Expert Review of Anti-infective Therapy最新文献

Introduction: Hepatitis B virus (HBV) affects hundreds of millions globally, with many cases stemming from perinatal transmission. Chronic hepatitis B (CHB) in children can progress to cirrhosis and hepatocellular carcinoma (HCC) in adulthood. Treatment options include interferons and nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs) such as tenofovir alafenamide (TAF).

Areas covered: This review covers the epidemiology of pediatric CHB and current treatments, with a focus on tenofovir-based therapies, particularly tenofovir disoproxil fumarate (TDF) and TAF. TDF has been used for years, but its risks of bone mineral density loss and renal impairment have raised concerns. TAF, with lower systemic exposure, appears to mitigate these risks. Ongoing trials are evaluating TAF's safety in younger children. There are knowledge gaps in long-term safety and the potential for combination therapies.

Expert opinion: TAF offers a safer alternative to TDF for children with CHB, showing high antiviral efficacy and fewer side effects. However, more data is needed on its use in younger children and long-term safety. The future of CHB treatment in pediatrics may include combination therapies and personalized approaches, potentially improving outcomes and minimizing risks over a lifetime of treatment. As research progresses, TAF is likely to become a cornerstone in pediatric CHB management.

Introduction: The rising prevalence of difficult-to-treat, deep-seated invasive fungal diseases (IFD) has led to high mortality. Currently available antifungal treatments, administered predominantly orally or intravenously, may not sufficiently penetrate certain body sites, and/or are associated with systemic toxicity. Little is known about how to position alternative administration approaches such as inhalational and direct drug delivery routes.

Areas covered: This review provides an updated overview of unconventional drug delivery strategies for managing IFD, focusing on inhalational (to target the lungs) and direct delivery methods to the central nervous system, bone/joint, and eyes. Novel compounds (e.g. opelconazole) and existing antifungals with innovative drug delivery systems currently undergoing clinical trials and/or used off-label in the clinical setting are discussed.

Expert opinion: For both inhalational agents and direct delivery approaches, there are similar challenges that include the absence of: approved formulations for specific administration routes, delivery vehicles that are simple and safe to use whilst maintaining potency and efficiency of delivery, animal models suitable for investigating pharmacokinetic/pharmacodynamic profiles of inhaled antifungals, and consensus on the composite endpoints and intervals for of follow-up in clinical trials. To meet these challenges, cooperation of all stakeholders in drug development and regulation is required.

Introduction: Patients with hematological malignancies (PHMs) are at increased risk for infections caused by carbapenem-resistant organisms (CROs) due to frequent exposure to broad-spectrum antibiotics and prolonged hospital stays. These infections result in high mortality and morbidity rates along with delays in chemotherapy, longer hospitalizations, and increased health care costs.

Areas covered: Treatment alternatives for CRO infections in PHMs.

Expert opinion: The best available treatment option for KPC and OXA-48 producers is ceftazidime/avibactam. Imipenem/cilastatin/relebactam and meropenem/vaborbactam remain as the alternative options. They can also be used as salvage therapy in KPC-positive Enterobacterales infections resistant to ceftazidime/avibactam, if in vitro susceptibility is shown. Treatment of metallo-β-lactamase producers is an unmet need. Ceftazidime/avibactam plus aztreonam or aztreonam/avibactam seems to be the most reliable option for metallo-β-lactamase producers. As a first-line option for carbapenem-resistant Pseudomonas aeruginosa infections, ceftolozane/tazobactam is preferable and ceftazidime/avibactam and imipenem/cilastatin/relebactam constitute alternative regimens. Although sulbactam/durlobactam is the most reliable option against carbapenem-resistant Acinetobacter baumannii infections, its utility as monotherapy and in PHMs is not yet known. Cefiderocol can be selected as a 'last-resort' option for CRO infections. New risk score models supported by artificial intelligence algorithms can be used to predict the exact risk of infections in previously colonized patients.

Background: We report results from the national CLEAR (Canadian Leadership on Antimicrobial Real-Life Usage) registry on the usage of ceftolozane/tazobactam in Canada from 2022 to 2024.

Research design and methods: The authors reviewed the final data using the national ethics approved CLEAR study. Thereafter, the literature is surveyed regarding the usage of ceftolozane/tazobactam to treat patients with HABP and VABP via PubMed (up to May 2024).

Results: Ceftolozane/tazobactam was primarily used as directed therapy to treat HABP and VABP caused by Pseudomonas aeruginosa. It was primarily used alone, or in combination with another agent, to treat resistant and multidrug-resistant (MDR) P. aeruginosa infections. Despite primarily being used to treat severely ill patients in intensive care units, its use was associated with relatively high microbiological/clinical cure rates, along with an excellent safety profile. Several reports attest to the microbiological/clinical efficacy and safety of using ceftolozane/tazobactam to treat HABP and VABP.

Conclusions: In Canada, ceftolozane/tazobactam is primarily used as directed therapy alone, or in combination, to treat MDR P. aeruginosa infections. Though mostly used to treat severely ill patients in the ICU, ceftolozane/tazobactam use in HABP and VABP is associated with relatively high microbiological/clinical cure rates and an excellent safety profile.

Introduction: Calcifications are the end stage of many parenchymal brain cysticerci and may occur either spontaneously or as the result of treatment with cysticidal drugs. These lesions, traditionally considered inert and asymptomatic, have been associated with several complications that seem to be mostly related to brain damage and inflammation ensuing as the result of the exposure of the host's immune system to parasitic antigens trapped within calcifications.

Areas covered: This review, based on the search of different electronic databases up to May 2024, focuses on the reported correlates and complications of calcified cysticerci (chronic headaches, seizures/epilepsy, hippocampal atrophy/sclerosis, gliomas), and the different interventions developed for their prevention and treatment. Common analgesics, non-steroidal anti-inflammatory drugs, corticosteroids, and antiseizure medications have been used with success but, with the exception of the latter, these drugs offer temporary relief of symptoms and support for their use is based on level 3 evidence.

Expert opinion: Several strategies may reduce the severity of clinical consequences of calcified cysticerci. Probably, the most relevant intervention would be the prevention of their occurrence or reduction in their size. In this view, the use of bisphosphonates appears as a potential option that needs to be tested in humans.

Introduction: The management of critically ill septic patients presents considerable challenges due to multifaceted physiological alterations. Rapid changes such as fluid shifts, hyperdynamic states, and altered renal clearance often require special attention for better clinical outcomes. Vital organ dysfunction, with or without MODS, often necessitates supportive management like RRT, ventilatory support, and ECMO. These interventions can significantly affect the PK/PD of administered antimicrobials, complicating effective treatment.

Area covered: Patient-specific parameters such as age, weight, and comorbid illnesses (e.g. cystic fibrosis, burns, and immunocompromised states) are critical determinants of antimicrobial pharmacokinetics. Understanding PK/PD determinants is crucial for developing optimized dosing regimens that enhance therapeutic efficacy and minimize toxicity in critically ill patients.

Expert opinion: Incorporating pharmacometrics approaches in dose optimization can significantly improve patient outcomes. This review focuses on the nuances of PK/PD for optimized antimicrobial dosing in critically ill septic patients, emphasizing the importance of individualized treatment plans to address the complex and dynamic needs of this patient population. The adoption of these advanced pharmacokinetic and pharmacodynamic principles into clinical practice is essential for advancing patient care and optimizing therapeutic outcomes in critically ill patients.

Introduction: Griseofulvin, discovered in 1939 and commercially available since 1959, was the first oral antifungal agent effective against dermatophytosis, particularly tinea capitis. Although it was eventually superseded by azole antifungals due to its long treatment duration and reliance on keratopoiesis, griseofulvin remains notable for its effectiveness and safety in treating tinea capitis, especially when caused by Microsporum canis. However, due to a decline in cases and commercial unavailability, alternative treatments are now required.

Areas covered: The following topics regarding to other treatments were discussed: (I) The efficacy of alternative antifungal agents such as terbinafine, itraconazole, and fluconazole, in the treatment of tinea capitis. (II) The use and role of topical therapies. (III) Experience in the management of tinea capitis.

Expert opinion: The usefulness of oral terbinafine as a replacement for griseofulvin in the treatment of tinea capitis and why it is the preferred drug in elderly patients was discussed. Challenges with Microsporum spp. and the use of fluconazole in pediatric patients were also analyzed. Support for the use of topical treatment as an adjunctive treatment for tinea capitis was highlighted.

Introduction: Lower respiratory tract infections (LRTI) remain a significant global cause of mortality and disability. Viruses constitute a substantial proportion of LRTI cases, with their pandemic potential posing a latent threat. After the SARS-CoV-2 pandemic, the resurgence of other respiratory viruses, including Influenza and Respiratory Syncytial Virus responsible for LRTI has been observed especially in susceptible populations.

Areas covered: This review details the inflammatory mechanisms associated with three primary respiratory viruses: SARS-CoV-2, Influenza, and Respiratory Syncytial Virus (RSV). The focus will be on elucidating the activation of inflammatory pathways, understanding cellular contributions to inflammation, exploring the role of interferon and induced cell death in the response to these pathogens and detailing viral evasion mechanisms. Furthermore, the distinctive characteristics of each virus will be explained.

Expert opinion: The study of viral pneumonia, notably concerning SARS-CoV-2, Influenza, and RSV, offers critical insights into infectious and inflammatory mechanisms with wide-ranging implications. Addressing current limitations, such as diagnostic accuracy and understanding host-virus interactions, requires collaborative efforts and investment in technology. Future research holds promise for uncovering novel therapeutic targets, exploring host microbiome roles, and addressing long-term sequelae. Integrating advances in molecular biology and technology will shape the evolving landscape of viral pneumonia research, potentially enhancing global public health outcomes.

Introduction: The rise in antibiotic resistance to N. gonorrhoeae poses a substantial threat to effective gonorrhea treatment. Historical progression of resistance from sulfonamides to the more recent declines in efficacy of fluoroquinolones and susceptibilities of ceftriaxone highlight the urgent need for novel therapeutic approaches, necessitating the examination of alternative and new antibiotics.

Areas covered: This review examines the potential of repurposing older antibiotics for gonorrhea treatment with a focus on their efficacy and limitations. These include aztreonam, ertapenem, and fosfomycin. New oral drugs zoliflodacin and gepotidacin are in late clinical development, but there are concerns regarding their effectiveness for extragenital infections and the development of resistance.

Expert opinion: While ceftriaxone remains the best treatment for gonorrhea across all anatomic sites, resistance may eventually limit its use. Among older antibiotics, ertapenem shows the most potential as an alternative but shares the same administrative drawbacks as ceftriaxone. New oral drugs zoliflodacin and gepotidacin initially appeared promising, but their efficacy for pharyngeal infections and potential for resistance development are concerning. Phase 3 trial results have not been made available except through press releases, which perpetuates concerns. Understanding pharmacokinetic and pharmacodynamic profiles of antibiotics will be key in optimizing future treatment recommendations.