Colistin, also known as polymyxin E, is an antimicrobial agent that is effective against a variety of Gram-negative bacilli, especially the Enterobacteriaceae family. Recently, the wide dissemination of colistin-resistance has brought strong attention to the scientific society because of its importance as the last resort for the treatment of carbapenem-resistant Enterobacteriaceae infections and its possible horizontal transmission. The mobilized colistin resistance (mcr) gene was identified as the gene responsible for unique colistin resistance. Indeed, despite many studies that have revealed a pan variation in the existence of this gene, not only for the mcr genes main group but also for its many subgroups, the problem is growing and worsening day after day. In this regard, this review paper is set to review the updated data that has been published up to the end of 2019 third quarter, especially when related to colistin resistance by the mcr genes. It will include the present status of colistin resistance worldwide, the mcr gene dissemination in different sectors, the discovery of the mcr variants, and the global plan to deal with the threat of antimicrobial resistance. In line with global awareness, and to stop antibiotic misuse and overuse, especially in agricultural animals, the study will further discuss in detail the latest alternatives to colistin use in animals, which may contribute to the elimination of inappropriate antibiotic use and to the help in preventing infections. This review will advance our understanding of colistin resistance, while supporting the efforts toward better stewardship, for the proper usage of antimicrobial drugs in humans, animals, and in the environment.

Central aspects in the pathogenesis of scrub typhus, an infection caused by Orientia (O.) tsutsugamushi, have remained obscure. Its organ and cellular tropism are poorly understood. The purpose of this study was to analyze the kinetics of bacterial dissemination and associated inflammatory responses in infected tissues in an experimental scrub typhus mouse model, following infection with the human pathogenic strain Karp. We provide a thorough analysis of O. tsutsugamushi infection in inbred Balb/c mice using footpad inoculation, which is close to the natural way of infection. By a novel, highly sensitive qPCR targeting the multi copy traD genes, we quantitatively monitored the spread of O. tsutsugamushi Karp from the skin inoculation site via the regional lymph node to the internal target organs. The highest bacterial loads were measured in the lung. Using confocal imaging, we also detected O. tsutsugamushi at the single cell level in the lung and found a predominant macrophage rather than endothelial localization. Immunohistochemical analysis of infiltrates in lung and brain revealed differently composed lesions with specific localizations: iNOS-expressing macrophages were frequent in infiltrative parenchymal noduli, but uncommon in perivascular lesions within these organs. Quantitative analysis of the macrophage response by immunohistochemistry in liver, heart, lung and brain demonstrated an early onset of macrophage activation in the liver. Serum levels of interferon (IFN)-γ were increased during the acute infection, and we showed that IFN-γ contributed to iNOS-dependent bacterial growth control. Our data show that upon inoculation to the skin, O. tsutsugamushi spreads systemically to a large number of organs and gives rise to organ-specific inflammation patterns. The findings suggest an essential role for the lung in the pathogenesis of scrub typhus. The model will allow detailed studies on host-pathogen interaction and provide further insight into the pathogenesis of O. tsutsugamushi infection. Many details of the pathogenesis of scrub typhus, an infection caused by the intracellular bacterium Orientia tsutsugamushi that is endemic in Southeast Asia, have remained unclear until today. In this study, we present an experimental self-healing mouse model of scrub typhus based on footpad skin inoculation of the human pathogenic Karp strain of O. tsutsugamushi that shares many features with human infection. We established a novel quantitative PCR with increased sensitivity for the measurement of bacterial organ loads of infected mice. It was thereby shown that O. tsutsugamushi initially accumulated in the regional lymph node and subsequently spread to many organs with the highest bacterial loads found in the lung. The predominant host cells in the lung were macrophages located in the parenchymal interstitium, rather than endothelial cells. Our data also show unexpected organ-specific differences in the dynamics of macrophage activation. This mouse model will help to advance our understanding of scrub typhus pathogenesis.

T cells are known to contribute to immune protection against scrub typhus, a potentially fatal infection caused by the obligate intracellular bacterium Orientia (O.) tsutsugamushi. However, the contribution of CD8+ T cells to protection and pathogenesis during O. tsutsugamushi infection is still unknown. Using our recently developed BALB/c mouse model that is based on footpad inoculation of the human-pathogenic Karp strain, we show that activated CD8+ T cells infiltrate spleen and lung during the third week of infection. Depletion of CD8+ T cells with monoclonal antibodies resulted in uncontrolled pathogen growth and mortality. Adoptive transfer of CD8+ T cells from infected animals protected naïve BALB/c mice from lethal outcome of intraperitoneal challenge. In C57Bl/6 mice, the pulmonary lymphocyte compartment showed an increased percentage of CD8+ T cells for at least 135 days post O. tsutsugamushi infection. Depletion of CD8+ T cells at 84 days post infection caused reactivation of bacterial growth. In CD8+ T cell-deficient beta 2-microglobulin knockout mice, bacterial replication was uncontrolled, and all mice succumbed to the infection, despite higher serum IFN-γ levels and stronger macrophage responses in liver and lung. Moreover, we show that CD8+ T cells but not NKT cells were required for hepatocyte injury: elevated concentrations of serum alanine aminotransferase and infection-induced subcapsular necrotic liver lesions surrounded by macrophages were found in C57Bl/6 and CD1d-deficient mice, but not in beta 2-microglobulin knockout mice. In the lungs, peribronchial macrophage infiltrations also depended on CD8+ T cells. In summary, our results demonstrate that CD8+ T cells restrict growth of O. tsutsugamushi during acute and persistent infection, and are required to protect from lethal infections in BALB/c and C57BL/6 mice. However, they also elicit specific pathologic tissue lesions in liver and lung. Orientia (O.) tsutsugamushi is the causative agent of scrub typhus, a potentially fatal disease that is endemic in South East Asia. This bacterium replicates in the cytoplasm of its host cells. The obligate intracytoplasmic lifestyle resembles that of many viruses, but among pathogenic bacteria it is unique to O. tsutsugamushi and the closely related Rickettsia spp. CD8+ T cells are specialized on the recognition of cytoplasm-derived antigens and are therefore important in antiviral and antitumor immunity. Using two different mouse models, we show that CD8+ T cells protected against lethal outcome of O. tsutsugamushi infection. Moreover, CD8+ T cells were implicated in the development of tissue lesions in liver and lung. Mice that lack CD8+ T cells due to a genetic defect developed a massively increased macrophage response that failed to control the infection. In protected wildtype mice, the CD8+ T cell-driven immune response elicited the recruitment of macrophages to distinct locations in liver and lung. We also show that CD8+ T cells were important to prevent replication of O. tsutsugamushi many weeks after the recovery from any signs of disease. Therefore we propose that a well-balanced relation between pathogen burden and a potentially harmful CD8+ T cell-dependent immune response becomes established during infection with O. tsutsugamushi.

Background: A strong understanding of infection prevention and control (IPC) procedures and comprehensive training among healthcare workers is essential for effective IPC programs. These elements play a crucial role in breaking the chain of nosocomial infections by preventing the transmission of resistant organisms to patients and staff members. This study mapped the components of IPC education and training across various member states of the World Health Organization (WHO) in the Eastern Mediterranean Region (EMR) at national, academic, and healthcare institutional levels. Methods: A self-administered structured online questionnaire based on the WHO “Core Component 3” of IPC programs at the national and acute healthcare facility levels (IPC education and training) was given to national IPC focal persons in each of the WHO’s EMR countries between February and March 2023. Results: From 14 of the 22 countries,15 IPC persons participated in the survey. Most countries have scattered nonhomogeneous IPC education programs in human health undergraduate majors without considering it a standalone module. Academic institutions are rarely involved, and elaborate and predefined undergraduate IPC education programs provided by universities are present in 21.4% of the countries. In 71.4% of these countries, postgraduate training targeting IPC professionals is provided by national IPC teams, primarily based on national IPC guidelines developed with the aid of the WHO. Generally, healthcare worker training relies heavily on healthcare facilities in 92.9% of the countries, rather than on a national training program. In 42.9% of the countries, practicing IPC physicians are not necessarily specialists of infectious disease or medical microbiologists and IPC nurses are not required to specialize in IPC. However, nonspecialized IPC professionals are expected to undergo training upon employment and before beginning practice. Nongovernmental organizations such as the WHO play a significant role in IPC education and in supporting national IPC authorities in establishing national IPC guidelines, as it is the case in 78.6% of these countries. Conclusion: Clear disparities exist in IPC education and training across different countries in the WHO’s EMR. Establishing a regional scientific network specializing in IPC would help bridge the existing gaps and standardize this education within individual countries and across countries in the region. This region needs to establish IPC certification standards and standardized education curricula.

This study aimed to determine the prevalence of Antimicrobial Resistance Genes (ARGs), with a focus on colistin resistance in clinical A. baumannii, as well as the risk factors associated with A. baumannii infection in Jordanian patients. In total, 150 A. baumannii isolates were obtained from patients at a teaching hospital. The isolates were tested for antimicrobial susceptibility using disc diffusion and microdilution methods. PCR amplification was used to detect ARGs, and statistical analysis was conducted to evaluate the influence of identified risk factors on the ARGs acquisition. More than 90% of A. baumannii isolates were resistant to monobactam, carbapenem, cephalosporins, Fluoroquinolones, penicillin, and β-lactam agents. Moreover, 20.6% of the isolates (n = 31) were colistin-resistant. Several ARGs were also detected in A. baumannii isolates. Univariate analysis indicated that risk factors and the carriage of ARGs were significantly associated P ≤ (0.05) with gender, invasive devices, immunodeficiency, systemic diseases, tumors, and covid-19. Logistic regression analysis indicated seven risk factors, and three protective factors were associated with the ARGs (armA, strA, and strB) P ≤ (0.05). In contrast, tetB and TEM were associated with 2 risk factors each P ≤ (0.05). Our study indicates a high prevalence of MDR A. baumannii infections in ICU patients, as well as describing the case of colistin-resistant A. baumannii for the first time in Jordan. Additionally, the risk factors associated with ARGs-producing A. baumannii infections among ICU patients suggest a rapid emergence and spread of MDR A. baumannii without adequate surveillance and control measures.

Antimicrobial resistance (AMR) is a global threat that requires serious attention, particularly when it is developed against colistin, which is considered one of the 'last-resort' antibiotics for curing an infection. This study aimed to investigate the AMR profile of the Klebsiella (K.) pneumoniae clinical isolates and to obtain the comprehensive characteristics of the carbapenemases among the carbapenem-resistant K. pneumoniae (CR-KP) when isolated. In addition, to detect the colistin resistance and investigate the MCR genes in the clinical K. pneumoniae isolates for the first time in Jordan. A total of 179 K. pneumoniae isolates were cultured and they were confirmed using the VITEK 2 system and PCR. The antibiotic susceptibilities, extended-spectrum beta-lactamase (ESβL), multidrug-resistant (MDR), and CR-KP were determined by using the VITEK 2 system, disc diffusion, and the minimum inhibitory concentration (MIC) test. PCR was performed to detect the MCR and carbapenemase genes. The rates of ESβL, MDR, and CR-KP were 48 %, 62 %, and 12.8 %, respectively. High colistin resistance of 49.7 % (89/179) was found. Only one MCR-1 (1.1 %) out of the 89 colistin resistance isolates was detected. Many of the isolates harbored the ESβL genes. In particular, the carbapenem genes were detected in 26 isolates, with 46 % KPC enzyme genes (12/26), 23 % IMP genes (6/26), 19 % OXA-48 genes (5/26), 11.5 % NDM-1 genes (3/26) but no VIM gene was found. The statistical analyses revealed a significant association between colistin resistance and MDR (P ≤ 0.05, Chi-square test). An association between colistin resistance and the Piperacillin, Ceftazidime, Cefpodoxime, Imipenem, Aztreonam, and Tobramycin resistance was noted. The study's findings demonstrated the presence of the MCR-1 gene in the K. pneumoniae clinical isolates for the first time in Jordan and indicated that the KPC and IMP encoded carbapenemases were the most prevalent K. pneumoniae carbapenemases in Jordan patients.