The chemical transformation of lathyrane nucleus through reduction and oxidation reactions using Euphorbia Factor L1 (EFL1) and Euphorbia Factor L1 (EFL3) as examples were investigated, along with a co-modification strategy of lathyrane nucleus and its side ester chain. A total of 38 lathyrane derivatives (5-42) including 34 new compounds were obtained, which greatly enriched the structural diversity of the lathyrane-type diterpenoids. Cytotoxicity against drug-sensitive and drug (adriamycin, ADM) resistant MCF-7 cells showed that 23 out of 38 transformed derivatives possessed obvious cytotoxic activity with IC50 values ranging from 7.0 to 41.1 μM and 3.2 to 45.5 μM, respectively, against both cells, compared to the noncytotoxic EFL1 and EFL3. The multidrug resistance (MDR) reversing activities of these lathyrane derivatives were further evaluated in MCF-7/ADM. Three transformed compounds (reversal fold, RF = 151.33, 62.94 and 47.3 for 27, 37 and 42) showed markedly higher activity than EFL1 (RF = 32.92) and EFL3 (RF = 39.68). Structure-activity relationship study revealed an essential role of C-6/17 and C-12/13 double bonds on lathyrane nucleus for exerting MDR reversal activity. Western blotting analysis showed that 42 could reduce the expression level of P-glycoprotein (P-gp) in MCF-7/ADM cells; however, the most active compound 27 with an unnatural 5/7/7/4 fused-ring diterpenoid skeleton, had no inhibitory effect on P-gp expression.

Managing multidrug-resistant (MDR) HIV infections in children is particularly challenging due to the lack of experience with new drugs in the pediatric setting. Second-line albuvirtide (ABT) with an optimized antiretroviral background therapy was approved for adults and adolescents after first-line treatment failure. This paper describes the treatment outcomes and adverse effects of an ABT-based dual-active antiretroviral treatment regimen in a child with MDR HIV strains.
A 13 year-old Chinese female patient infected with MDR HIV strains showed a decrease in viral load (from 4.48 log10 to 1.73 log10) and an increase in CD4 + T cells (from 15 to 308 cells/µl) after 12 months of treatment with an ABT-based antiretroviral regimen. The child showed no relevant drug-related adverse reactions.
The case reported here could suggest that an ABT-based antiretroviral therapy might be beneficial and without relevant toxicity in children with MDR HIV. Infectiologists specializing in managing HIV should be prepared to manage an increasing number of children with MDR HIV. ABT might be a new treatment option for MDR HIV infection in children.

To identify the risk factors for multidrug resistant tuberculosis (MDR-TB) among patients with TB at selected MDR-TB treatment initiative centres, southern Ethiopia, 2021.
An unmatched case-control study was employed.
Multidrug resistance treatment initiative centres in southern Ethiopia (Nigist Elen Mohamed Memorial Comprehensive Specialized Hospital and Butajira General Hospital).
A total sample size of 392 (79 cases and 313 controls) were selected by the systematic sampling technique. Cases were all patients with TB with culture proven or line probe assay confirmed Mycobacterium tuberculosis resistant to at least both isoniazid and rifampicin and registered on second-line TB treatment. Controls were all patients with bacteriological (molecular) proven drug-susceptible TB strains and whose recent smear results were turned to negative and registered as cured. Both bivariate and multivariable logistic regression analysis was used to identify risk factors of MDR-TB infections.
Identifying the risk factors for MDR-TB.
A total of 392 participants (79 cases and 313 controls) were interviewed. Multivariable analysis showed that direct contact with known patients with TB (AOR =4.35; 95% CI: 1.45 to 9.81), history of previous TB treatment (AOR=2.51; 95% CI: 1.50 to 8.24), history of cigarette smoking (AOR=3.24; 95% CI :2.17 to 6.91) and living in rural area (AOR=4.71; 95% CI :3.13 to 9.58) were identified risk factors for MDR-TB infections.
The study findings revealed that direct contact with known patients with TB, previous history of TB treatment, history of cigarette smoking and rural residence were potential risk factors for the occurrence of MDR-TB. In order to reduce the burden of drug resistance, strategies of controlling MDR-TB in the study area should emphasise on enhancing public health education and reducing treatment interruptions of patients with TB and drug-resistant TB.

Multi-drug resistant organisms (MDR-Os) are emerging as a significant cause of surgical site infections (SSI), but clinical outcomes and risk factors associated to MDR-Os-SSI have been poorly investigated in general surgery. Aims were to investigate risk factors, clinical outcomes and costs of care of multi-drug resistant organisms (MDR-Os-SSI) in general surgery. From January 2018 to December 2019, all the consecutive, unselected patients affected by MDR-O SSI were prospectively evaluated. In the same period, patients with non-MDR-O SSI and without SSI, matched for clinical and surgical data were used as control groups. Risk factors for infection, clinical outcome, and costs of care were compared by univariate and multivariate analysis. Among 3494 patients operated on during the study period, 47 presented an MDR-O SSI. Two control groups of 47 patients with non-MDR-O SSI and without SSI were identified. MDR-Os SSI were caused by poly-microbial etiology, meanly related to Gram negative Enterobacteriales. MDR-Os-SSI were related to major postoperative complications. At univariate analysis, iterative surgery, open abdomen, intensive care, hospital stay, and use of aggressive and expensive therapies were associated to MDR-Os-SSI. At multivariate analysis, only iterative surgery and the need of total parenteral and immune-nutrition were significantly associated to MDR-Os-SSI. The extra-cost of MDR-Os-SSI treatment was 150% in comparison to uncomplicated patients. MDR-Os SSI seems to be associated with major postoperative complications and reoperative surgery, they are demanding in terms of clinical workload and costs of care, they are rare but increasing, and difficult to prevent with current strategies.

CD14+ monocytes present antigens to adaptive immune cells via monocytic human leukocyte antigen receptor (mHLA-DR), which is described as an immunological synapse. Reduced levels of mHLA-DR can display an acquired immune defect, which is often found in sepsis and predisposes for secondary infections and fatal outcomes. Monocytic HLA-DR expression is reliably induced by interferon- γ (IFNγ) therapy.
We report a case of multidrug-resistant superinfected COVID-19 acute respiratory distress syndrome (ARDS) on extracorporeal membrane oxygenation (ECMO) support. The resistance profiles of the detected Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Citrobacter freundii isolates were equipped with resistance to all four antibiotic classes including carbapenems (4MRGN) and Cefiderocol in the case of K. pneumoniae. A causal therapeutic antibiotic strategy was not available. Therefore, we measured the immune status of the patient aiming to identify a potential acquired immune deficiency. Monocyte HLA-DR expression identified by FACS analysis revealed an expression level of 34% positive monocytes and suggested severe immunosuppression. We indicated IFNγ therapy, which resulted in a rapid increase in mHLA-DR expression (96%), rapid resolution of invasive bloodstream infection, and discharge from the hospital on day 70.
Superinfection is a dangerous complication of COVID-19 pneumonia, and sepsis-induced immunosuppression is a risk factor for it. Immunosuppression is expressed by a disturbed antigen presentation of monocytes to cells of the adaptive immune system. The case presented here is remarkable as no validated antibiotic regimen existed against the detected bacterial pathogens causing bloodstream infection and severe pneumonia in a patient suffering from COVID-19 ARDS. Possible restoration of the patient\'s own immunity by IFNγ was a plausible option to boost the patient\'s immune system, eliminate the identified 4MRGNs, and allow for lung recovery. This led to the conclusion that immune status monitoring is useful in complicated COVID-19-ARDS and that concomitant IFNγ therapy may support antibiotic strategies.
After a compromised immune system has been detected by suppressed mHLA-DR levels, the immune system can be safely reactivated by IFNγ.

暂无摘要。

Semi-intensive equine breeding system favors gastrointestinal nematode infections. The treatment of these infections is based on the use of anthelmintics. However, the inappropriate use of these drugs has led to parasitic resistance to the available active principles. The objective of this study was to evaluate the efficacy of the main classes of antiparasitic (ATP) used in control in adult and young animals, including: benzimidazoles (fenbendazole), pyrimidines (pyrantel pamoate), macrocyclic lactones (ivermectin and moxidectin), as well as the combination of active ingredients (ivermectin + pyrantel pamoate). The study was carried out in two military establishments, located in Rio Grande do Sul (RS), from January to December, 2018. The intervals between the treatments of the animals were performed from 30 to 90 days. Coproparasitological evaluations were determined by the egg count reduction in the faeces. Cyatostomine larvae were identified in pre and post-treatment cultures. The results demonstrated the multiple parasitic resistance of cyathostomins to fenbendazole, moxidectin in young animals, and to fenbendazole, pyrantel pamoate in adult animals. Thus, it is necessary to define or diagnose parasitic resistance to assist in the creation of prophylactic parasitic control, using suppressive treatment with ATP associated with integrated alternatives. The progress of parasitic resistance can be slowed.

BACKGROUND: The risk factors for multi-drug resistant infection (MDRI) in the pediatric intensive care unit (PICU) remain unclear. It\'s necessary to evaluate the epidemiological characteristics and risk factors for MDRI in PICU, to provide insights into the prophylaxis of MDRI clinically.
METHODS: Clinical data of 79 PICU children with MDRI were identified, and 80 children in PICU without MDRI in the same period were selected as control group. The related children\'s characteristics, clinical care, microbiologic data, treatments provided, and outcomes of the patients with were reviewed and collected. Univariate and multivariate logistic regression analyses were performed to identify the potential risks of MDRI in PICU.
RESULTS: Of the diagnosed 79 cases of MDRI, there were28 cases of CR-AB, 24 cases of MRSA, 22 cases of PDR-PA,3 cases of VRE and 2 cases of CRE respectively. Univariate analyses indicated that the length of PICU stay, the duration of mechanical ventilation > 5 days, parenteral nutrition, coma, urinary catheter indwelling, invasive operation, 2 or more antibiotics use were associated with MDRIs (all p < 0.05); The logistic multiple regression analyses indicated that coma, parenteral nutrition, 2 or more antibiotics use and the duration of mechanical ventilation > 5 days were independent risk factors associated with MDRI (all p < 0.05).
CONCLUSIONS: This present study has identified several potentially modifiable risk factors for MDRI in PICU, it\'s conducive to take appropriate measures targeting risk factors of MDRI for health care providers to reduce MDRI.

Urinary tract infections (UTIs) are frequent in women. Cystitis after intercourse (post-coital cystitis) accounts for 60% of recurrent cases. Most physicians treat recurrent UTIs (R-UTIs) with multiple courses of antibiotics. The high prevalence indicates that this bacteria-oriented approach in the long term is ineffective for many women. A change in clinical behavior regarding use of antibiotics and recognizing the importance of a patient\'s self-defense mechanisms are important considerations in combating antimicrobial resistance.
The intervention for each of two women with R-UTI was integrated treatment with a non-conventional and tailor-made homeopathy regimen, addressing multiple levels of disease simultaneously, for the prevention of recurrence as well as for treatment. Assessment of causal attribution of homeopathy treatment effect was carried out using the Modified Naranjo Criteria.
Case 1 presented with chronic multi-morbid conditions, including R-UTI which had become multi-drug resistant. With regular homeopathic treatment, her antibiotic use reduced, her diabetic profile improved, and she did not need prophylactic antibiotics. Case 2 suffered from R-UTI with post-coital cystitis and burning sensation, despite following all conventional advice for treatment and prophylaxis. Addition of homeopathy improved her quality of life and prevented relapses. The Modified Naranjo Criteria total score for each patient was +10/13 and +9/13, respectively.
Addition of homeopathy can be an effective approach in integrated management of antibiotic-resistant R-UTIs. Controlled research on the topic is thus indicated.

The discovery of drugs to treat tuberculosis (TB) was a major medical milestone in the twentieth century. However, from the outset, drug resistance was observed. Currently, of the 10 million people that exhibit TB symptoms each year, 450,000 have multidrug or extensively drug resistant (MDR or XDR) TB. While greater understanding of the host and pathogen (Mycobacterium tuberculosis, Mtb) coupled with scientific ingenuity will lead to new drugs and vaccines, in the meantime 4000 people die daily from TB. Thus, efforts to improve existing TB drugs should also be prioritized. Improved efficacy and decreased dose and associated toxicity of existing drugs would translate to greater compliance, life expectancy and quality of life of Mtb infected individuals. One potential strategy to improve existing drugs is to deliver them by inhalation as aerosols to the lung, the primary site of Mtb infection. Inhaled drugs are used for other pulmonary diseases, but they have yet to be utilized for TB. Inhaled therapies for TB represent an untapped opportunity that the pharmaceutical, clinical and regulatory communities should consider.