Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.

Nephrotoxicity caused by polymyxin in the treatment of drug-resistant Gram-negative bacterial infections：a meta-analysis / 中国药房

OBJECTIVE To evaluate the incidence of nephrotoxicity in patients with drug-resistant Gram-negative bacterial infections after the use of polymyxin， and to provide evidence-based reference for clinical rational drug use. METHODS PubMed， Embase， Web of Science， the Cochrane Library， Wanfang database， CNKI， VIP and SinoMed were searched to collect randomized controlled trials （RCTs） or cohort studies about the polymyxin （trial group） versus other antibiotics （control group） or polymyxin B （trial group） versus polymyxin E （control group）. After literature screening， data extraction and quality evaluation， RevMan 5.4.1 software was used for meta-analysis. RESULTS A total of 37 studies were included， including 4 RCTs and 33 cohort studies， with a total of 5 871 patients. The meta-analysis results showed that in RCT [RR＝2.64，95%CI （1.43，4.87），P＝0.002] and in cohort studies [RR＝1.59， 95%CI （1.27， 1.98）， P＜0.000 1]， the incidence of nephrotoxicity in the trial group was significantly higher than control group. The results of the subgroup analysis of cohort studies showed that the incidence of nephrotoxicity in the trial group （receiving polymyxin） was significantly higher than control group （receiving new β-lactam and β-lactamase inhibitors and tigecycline）； when Kidney Disease Improving Global Outcomes （KDIGO）， renal replacement therapy or 0.5 times increase in serum creatinine were used as the standard of nephrotoxicity， the incidence of nephrotoxicity in the trial group was significantly higher than the control group （P＜0.05）. The incidence of nephrotoxicity in patients receiving polymyxin E was significantly higher than those using polymyxin B [RR＝0.57， 95%CI （0.39，0.84）， P＝0.005]. CONCLUSIONS In the treatment of drug-resistant Gram-negative bacteria infections， the incidence of nephrotoxicity caused by polymyxin is relatively high. The TYU108F）； incidence of nephrotoxicity caused by polymyxin E is higher than polymyxin B.

Shorter Incubation Times for Detecting Multi-drug Resistant Bacteria in Patient Samples: Defining Early Imaging Time Points Using Growth Kinetics and Total Laboratory Automation

BACKGROUND: The transition from manual processing of patient samples to automated workflows in medical microbiology is challenging. Although automation enables microbiologists to evaluate all samples following the same incubation period, the essential incubation times have yet to be determined. We defined essential incubation times for detecting methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant gram-negative bacteria (MDRGN), and vancomycin-resistant enterococci (VRE). METHODS: We monitored the growth kinetics of MRSA, MDRGN, and VRE between two and 48 hours on chromogenic media to establish the time points of first growth, single colony appearance, and typical morphology for 102, 104, 106, and 108 colony forming units/mL. Subsequently, we imaged plates inoculated with 778 patient samples after 20, 24, and 36 hours. RESULTS: The first growth, single colony appearance, and typical morphology time points were inoculum-dependent. First growth appeared after 6–18 hours, 4–18 hours, and 8–48 hours for MRSA, MDRGN, and VRE, respectively, and single colonies appeared at 12–18 hours, 6–20 hours, and 12–48 hours, respectively. Typical morphology was visible at 14–22 hours and 12–48 hours for MRSA and VRE, but was not determined for MDRGN. By examining patient samples, ≥98% of MRSA and MDRGN were visible 20 hours after the start of incubation. Following 24 hours of incubation, only 79.5% of VRE were clearly visible on the respective plates. CONCLUSIONS: An incubation time of 20 hours is sufficient for detecting MRSA and MDRGN. VRE growth is much slower and requires additional imaging after 36 hours.

A retrospective study on the outcome of children with extensively drug-resistant gram-negative infection treated with Colistin vs. other Antimicrobials

Introduction@#The increasing trend of extensively drug-resistant gram-negative infections led to the reconsideration of colistin as a valuable therapeutic option.@*Objectives@#To describe the clinical profile and treatment response of children with extensively drug resistant (XDR) Gram-negative infections given colistin versus other antimicrobials.@*Methods@#This retrospective descriptive study involved patients treated for XDR Gram-negative infections from January 2014 to June 2017 in a tertiary hospital in Metro Manila. Descriptive statistics were used to summarize clinical characteristics of subjects. Treatment response to colistin versus other antimicrobial agents were compared in terms of success, failure, and toxicity. The Fisher-exact and Mann Whitney U tests were used to assess statistical differences between the colistin and non-colistin groups. @*Results@#Majority of patients with XDR Gramnegative infections had previous antibiotic exposure. More patients in the colistin group received TPN 43.2% vs 23.7% (p=0.035), had a longer hospital stay prior to the onset of XDR Gram-negative infection, 27 days vs. 15.5 days (p=0.001), and had a longer total hospital stay with a median of 52 days vs 30 days (p < 0.001). Treatment success was significantly higher in the colistin group at 70.3%, as against 46.5% in the non-colistin group (p=0.014). There was no difference in the treatment duration of both groups. The colistin group had longer time to clinical response, with a mean of 6.27 (+ 3.57) days compared with those from the non-colistin group, with a mean of 4.36 (+ 1.77)(p=0.008). The colistin group had more fungal infections during the course of treatment (p=0.001).@*Conclusion@#Based on our institutional experience, colistin is considered relatively effective and safe in treating XDR Gram-negative infections in children.

A Randomized, Phase IV, Comparison Study on the Efficacy and Safety of Tapocin(R) and Targocid(R) in Treating Infections Caused by Multi-Resistant Gram Positive Cocci / 감염과화학요법

BACKGROUND: Tapocin(R) is a recently produced Teicoplanin in Korea. To evaluate its clinical usefulness, we compared clinical outcome and safety of Tapocin(R) with those of Teicoplanin (Targocid(R)) against infection caused by multi-drug resistant gram positive cocci. MATERIALS AND METHODS: Twenty-four adult patients infected with multi-drug resistant gram positive cocci were enrolled and randomized into each treatment arm after informed consents were obtained. All patients were given one of the test articles for 7 to 14 days intravenously. Clinical outcome and safety were compared between the two groups. Statistical analysis was done by Chi-square test, Student's t-test, and Fisher's exact test. RESULTS: Twenty out of 24 enrolled patients could be evaluated for clinical efficacy and safety (10 patients for each treatment arm). The baseline characteristics were not significantly different between the two groups in terms of mean age, sex ratio, underlying diseases, site of infections, and causative microorganisms. MRSA was the most common organism: 66.67% in Tarpocin(R) and 91.67% in Targocid(R) groups. Total doses of Targocid(R) and Tapocin(R) administered were 24 and 23 vials, respectively. Fever resolved in 90% of treated subjects and there were no significant differences between the two groups. Bacteriological response shows that the causative microorganisms were eradicated except for one MRSA isolate from each group. Drug fever, as a side effect, was reported from one subject in each group. CONCLUSION: Efficacy and safety of Tapocin(R) is comparable to those of Targocid(R) for the treatment of infections with multi-drug resistant gram-positive cocci.

A Randomized, Phase IV, Comparison Study on the Efficacy and Safety of Tapocin(R) and Targocid(R) in Treating Infections Caused by Multi-Resistant Gram Positive Cocci / 감염과화학요법

BACKGROUND: Tapocin(R) is a recently produced Teicoplanin in Korea. To evaluate its clinical usefulness, we compared clinical outcome and safety of Tapocin(R) with those of Teicoplanin (Targocid(R)) against infection caused by multi-drug resistant gram positive cocci. MATERIALS AND METHODS: Twenty-four adult patients infected with multi-drug resistant gram positive cocci were enrolled and randomized into each treatment arm after informed consents were obtained. All patients were given one of the test articles for 7 to 14 days intravenously. Clinical outcome and safety were compared between the two groups. Statistical analysis was done by Chi-square test, Student's t-test, and Fisher's exact test. RESULTS: Twenty out of 24 enrolled patients could be evaluated for clinical efficacy and safety (10 patients for each treatment arm). The baseline characteristics were not significantly different between the two groups in terms of mean age, sex ratio, underlying diseases, site of infections, and causative microorganisms. MRSA was the most common organism: 66.67% in Tarpocin(R) and 91.67% in Targocid(R) groups. Total doses of Targocid(R) and Tapocin(R) administered were 24 and 23 vials, respectively. Fever resolved in 90% of treated subjects and there were no significant differences between the two groups. Bacteriological response shows that the causative microorganisms were eradicated except for one MRSA isolate from each group. Drug fever, as a side effect, was reported from one subject in each group. CONCLUSION: Efficacy and safety of Tapocin(R) is comparable to those of Targocid(R) for the treatment of infections with multi-drug resistant gram-positive cocci.