pathology lose their preeminence.

Purpose of review To discuss novel antibiotics under clinical development, focusing on agents showing in-vitro activity against metallo-β-lactamases (MBL)-producing carbapenem-resistant Gram-negative bacteria (CR-GNB). Recent findings Currently, only a few approved agents show activity, alone or in synergistic combinations, against MBL-producing CR-GNB. If approved by regulatory agencies in case of favorable results from ongoing (and, for some agents, already completed) phase-3 studies, some novel β-lactam/β-lactamase inhibitor (BL/BLI) combinations could become available in the next few years as additional important options for treating MBL-producing CR-GNB infections. Additional interesting agents that belong both to BL/BLI combinations and to antibiotic classes other than BL and BL/BLI combinations have also shown activity against MBL-producing CR-GNB, with most of them being in early phases of clinical development. Summary Improving the use of these novel agents through virtuous antimicrobial stewardship frameworks able to guarantee both the efficacious treatment of infections requiring their use and the avoidance of their use whenever not necessary remains a challenge of utmost importance that should not be overlooked.

Purpose of review Culturing preservation fluids of solid organs before transplantation is not a standardized procedure. In this review, we aim to describe the state-of-the-art of literature evidence in this debated setting with a special focus on Gram-negative bacteria (GNB). Recent findings Contamination of preservation fluids is frequent, but preservation fluids related infections are rare and most commonly caused by high-risk pathogens, including GNB. GNB preservation fluids related infections are characterized by high morbidity and mortality. Recent studies showed improved outcomes in solid organ transplant recipients receiving antibiotic therapy tailored according to preservation fluids cultures especially when multidrug-resistant GNB are found. A robust procurement network is needed to alert recipients’ centers in cases of positivity and the support of transplant infectious diseases specialists is essential to choose the best therapy. Summary Culturing preservation fluids is a further step into preventing donor-derived infections. Interpreting and managing GNB positivity require a multidisciplinary team with specific skills. Standardized randomized trials are needed for insight into the real utility of preservation fluids cultures, the role of preservation fluids positivity, and the impact of antimicrobial therapy.

Purpose of review To correlate the resistance mechanisms and the susceptibility to new antibiotics in Pseudomonas aeruginosa. Recent findings Definition of antibiotic resistance in Pseudomonas aeruginosa is still debated. Carbapenem-resistant Pseudomonas aeruginosa (CRPA) and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA) are used but which of them better correlate with the risk of mortality remains debated. Mechanisms underlying resistance in Pseudomonas aeruginosa are complex and may be combined, resulting in unpredictable phenotype and cross-resistance. Thus, not all CRPA are alike and tailoring antibiotic therapy on resistance mechanisms is challenging. Summary Current guidelines recommend the use of new antipseudomonal agents for CRPA or DTR-PA infections but they don’t provide specific information on how tailoring antibiotic therapy on underlying resistance mechanisms. This review may be useful to understand which mechanisms are involved in CRPA and may have practical implications helping clinicians to select an appropriate antibiotic regimen. Several antibiotics are now available for Pseudomonas aeruginosa but their rational use is important to avoid development of future resistance. The knowledge of local epidemiology and most common resistance mechanisms may guide empirical therapy, but targeted antibiotic therapy should be re-evaluated as soon as susceptibility testing profile is available and selected according to Pseudomonas aeruginosa phenotype.

Infection and Immunity, Ahead of Print.

Antimicrobial Agents and Chemotherapy, Ahead of Print.

Antimicrobial Agents and Chemotherapy, Ahead of Print.

Antimicrobial Agents and Chemotherapy, Ahead of Print.