Combining Aloin with TIENAM ameliorates cecal ligation and puncture-induced sepsis in mice by attenuating inflammation and modulating abdominal cavity microbiota.

Despite the high mortality rate, sepsis lacks specific and effective treatment options. Conventional antibiotics, such as TIENAM (TIE; imipenem and cilastatin sodium for injection), face challenges owing to the emergence of bacterial resistance, which reduces their effectiveness and causes adverse effects. Addressing resistance and judicious drug use is crucial. Our research revealed that aloin (Alo) significantly boosts survival rates and reduces inflammation and bacterial load in mice with sepsis, demonstrating strong antimicrobial activity. Using a synergistic Alo + TIE regimen in a cecal ligation and puncture (CLP)-induced sepsis model, we observed a remarkable increase in survival rates from 10 % to 75 % within 72 h compared with the CLP group alone. This combination therapy also modulated inflammatory markers interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α, mitigated tissue damage, regulated immune cells by lowering NK, activated CD8+ and CD4+ T cells while increasing peritoneal macrophages, and decreased the bacterial load in the peritoneal cavity. We noted a significant shift in the abdominal cavity microbiota composition post-treatment, with a decrease in harmful bacteria, such as Lachnospiraceae_NK4A136_group, Klebsiella, Bacillus, and Escherichia, and an increase in beneficial bacteria, such as Lactobacillus and Mucispirillum. Our study emphasizes the efficacy of combining Alo with TIE to combat sepsis, and paves the way for further investigations and potential clinical applications aiming to overcome the limitations of TIE and enhance the therapeutic prospects of Alo.

A randomized non-inferiority study comparing imipenem/cilastatin/relebactam with standard-of-care Gram-negative coverage in cancer patients with febrile neutropenia.

BACKGROUND: Antibiotic overuse leads to the emergence of antibiotic resistance that threatens immunocompromised cancer patients. Infections caused by MDR Gram-negative pathogens are difficult to treat and associated with high mortality. Hence, empirical therapy with standard-of-care (SOC) antibiotics could be suboptimal in these vulnerable patients. New antibiotics covering potential resistant pathogens may be considered. METHODS: We conducted a randomized non-inferiority study comparing safety and efficacy of imipenem/cilastatin/relebactam (IPM/REL), a ß-lactam/ß-lactamase inhibitor combination, with SOC antibiotics (cefepime, piperacillin/tazobactam or meropenem) in cancer patients with febrile neutropenia. Patients received at least 48 h of IV antibiotics and were assessed at end-of-IV (EOIV) therapy, test of cure (TOC; Days 21-28), and late follow-up (LFU; Days 35-42). RESULTS: A total of 100 patients were enrolled (49 IPM/REL and 50 SOC). Demographics and rates of documented microbiological infections were similar in both groups. In the SOC arm, 86% of antibiotics consisted of cefepime. Patients on IPM/REL had a higher favourable clinical response at EOIV than those on SOC (90% versus 74%; P = 0.042); however, responses were similar at TOC and LFU. Microbiological eradication was comparable at all three timepoints. Study drug-related adverse events and adverse events leading to drug discontinuation were similar in both groups, with no study drug-related mortality. CONCLUSIONS: Our results suggest that compared with SOC antibiotics, predominantly cefepime, IPM/REL for empirical coverage of febrile neutropenia in cancer patients is generally safe and could be associated with a better clinical outcome at EOIV. The current SOC consisting mainly of agents that do not cover for ESBL-producing and carbapenem-resistant Enterobacterales bacteria should be reconsidered.

High adsorption capacity of hemoperfusion on imipenem in critically ill patients with septic shock: a case report.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by an excessive host response to infection, manifested by elevated levels of inflammatory cytokines. At present, the use of hemoperfusion to remove inflammatory cytokines from the bloodstream has been expanding. Meanwhile, the pharmacokinetics and pharmacodynamics characteristics of antibiotics in critically ill patients may be impacted by hemoperfusion. CASE PRESENTATION: The patient was a 69-year-old male with poorly controlled type 2 diabetes. When admitted to the ICU, Multiple Organ Dysfunction Syndrome (MODS) appeared within 48 h, and he was suspected of septic shock due to acute granulocytopenia and significantly increased procalcitonin. Broad-spectrum antibiotics imipenem was administered according to Sepsis 3.0 bundle and hemoperfusion lasting 4 h with a neutron-macroporous resin device (HA-380, Jafron, China) five times was conducted to lower the extremely high value of serum inflammatory factors. Blood samples were collected to measure imipenem plasma concentration to investigate the effect of hemoperfusion quantitatively. This study showed that 4 h of hemoperfusion had a good adsorption ability on inflammatory factors and could remove about 75.2% of imipenem. CONCLUSIONS: This case demonstrated the high adsorption capacity of hemoperfusion on imipenem in critically ill patients. It implies a timely imipenem supplement is required, especially before hemoperfusion.

A Systematic Review of the Pharmacokinetics and Pharmacodynamics of Novel Beta-Lactams and Beta-Lactam with Beta-Lactamase Inhibitor Combinations for the Treatment of Pneumonia Caused by Carbapenem-Resistant Gram-Negative Bacteria.

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. OBJECTIVES: 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.

Efficacies of omadacycline + amikacin + imipenem and an all-oral regimen omadacycline + clofazimine + linezolid in a mouse model of M. abscessus lung disease.

Treatment outcomes for Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) disease are still unsatisfactory, mainly due to issues with drug toxicity, tolerability, and efficacy. Treating Mab disease is challenging due to its high baseline antibiotic resistance, initial requirement for intravenous therapy, and poor medication tolerance. Omadacycline, a new tetracycline, is active against Mab. Since any new antibiotic effective against Mab is expected to be used in combination with other antibiotics, we evaluated the efficacy of two triple-drug combinations comprising omadacycline, omadacycline + amikacin + imipenem, and omadacycline + clofazimine + linezolid against two contemporary Mab clinical isolates in a mouse model of Mab lung disease. Antibiotic administration was initiated 1-week post-infection and was given daily, with Mab burden in the lungs at treatment completion serving as the endpoint. Omadacycline alone moderately reduced Mab levels and maintained better health in mice compared to untreated ones, which typically suffered from the infection. The omadacycline + clofazimine + linezolid combination showed immediate bactericidal activity and enhanced efficacy over 6 weeks, particularly against the more resistant strain (M9507). However, the clofazimine + linezolid combination lacked early bactericidal activity. When combined with amikacin and imipenem, omadacycline did not improve the regimen's effectiveness over 4 weeks of treatment. Our study showed that omadacycline + clofazimine + linezolid exhibited significant bactericidal activity over an extended treatment duration. However, adding omadacycline to amikacin and imipenem did not improve regimen effectiveness against the evaluated clinical isolates within 4 weeks. Further research in Mab disease patients is needed to determine the most effective omadacycline-containing regimen.IMPORTANCEMycobacteroides abscessus is a common environmental bacterium that causes infections in people with compromised lung function, including those with bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, and weakened immune systems, especially among older individuals. Treating M. abscessus disease is challenging due to the limited effectiveness and toxicity of current antibiotics, which often require prolonged use. Omadacycline, a new antibiotic, shows promise against M. abscessus. Using a mouse model that mimics M. abscessus disease in humans, we studied the effectiveness of including omadacycline with recommended antibiotics. Adding omadacycline to clofazimine and linezolid significantly improved treatment outcomes, rapidly clearing the bacteria from the lungs and maintaining effectiveness throughout. This oral combination is convenient for patients. However, adding omadacycline to amikacin and imipenem did not improve treatment effectiveness within 4 weeks. Further study with M. abscessus patients is necessary to optimize omadacycline-based treatment strategies for this disease.

An optimized cyclophosphamide-treated mouse model of Mycobacterium abscessus pulmonary infection.

Mycobacterium abscessus pulmonary infections are increasingly problematic, especially for immunocompromised individuals and those with underlying lung conditions. Currently, there is no reliable standardized treatment, underscoring the need for improved preclinical drug testing. We present a simplified immunosuppressed mouse model using only four injections of cyclophosphamide, which allows for sustained M. abscessus lung burden for up to 16 days. This model proved effective for antibiotic efficacy evaluation, as demonstrated with imipenem or amikacin.

An elderly male with septic arthritis and bacteremia.

Rhodococcus hoagii is a gram positive actinomycete found in horses and cattle. Humans can be infected by ingestion or inhalation through contaminated food or soil. The organism usually infects immunosuppressed hosts with pneumonia being the common presentation. We present a case of an 89 years old, apparently immunocompetent host presenting with fever, encephalopathy and arthritis who grew Rhodococcus hoagii in blood and synovial fluid, The patient responded well to a combination of vancomycin, azithromycin and imipenem-cilastatin. Our case demonstrates that extra-pulmonary manifestations such as septic arthritis and bacteremia can be seen in immune competent hosts.

A challenging case of carbapenem resistant Klebsiella pneumoniae-related pyogenic liver abscess with capsular polysaccharide hyperproduction: a case report.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are a major public health problem, necessitating the administration of polymyxin E (colistin) as a last-line antibiotic. Meanwhile, the mortality rate associated with colistin-resistant K. pneumoniae infections is seriously increasing. On the other hand, importance of administration of carbapenems in promoting colistin resistance in K. pneumoniae is unknown. CASE PRESENTATION: We report a case of K. pneumoniae-related pyogenic liver abscess in which susceptible K. pneumoniae transformed into carbapenem- and colistin-resistant K. pneumoniae during treatment with imipenem. The case of pyogenic liver abscess was a 50-year-old man with diabetes and liver transplant who was admitted to Abu Ali Sina Hospital in Shiraz. The K. pneumoniae isolate responsible for community-acquired pyogenic liver abscess was isolated and identified. The K. pneumoniae isolate was sensitive to all tested antibiotics except ampicillin in the antimicrobial susceptibility test and was identified as a non-K1/K2 classical K. pneumoniae (cKp) strain. Multilocus sequence typing (MLST) identified the isolate as sequence type 54 (ST54). Based on the patient's request, he was discharged to continue treatment at another center. After two months, he was readmitted due to fever and progressive constitutional symptoms. During treatment with imipenem, the strain acquired blaOXA-48 and showed resistance to carbapenems and was identified as a multidrug resistant (MDR) strain. The minimum inhibitory concentration (MIC) test for colistin was performed by broth microdilution method and the strain was sensitive to colistin (MIC < 2 µg/mL). Meanwhile, on blood agar, the colonies had a sticky consistency and adhered to the culture medium (sticky mucoviscous colonies). Quantitative real-time PCR and biofilm formation assay revealed that the CRKP strain increased capsule wzi gene expression and produced slime in response to imipenem. Finally, K. pneumoniae-related pyogenic liver abscess with resistance to a wide range of antibiotics, including the last-line antibiotics colistin and tigecycline, led to sepsis and death. CONCLUSIONS: Based on this information, can we have a theoretical hypothesis that imipenem is a promoter of resistance to carbapenems and colistin in K. pneumoniae? This needs more attention.

Sub-inhibitory concentrations of colistin and imipenem impact the expression of biofilm-associated genes in Acinetobacter baumannii.

Acinetobacter baumannii is an opportunistic pathogen that is responsible for nosocomial infections. Imipenem and colistin are drugs that are commonly used to treat severe infections caused by A. baumannii, such as sepsis, ventilator-associated pneumonia, and bacteremia. However, some strains of A. baumannii have become resistant to these drugs, which is a concern for public health. Biofilms produced by A. baumannii increase their resistance to antibiotics and the cells within the inner layers of biofilm are exposed to sub-inhibitory concentrations (sub-MICs) of antibiotics. There is limited information available regarding how the genes of A. baumannii are linked to biofilm formation when the bacteria are exposed to sub-MICs of imipenem and colistin. Thus, this study's objective was to explore this relationship by examining the genes involved in biofilm formation in A. baumannii when exposed to low levels of imipenem and colistin. The study found that exposing an isolate of A. baumannii to low levels of these drugs caused changes in their drug susceptibility pattern. The relative gene expression profiles of the biofilm-associated genes exhibited a change in their expression profile during short-term and long-term exposure. This study highlights the potential consequences of overuse and misuse of antibiotics, which can help bacteria become resistant to these drugs.

Regulation of overexpressed efflux pump encoding genes by cinnamon oil and trimethoprim to abolish carbapenem-resistant Acinetobacter baumannii clinical strains.

Resistance mechanisms are a shelter for Acinetobacter baumannii to adapt to our environment which causes difficulty for the infections to be treated and WHO declares this organism on the top of pathogens priority for new drug development. The most common mechanism that develops drug resistance is the overexpression of the efflux pump, especially Resistance-nodulation-cell division (RND) family, to almost most antibiotics. The study is designed to detect RND efflux pump genes in A. baumannii, and its correlation to multidrug resistance, in particular, the carbapenems resistance Acinetobacter baumannii (CRAB), and using different inhibitors that restore the antibiotic susceptibility of imipenem. Clinical A. baumannii isolates were recovered from different Egyptian hospitals in Intensive care unit (ICU). The expression of genes in two strains was analyzed using RT-PCR before and after inhibitor treatment. About 100 clinical A. baumannii isolates were recovered and identified and recorded as MDR strains with 75% strains resistant to imipenem. adeB, adeC, adeK, and adeJ were detected in thirty- seven the carbapenems resistance Acinetobacter baumannii (CRAB) strains. Cinnamomum verum oil, Trimethoprim, and Omeprazole was promising inhibitor against 90% of the carbapenems resistance Acinetobacter baumannii (CRAB) strains with a 2-6-fold decrease in imipenem MIC. Downregulation of four genes was associated with the addition of those inhibitors to imipenem for two the carbapenems resistance Acinetobacter baumannii (CRAB) (ACN15 and ACN99) strains, and the effect was confirmed in 24 h killing kinetics. Our investigation points to the carbapenems resistance Acinetobacter baumannii (CRAB) strain's prevalence in Egyptian hospitals with the idea to revive the imipenem activity using natural and chemical drugs as inhibitors that possessed high synergistic activity.

Rhodococcus infection: a 10-year retrospective analysis of clinical experience and antimicrobial susceptibility profile.

Rhodococcus equi is an opportunistic pathogen known to cause pulmonary and extrapulmonary disease among immunocompromised patients. Treatment is frequently challenging due to intrinsic resistance to multiple antibiotic classes. While non-equi Rhodococcus spp. are prevalent, their clinical significance is poorly defined. There is also limited data on antibiotic susceptibility testing (AST) of Rhodococcus infection in humans. We conducted a single-center, retrospective cohort study evaluating clinical characteristics, microbiologic profile, and AST of Rhodococcus infections between June 2012 and 2022 at our tertiary academic medical center. Identification of Rhodococcus spp. was performed by Sanger 16S rRNA gene sequencing and/or matrix-assisted laser desorption ionization-time of flight mass spectrometry, and AST was performed by agar dilution. Three hundred twenty-two isolates of Rhodococcus spp. were identified from blood (50%), pulmonary (26%), and bone/joint (12%) sources. R. equi/hoagii, R. corynebacterioides, and R. erythropolis were the most frequently isolated species, with 19% of isolates identified only to genus level. One hundred ninety-nine isolates evaluated for AST demonstrated high-level resistance to amoxicillin/clavulanate, cephalosporins, and aminoglycosides. More than 95% susceptibility to imipenem, vancomycin, linezolid, rifampin, and clarithromycin was observed. Non-equi species showed a significantly more favorable AST profile relative to R. equi. Clinically significant Rhodococcus infection was rare with 10 cases diagnosed (majority due to R. equi) and managed. The majority of patients received 2- or 3-drug combination therapy for 2-6 months, with favorable clinical response. Significant differences in AST were observed between R. equi and non-equi species. Despite high antimicrobial resistance to several antibiotic classes, imipenem and vancomycin remain appropriate empiric treatment options for R. equi. Future research evaluating mechanisms underlying antimicrobial resistance is warranted.

Therapeutic drug monitoring of imipenem/cilastatin and meropenem in critically ill adult patients.

OBJECTIVES: To investigate the factors influencing imipenem/cilastatin (IMI) and meropenem (MEM) concentrations in critically ill adult patients and the role of these concentrations in the clinical outcome. METHODS: Plasma trough concentrations of IMI and MEM were detected by high-performance liquid chromatography. A target value of 100%-time above MIC was used for the drugs. RESULTS: A total of 186 patients were included, with 87 receiving IMI and 99 receiving MEM. The percentages of patients reaching the target IMI and MEM concentrations were 44.8% and 38.4%, respectively. The proportions of patients infected with drug-resistant bacteria were 57.5% and 69.7% in the IMI group and MEM group, respectively. In the multivariate analysis, the risk factors for an IMI concentration that did not reach the target were infection with drug-resistant bacteria, and those for MEM were infection with drug-resistant bacteria, estimated glomerular filtration rate, and diabetes mellitus. A total of 47.1% of patients had good outcomes in the IMI cohort, and 38.1% of patients had good outcomes in the MEM cohort. The duration of mechanical ventilation and IMI concentration were associated with ICU stay in patients in the IMI cohort, while MEM concentration and severe pneumonia affected the clinical outcome of patients in the MEM cohort. CONCLUSION: Infection with drug-resistant bacteria is an important factor influencing whether IMI and MEM concentrations reach the target. Furthermore, IMI and MEM concentrations are associated with the clinical outcome, and elevated doses of IMI and MEM should be given to patients who are infected with drug-resistant bacteria.

Effect of Klebsiella-specific phage on multidrug-resistant Klebsiella pneumoniae- an experimental study.

BACKGROUND: The objective of this study was to study the effect of Klebsiella-specific phage isolated from sewage with and without the combination of antibiotics (imipenem) on the growth of clinical isolates of multidrug-resistant Klebsiella pneumoniae by time-kill assay and also to study the effect of bacteriophage and bacteriophage-antibiotic (imipenem) combination on biofilm production. METHODS: A total of 40 MDR K. pneumoniae isolates were used. Klebsiella-specific phage was isolated using K. pneumoniae subspp. pneumoniae ATCC 33495 as the host from sewage. In vitro time kill curve assays were performed to evaluate the effect of Klebsiella-specific phage with and without the combination of antibiotics on the viable cell counts of MDR K. pneumoniae isolates. Microtiter plate method of O'Toole and Kolter was used to study the effect of Klebsiella-specific phage with and without the combination of antibiotics on biofilm production. For the Time kill assay, results were analyzed for significant differences using Friedman test. Tests for significant differences between the different groups were found using the Mann-Whitney U test. The correlation between the formation of biofilm was analyzed using Karl Pearson's coefficient of correlation. P value of <0.05 was considered to be statistically significant. RESULTS: In vitro time-kill assay showed a 0.4 log decline and a 0.5 log decline in K. pneumoniae colony counts at 4 h, when phage was administered individually and in combination with imipenem, respectively (p < 0.001). Phage and phage-imipenem combinations reduced the ability of K. pneumoniae to produce biofilm by 38 % and 53 %, respectively. CONCLUSION: In conclusion, this study suggests that phage therapy has inhibiting activity against MDR K. pneumoniae. It is found to reduce bacterial cell count and biofilm formation but does not have a total cidal effect. However, in order to get a notable result, a phage cocktail or combination of phage with other antibiotic(s) is suggested.

Study on the Mechanism of Levofloxacin Combined with Imipenem Against Pseudomonas aeruginosa.

Pseudomonas aeruginosa can develop resistance. Therefore, it is necessary to design proper treatment for it. Pseudomonas aeruginosa can develop resistance against levofloxacin due to the development of efflux pumps. However, the development of these efflux pumps cannot develop resistance against imipenem. Additionally, the MexCDOprJ efflux system which is responsible for the resistance of Pseudomonas aeruginosa to levofloxacin is highly susceptible to imipenem. The objective of the study was to evaluate the emergence of resistance of Pseudomonas aeruginosa against 750 mg levofloxacin, 250 mg imipenem, and a combination of 750 mg levofloxacin and 250 mg imipenem. An in vitro pharmacodynamic model was selected for the evaluation of the emergence of resistance. Pseudomonas aeruginosa strain 236, Pseudomonas aeruginosa strain GB2, and Pseudomonas aeruginosa strain GB65 were selected. Susceptibility testing of both antibiotics was done by agar dilution methodology. A disk diffusion bioassay was performed for antibiotics. RT-PCR measurement was done for the evaluation of expressions of Pseudomonas aeruginosa genes. Samples were tested at 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, and 30 h. Levofloxacin and imipenem both individually reported a decrease in colony-forming unit per milliliter of strength in the initial stage but in the later stage both develop resistance individually. Levofloxacin with imipenem had no resistance to Pseudomonas aeruginosa during 30 h. Time after the start of development of resistance or decrease in clinical efficacy was higher for levofloxacin and imipenem combination in all strains. The concentration of Pseudomonas aeruginosa at the time after the start of development of resistance or decrease in clinical efficacy was fewer for levofloxacin and imipenem combination. Levofloxacin with imipenem is recommended for the treatment of infection due to Pseudomonas aeruginosa.

Relationship of imipenem therapeutic drug monitoring to clinical outcomes in critically ill patients: a retrospective cohort study.

The primary objective of this study was to evaluate the predictors associated with target concentration (non-)attainment of imipenem in critically ill patients. The secondary objective was to explore the correlation between achieving imipenem target concentrations and clinical outcomes of therapy. A retrospective cohort study was conducted in critically ill patients treated with imipenem. Clinical data were extracted from the patients' electronic medical records. The pharmacokinetic/pharmacodynamic target was defined as free imipenem concentrations above the minimum inhibitory concentration (MIC) of the pathogen at 100% (100%fT>MIC) of the dosing interval. Factors associated with the non-attainment of target concentrations were evaluated using binomial logistic regression. Kaplan-Meier analysis was used to investigate the correlation between (non-)attainment targets and 30-day mortality. A total of 406 patients were included, and 55.4% achieved the target of 100%fT>MIC. Regression analysis identified an initial daily dose of imipenem ≤ 2 g/day, augmented renal clearance, age ≤ 60 years, recent surgery, and absence of positive microbiology culture as risk factors for target non-attainment. Achieving the 100%fT>MIC target was significantly associated with clinical efficacy but not with 30-day mortality. Selective application of therapeutic drug monitoring in the early stages of imipenem treatment for critically ill patients can improve clinical outcomes. Further research should explore the potential benefits of TDM-guided dosing strategies for imipenem in critical care settings.

In vitro activity of ceftazidime-avibactam, imipenem-relebactam, aztreonam-avibactam, and comparators toward carbapenem-resistant and hypervirulent Klebsiella pneumoniae isolates.

IMPORTANCE: To our knowledge, this is the first study to report the in vitro activity of two novel antimicrobial drugs, including imipenem-relebactam (IMR) and aztreonam-avibactam (AZA), toward carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-hvKP) strains. Our in vitro activity study revealed that only few antibacterial agents (including several novel agents) exhibit high antimicrobial activity toward carbapenem-resistant Klebsiella pneumoniae (CRKP) and CR-hvKP isolates. IMR and AZA may be promising therapeutic agents for the treatment of infections caused by CRKP and CR-hvKP isolates.

Carbapenemase-Producing Bacteria Isolated from ICU Patients of a Peruvian Government Hospital during the COVID-19 Pandemic: A Descriptive Analysis.

Background and Objectives: In Peru, the presence of antimicrobial-resistant bacteria is a constant concern in hospitals and has likely increased in frequency during the pandemic. The objective of the study was to analyze the frequency of carbapenemase-producing bacteria resistant to two carbapenems (Imipenem and Meropenem), which were isolated from Peruvian patients in the intensive care unit of the Victor Lazarte Echegaray Hospital in Trujillo (Peru) during the COVID-19 pandemic. Materials and Methods: The biological samples of the patients hospitalized in the ICU were processed in the Microbiology Diagnostic Laboratory of the Víctor Lazarte Echegaray Hospital between May 2021 and March 2022. Antimicrobial sensitivity was determined with the automated system AutoScan-4, and for the identification of the type of carbapenemase, the RESISIT-3 O.K.N K-SET cassettes were used. Results: The results show that 76 cultures (76/129) had resistance to the two carbapenems (imipenem or meropenem), where the most frequent were Klebsiella pneuomoniae (31.6%), Pseudomonas aeruginosa (26.3%), and Acinetobacter baumannii (14.5%). Pseudomonas aeruginosa cultures showed at least three carbapenemase types (KPC, NDM, and OXA-48), while A. baumannii, Escherichia coli, and Burkholderia cepacia complex presented at least two carbapenemases (NDM and OXA-48). The carbapenemase NDM was detected in Enterobacter cloacae, Morganella morganii, and Proteus mirabilis, while KPC was present in all Klebsiella pneumoniae and Klebsiella oxytoca cultures. Conclusions: The samples from patients hospitalized in the Victor Lazarte Echegaray Hospital ICU showed a high prevalence of imipenem- and meropenem-resistant bacteria. These findings are relevant and concerning from the perspective of antibiotic-resistant bacteria monitoring, control, and disinfection. Thus, an appropriate antibiotic policy must be implemented.

Multifunctional Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9-Based Nanobomb against Carbapenem-Resistant Acinetobacter baumannii Infection through Cascade Reaction and Amplification Synergistic Effect.

Carbapenems have been considered to be the preferred antibiotics against Acinetobacter baumannii thus far. However, carbapenem-resistant Acinetobacter baumannii (CRAB) has gradually escalated worldwide, and it frequently causes respiratory and bloodstream infections. Its resistance may lead to high mortality. Thus, there is an urgent need to develop antibacterial drugs. In our research, the pH-sensitive sgRNA-I/L@ZS nanosystem delivered imipenem and better released it in infected tissues to synergistically damage bacteria with nanoparticles. Gene editing of the CRISPR-Cas9 nanosystem amplified the synergistic effect by reversing the drug-resistance of imipenem. Nitric oxide, which l-arginine reacted with ROS to produce in cascade reaction and bacterial infection sites, was beneficial to heal the infected tissues and induce bacteria death for further enhancing antibacterial effects. In addition, this nanocomposite influenced host-bacteria interactions and restrained and destroyed biofilms. The sgRNA-I/L@ZS nanosystem, similar to a nanobomb, was a high-efficiency bactericide against CRAB. Eventually, in acute pneumonia and peritonitis mouse models, the sgRNA-I/L@ZS nanosystem could combat bacteria and protect tissues from infection. It had marked suppressive effects on inflammation and promoted healing and proliferation of infected tissues. This multifunctional nanosystem is expected to be an effective antibacterial agent in the clinic based on good biocompatibility and no toxic side effects. Therefore, developing the nanocomposites will take a favorable step toward solving intractable public health issues.

bla KPC-2 overexpression and bla GES-5 carriage as major imipenem/relebactam resistance mechanisms in Pseudomonas aeruginosa high-risk clones ST463 and ST235, respectively, in China.

Pseudomonas aeruginosa high-risk clones pose severe threats to public health. Here, we characterize the imipenem/relebactam (IR) resistance mechanisms in P. aeruginosa high-risk clones sequence type 235 (ST235) and ST463 in China. Minimum inhibitory concentrations (MICs) were determined, and Illumina short-read sequencing was performed for 1,168 clinical carbapenem-resistant P. aeruginosa (CRPA) isolates. The gene copy number and expression level were analyzed by Illumina sequencing depth and reverse transcription-quantitative PCR, respectively. Resistance conferred by bla GES-5 was evaluated by cloning experiments. ST463 and ST235 accounted for 9.8% (115/1,168) and 4.5% (53/1,168) of total isolates, respectively, and showed high frequencies of extensively drug-resistant and difficult-to-treat resistant phenotypes. The overall IR-resistant rate in CRPA was 21.0% (245/1,168). However, the IR resistance rate was 81.7% (94/115) in ST463-PA and 52.8% (28/53) in ST235-PA. Of the ST463 isolates, 92.2% (106/115) were Klebsiella pneumoniae carbapenemase-producing P. aeruginosa (KPC-PA), and all 94 IR-resistant ST463-PA produced KPC-2. Compared to IR-susceptible ST463 KPC-2-PA, IR-resistant ST463 KPC-2-PA exhibited significantly higher bla KPC-2 copy numbers and expression levels. In ST463 KPC-2-PA, 16 mg/L relebactam resulted in additional fourfold reductions in imipenem MIC50/90 values compared to 4 mg/L relebactam. In ST235, 1.9% (1/53) carried bla IMP carbapenemase and 54.7% (29/53) carried bla GES carbapenemase. Other than the IMP producer, all 27 IR-resistant ST235-PA produced GES-5. Cloning experiments revealed that imipenem resistance in bla GES-5-carrying PAO1 transformants was generally unaffected by relebactam. In conclusion, IR-resistant CRPA isolates in China were mainly distributed in P. aeruginosa high-risk clones ST463 and ST235. The major underlying IR resistance mechanisms were bla KPC-2 overexpression and bla GES-5 carriage.