SUMMARYDespite the early recognition of their therapeutic potential and the current escalation of multidrug-resistant (MDR) pathogens, the adoption of bacteriophages into mainstream clinical practice is hindered by unfamiliarity with their basic pharmacokinetic (PK) and pharmacodynamic (PD) properties, among others. Given the self-replicative nature of bacteriophages in the presence of host bacteria, the adsorption rate, and the clearance by the host\'s immunity, their PK/PD characteristics cannot be estimated by conventional approaches, and thus, the introduction of new considerations is required. Furthermore, the multitude of different bacteriophage types, preparations, and treatment schedules impedes drawing general conclusions on their in vivo PK/PD features. Additionally, the drawback of acquired bacteriophage resistance of MDR pathogens with clinical and environmental implications should be taken into consideration. Here, we provide an overview of the current state of the field of PK and PD of bacteriophage therapy with a focus on its application against MDR Gram-negative infections, highlighting the potential knowledge gaps and the challenges in translation from the bench to the bedside. After reviewing the in vitro PKs and PDs of bacteriophages against the four major MDR Gram-negative pathogens, Klebsiella pneumoniae, Acinetobacter baumannii complex, Pseudomonas aeruginosa, and Escherichia coli, specific data on in vivo PKs (tissue distribution, route of administration, and basic PK parameters in animals and humans) and PDs (survival and reduction of bacterial burden in relation to the route of administration, timing of therapy, dosing regimens, and resistance) are summarized. Currently available data merit close scrutiny, and optimization of bacteriophage therapy in the context of a better understanding of the underlying PK/PD principles is urgent to improve its therapeutic effect and to minimize the occurrence of bacteriophage resistance.

BACKGROUND: Novel beta-lactams show activity against many multidrug-resistant Gram-negative bacteria that cause severe lung infections. Understanding pharmacokinetic/pharmacodynamic characteristics of these agents may help optimise outcomes in the treatment of pneumonia.
OBJECTIVE: To describe and appraise studies that report pulmonary pharmacokinetic and pharmacodynamic data of cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam and meropenem/vaborbactam.
METHODS: MEDLINE (PubMed), Embase, Web of Science and Scopus libraries were used for the literature search. Pulmonary population pharmacokinetic and pharmacokinetic/pharmacodynamic studies on adult patients receiving cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, and meropenem/vaborbactam published in peer-reviewed journals were included. Two independent authors screened, reviewed and extracted data from included articles. A reporting guideline for clinical pharmacokinetic studies (ClinPK statement) was used for bias assessment. Relevant outcomes were included, such as population pharmacokinetic parameters and probability of target attainment of dosing regimens.
RESULTS: Twenty-four articles were included. There was heterogeneity in study methods and reporting of results, with diversity across studies in adhering to the ClinPK statement checklist. Ceftolozane/tazobactam was the most studied agent. Only two studies collected epithelial lining fluid samples from patients with pneumonia. All the other phase I studies enrolled healthy subjects. Significant population heterogeneity was evident among available population pharmacokinetic models. Probabilities of target attainment rates above 90% using current licensed dosing regiments were reported in most studies.
CONCLUSIONS: Although lung pharmacokinetics was rarely described, this review observed high target attainment using plasma pharmacokinetic data for all novel beta-lactams. Future studies should describe lung pharmacokinetics in patient populations at risk of carbapenem-resistant pathogen infections.

Enterococci spp. are Gram-positive bacteria that cause mild to severe infections, many associated with the oral cavity, such as periapical infections and healthcare-associated infections (HAIs). Many of these infections become serious diseases that are difficult to resolve, specifically when multidrug-resistant (MDR) strains cause them. In recent years, the number of MDR strains of Enterococcus spp. has increased significantly. This increased prevalence of MDR strains produces significant pressure to generate more antimicrobial therapies, but there is a decline in the production of new antibiotics, driving the development of complementary therapies, such as photodynamic therapy (PDT). PDT combines a photosensitizer agent (PS), light, and oxygen to cause photooxidative stress in bacterial cells. PDT can eradicate Enterococcus spp. contaminations, improve the classic cleaning processes, and eradicate the bacteria in dental pieces. PDT\'s effectiveness can be improved with nanoparticles that function as carriers. Our work aims to describe the advances in PDT against Enterococcus spp. as a complement to antibiotic therapy, focusing on infections by Enterococcus faecium and Enterococcus faecalis, dental hygiene, and using nanoparticles to improve the antimicrobial effect. A systematic bibliographic search without a meta-analysis was conducted on various databases, using inclusion and exclusion criteria to identify the most relevant research. Of the 193 non-redundant articles found, 65 were selected for a systematic review, from which a summary table was created and a manual description was made. Photodynamic therapy for treating E. faecium and E. faecalis is a widely studied area, with promising results concerning bactericidal effectiveness and reductions in biofilm formation, particularly in regard to dental hygiene. Because most of the studies were conducted in vitro or ex vivo, the results indicated that there were not sufficient data to initiate clinical trials for safety and efficacy studies on humans.

BACKGROUND: Finding individuals with drug-resistant tuberculosis (DR-TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge, systematic reviews assessing the effectiveness, cost-effectiveness, acceptability, and feasibility of different DR-TB case-finding strategies to inform research, policy, and practice, have not been conducted and the scope of primary research is unknown.
OBJECTIVE: We therefore assessed the available literature on DR-TB case-finding strategies.
METHODS: We looked at systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that sought to improve DR-TB case detection specifically. We excluded studies that included patients seeking care for tuberculosis (TB) symptoms, patients already diagnosed with TB, or were laboratory-based. We searched the academic databases of MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL (Cumulated Index to Nursing and Allied Health Literature), Epistemonikos, and PROSPERO (The International Prospective Register of Systematic Reviews) using no language or date restrictions. We screened titles, abstracts, and full-text articles in duplicate. Data extraction and analyses were carried out in Excel (Microsoft Corp).
RESULTS: We screened 3646 titles and abstracts and 236 full-text articles. We identified 6 systematic reviews and 61 primary studies. Five reviews described the yield of contact investigation and focused on household contacts, airline contacts, comparison between drug-susceptible tuberculosis and DR-TB contacts, and concordance of DR-TB profiles between index cases and contacts. One review compared universal versus selective drug resistance testing. Primary studies described (1) 34 contact investigations, (2) 17 outbreak investigations, (3) 3 airline contact investigations, (4) 5 epidemiological analyses, (5) 1 public-private partnership program, and (6) an e-registry program. Primary studies were all descriptive and included cross-sectional and retrospective reviews of program data. No trials were identified. Data extraction from contact investigations was difficult due to incomplete reporting of relevant information.
CONCLUSIONS: Existing descriptive reviews can be updated, but there is a dearth of knowledge on the effectiveness, cost-effectiveness, acceptability, and feasibility of DR-TB case-finding strategies to inform policy and practice. There is also a need for standardization of terminology, design, and reporting of DR-TB case-finding studies.

Candida auris, a rapidly emerging multidrug-resistant fungal pathogen, poses a global health threat, with cases reported in over 47 countries. Conventional detection methods struggle, and the increasing resistance ofC. auristo antifungal agents has limited treatment options. Nanoparticle-based therapies, utilizing materials like silver, carbon, zinc oxide, titanium dioxide, polymer, and gold, show promise in effectively treating cutaneous candidiasis. This review explores recent advancements in nanoparticle-based therapies, emphasizing their potential to revolutionize antifungal therapy, particularly in combatingC. aurisinfections. The discussion delves into mechanisms of action, combinations of nanomaterials, and their application against multidrug-resistant fungal pathogens, offering exciting prospects for improved clinical outcomes and reduced mortality rates. The aim is to inspire further research, ushering in a new era in the fight against multidrug-resistant fungal infections, paving the way for more effective and targeted therapeutic interventions.

BACKGROUND: Sulbactam-durlobactam (SUL-DUR) has been tested in vitro for its ability to generate resistance in clinical isolates of Acinetobacter species. According to prior studies, combining durlobactam with sulbactam causes sulbactam-resistant isolates to become more active and revert to susceptibility. We aimed to conduct a systematic review of the in vitro activity of SUL-DUR on A. baumannii (Ab) isolates, including carbapenem-resistant A. baumannii (CRAb), to provide an overview for physicians dealing with Ab infections.
METHODS: The following keywords were searched in the PubMed, Google Scholar, and EMBASE databases to look for eligible original works that have been published without restrictions till June 30, 2023: A. baumannii and sulbactam-durlobactam, SUL-DUR, durlobactam, and sulbactam-ETX2514. We also searched clinicaltrials.gov and the Clinical Trials Registry of India (CTRI) for clinical trials involving sulbactamdurlobactam and Acinetobacter.
RESULTS: There were a total of 852 abstracts found. Among them, 633 articles with titles, abstracts, and keywords were reviewed, and 574 articles were removed after the initial screening. A total of 59 full-text eligible articles were evaluated, and 51 of them were eliminated because they did not satisfy the criteria set for inclusion. The full texts of the final 8 in vitro studies on A. baumanii and sulbactam/durlobactam were further evaluated. There were 5 trials on A. baumanii and sulbactam/durlobactam found on clinicaltrials.gov and the Clinical Trial Registry of India (CTRI).
CONCLUSIONS: The findings from the studies show that SUL-DUR might be a successful therapeutic option for multidrug-resistant-Ab infections. Future clinical trials will be required to validate the possibility of using this combination to treat multidrug-resistant A. baumannii infections.

The rising prevalence of multidrug-resistant (MDR) and extended-spectrum beta lactamase-resistant (ESBL) Klebsiella pneumoniae (K. pneumoniae) is an important global public health challenge. This threat is even more pertinent in clinical settings. Morbidity and mortality associated with this condition are alarming particularly in the developing regions of the world. A comprehensive evaluation of the epidemiology of this phenomenon will assist towards the global effort of reducing its burden. So, this systematic review and meta-analysis was conducted to evaluate the epidemiology of MDR K. pneumoniae in South-Eastern Asia (SEA). The study was done under the PRISMA guidelines and was preceded by the development of a priori protocol. The protocol was then registered in PROSPERO-the public registry for systematic reviews. Seven important outcomes which include the assessment of the overall MDR K. pneumoniae prevalence were designed to be evaluated. A literature search was carried out in five selected electronic databases and 4389 were screened. Of these articles, 21 studies that met the eligibility criteria were included in the review. Relevant data were extracted from the included studies. By conducting a quality effect meta-analysis, the pooled prevalence for MDR and ESBL K. pneumoniae in SEA was estimated at 55% (CI 9-96) and 27% (CI 32-100) respectively. The review also identified ESBL genes types of allodemic situations occurring mostly in respiratory tract infections. The high prevalence of MDR and ESBL K. pneumoniae in this subregion is highly significant and of both public health and clinical relevance. Overall, the findings of this review will assist in the effective prevention and control of this threat in SEA.

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Acinetobacter baumannii (A. baumannii) is one of the most common bacteria in nosocomial infections. Inappropriate usage of antibiotics has led to expanding emergence resistance to A. baumannii as a multidrug-resistant (MDR) strain. Empirical antibiotic therapy is necessary to evaluate the resistant gene pattern of MDR A. baumannii. For this purpose, the present study evaluated the resistance genes pattern of MDR A. baumannii collected from hospitalized patients using a genotypic diagnostic technique. To find evidence related to the study objectives, databases were searched such as Google Scholar, Web of Science, Science Direct, PubMed, and Scopus from 2000 to 2022, with specified keywords in the title and text of the articles. Articles were included based on inclusion and exclusion criteria. The mentioned database displayed 284 articles. After screening, 65 eligible articles were included. The results showed that various b-lactamases genes, aminoglycoside-modifying enzymes (AMEs) genes, and pump-expressing genes are resistance gene patterns in MDR A. baumannii isolates. MDR A. baumannii has significantly become resistant to b-lactams, carbapenems, and aminoglycosides.

The spread of polymyxin-resistant Klebsiella pneumoniae strains represents an emerging health challenge, limiting treatment options for the patients. Thus, the development of new antimicrobials is an urgent requirement. Antimicrobial peptides (AMPs) are a large class of compounds that are part of innate immune response; these peptides are promising compounds in the field of antimicrobial resistance and are present in all organisms. The present review evaluated patents on antimicrobial peptides tested against polymyxin-resistant K. pneumoniae, available on Espacenet as of September 2022. A total of 1313 patents were examined and 1197 excluded as they were out of focus for this review; 104 patents of peptides tested against K. pneumoniae were included; of which only 14 were tested against polymyxin-resistant K. pneumoniae strains. The results indicated that all AMPs evaluated were in the experimental or pre-clinical phase; the clinical phase is pending. Furthermore, a few peptides were tested effectively against polymyxin-resistant K. pneumoniae. Although, the research and patent filing alone are not enough to develop a suitable antimicrobial therapy, they can represent good starting point upon which to develop new antimicrobials. More investment is required to push these pharmaceuticals through the stages of development to introduce them into the market.