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Abstract 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.

ABSTRACT: Objectives: The main aim of this study was to evaluate the antibiofilm activity of cefiderocol alone and in combination with imipenem vs. sessile cells of Pseudomonas aeruginosa, assessing a potential synergistic bactericidal effect. Methods: Ten P. aeruginosa clinical isolates from infected implants and bloodstream were included in the study. Cefiderocol was tested alone and in combination with imipenem on 24-h-old P. aeruginosa biofilm formed on porous glass beads. For each antibiotic formulation, minimum bactericidal biofilm concentration (MBBC), defined as the lowest concentration that determined a reduction of at least 3 log10 CFU/mL compared with the untreated control, was evaluated. Scanning electron microscopy (SEM) was used to investigate the biofilm of P. aeruginosa treated with cefiderocol, imipenem, or their combination. Results: Cefiderocol and imipenem were tested alone on P. aeruginosa biofilm and a reasonable reduction in the number of viable cells was observed, especially at high drug concentrations tested. The synergistic effect of cefiderocol in combination with imipenem was evaluated for five selected isolates. Cotreatment with the two drugs led to a remarkable reduction of cell viability by resulting in synergistic bactericidal activity in all tested strains and in synergistic eradicating activity in only one isolate. SEM analysis revealed that, in cefiderocol-treated biofilm, bacterial cells became more elongated than in the untreated control, forming filaments in which bacterial division seems to be inhibited. Conclusions: Cefiderocol exhibited an encouraging antibiofilm activity against tested strains, representing a valid option for the treatment of P. aeruginosa biofilm-associated infections, especially when administered in combination with imipenem.

Abstract Therapeutic drug monitoring is an important clinical testing of the drugs to monitor their concentrations in plasma in order to guarantee their optimal impact, and to avoid any side effects resulting from drug-drug interactions. A green reversed-phase high-performance liquid chromatographic method using a photodiode array detector (RP-HPLC-PDA) was developed for the simultaneous determination of three carbapenem antibiotics (Imipenem, ertapenem, and meropenem) with the co-formulated drug (cilastatin) and contraindicated drugs (probenecid and warfarin) in spiked human plasma. The separation was achieved at 25 °C using a gradient elution of a mixture of mobile phase A: methanol and mobile phase B: phosphate buffer (pH 3.0). The photodiode array detector was adjusted at 220 nm. Bioanalytical method validation was carried out as per the FDA guidelines, and the method showed good linearity ranges for the six drugs that included their Cmax levels along with low limits of quantification. Based on the results, the method was found to be accurate and precise; with high % recovery and good % RSD, respectively. The method was successfully applied to spiked human plasma, signifying a good potential to be implemented in future TDM studies of these drugs when co-administered together.

Abstract Background In Japan, carbapenem-resistant Enterobacterales (CRE) infections were incorporated into the National Epidemiological Surveillance of Infectious Diseases (NESID) in 2014, necessitating mandatory reporting of all CRE infections cases. Subsequently, pathogen surveillance was initiated in 2017, which involved the collection and analysis of CRE isolates from reported cases to assess carbapenemase gene possession. In this surveillance, CRE is defined as (i) minimum inhibitory concentration (MIC) of meropenem ≥2 mg/L (MEPM criteria) or (ii) MIC of imipenem ≥2 mg/L and MIC of cefmetazole ≥64 mg/L (IPM criteria). This study examined whether the current definition of CRE surveillance captures cases with a clinical and public health burden. Methods CRE isolates from reported cases were collected from the public health laboratories of local governments, which are responsible for pathogen surveillance. Antimicrobial susceptibility tests were conducted on these isolates to assess compliance with the NESID CRE definition. The NESID data between April 2017 and March 2018 were obtained and analyzed using antimicrobial susceptibility test results. Results In total, 1681 CRE cases were identified during the study period, and pathogen surveillance data were available for 740 (44.0%) cases. Klebsiella aerogenes and Enterobacter cloacae complex were the dominant species, followed by Klebsiella pneumoniae and Escherichia coli. The rate of carbapenemase gene positivity was 26.5% (196/740), and 93.4% (183/196) of these isolates were of the IMP type. Meanwhile, 315 isolates were subjected to antimicrobial susceptibility testing. Among them, 169 (53.7%) fulfilled only the IPM criteria (IPM criteria-only group) which were susceptible to meropenem, while 146 (46.3%) fulfilled the MEPM criteria (MEPM criteria group). The IPM criteria-only group and MEPM criteria group significantly differed in terms of carbapenemase gene positivity (0% vs. 67.8%), multidrug resistance rates (1.2% vs. 65.8%), and mortality rates (1.8% vs 6.9%). Conclusion The identification of CRE cases based solely on imipenem resistance has had a limited impact on clinical management. Emphasizing resistance to meropenem is crucial in defining CRE, which pose both clinical and public health burden. This emphasis will enable the efficient allocation of limited health and public health resources and preservation of newly developed antimicrobials.

Yueliang Chen,1,* Yun Han,2,3,* Feng Guo,1 Zhenwei Yu2,3 1Intensive Care Unit, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 3Research Center for Clinical Pharmacy, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng Guo; Zhenwei Yu, Email 3408003@zju.edu.cn; yzw_srrsh@zju.edu.cnAbstract: Imipenem is a broad-spectrum antibiotic that has been used in treating severe infections and exhibits a time-dependent PK/PD profile. Its dose should be adjusted based on renal function. However, there is little experience with imipenem dosing in obese adolescent patients with augmented renal clearance (ARC) and history of schizophrenia. This case reported successful dosing of imipenem in an obese adolescent patient with ARC based on therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD). A 15-year-old male adolescent patient with history of schizophrenia was diagnosed with ventilator-associated pneumonia due to carbapenem-susceptible Klebsiella pneumoniae and received imipenem treatment (0.5 g every 8 hours with a 1-hour infusion). However, the exposure of imipenem was suboptimal due to ARC, and there is no available model for MIPD in this patient. Thus, we utilized prediction error to find a population pharmacokinetic model that fit this patient and ran Maximum a posteriori Bayesian estimation and Monte Carlo simulation based on screened models to predict changes in drug concentrations. The dose of imipenem was adjusted to 0.5 g every 6 hours with a 2-hour infusion, and subsequent TDM revealed that dosing adjustment was accurate and successful. Finally, the patient’s status of infection improved. This study will be beneficial to imipenem dosing in similar cases in the future, thereby improving the safety and effectiveness of imipenem or other antibiotics.Keywords: case report, imipenem, therapeutic drug monitoring, population pharmacokinetic

Background: Antibiotic resistant infections were responsible for the deaths of 1.27 million people, with an overall 4.95 million deaths associated with complications from resistant bacterial infections globally. Aim: This study determined the antibiotics; aztreonam (ATM), meropenem (MEM) and imipenem (IMP) resistant Gram negative bacteria from inpatient department in FMC, Birnin Kebbi. Methods: Thirty (30) samples from different fomites in the inpatient department were aseptically collected using swab sticks. Streak plate technique was used to characterize and identify the bacterial isolates, then disc diffusion technique was employed to check the resistance pattern of the isolates to the antibiotics as in EUCAST guidelines version 12.0. Results: The biochemical technique further confirmed the occurrence of; Escherichia coli (E. coli) (35%), Pseudomonas aeruginosa (30%), Klebseilla pneumonia (20%) and Acinetobacter baumannii (A. baumannii) (15%). On the antibiotic resistance screening, E. coli and A. baumannii were found multi-drug resistant (MDR) to the antibiotics. The remaining isolates show resistance to the antibiotics except Pseudomonas aeruginosa and Klebsiella pneumonia were found sensitive to MEM and IPM respectively. Conclusion: Bacteria isolated are highly drug resistant to the antibiotics. The need for routine environmental sanitation, proper personal hygiene among the hospital participants, drug repositioning and molecular assay for rapid detection of MDR bacteria.

ABSTRACT 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.

Listeria are Gram-negative intracellular foodborne pathogens that can cause invasive infections with high mortality rates. In this work, the antibacterial activity of ten essential oils, infusion extracts, and decoction extracts of some medicinal plants was tested against Listeria monocytogenes and listeria ivanovii strains. The effects of different physical conditions including temperature, pH, sodium chloride, and some organic acids were studied. The results showed that the water extracts gave the maximum bacterial inhibition, while ethanolic extract was inactive against the tested Listeria spp. The antibiotic sensitivity of L. monocytogenes LMG10470 and L. ivanovii LMZ11352 was tested against five antibiotics including imipenem, levofloxacin, amikacin, ampicillin, and amoxicillin. Imipenem was the most effective antibiotic, resulting in inhibition zones of 40 mm and 31 mm for L. monocytogenes and L. ivanovii, respectively. When imipenem mixed with Syzygium aromaticum oil, Salvia officinalis oil, Pimpinella anisum infusion, and Mentha piperita infusion each, the water extract of Moringa oleifera leaves and seeds against LMG10470 and LMZ11352 resulted in broader antibacterial activity. The antimicrobial activity of both Pimpinella anisum and Mentha piperita plant extracts is related to a variety of bioactive compounds indicated by gas chromatography–mass spectrometry analysis of these two plant extracts. These two plant extracts seemed to contain many chemical compounds elucidated by gas chromatography–mass spectrometry (GC-MS) and infrared radiation spectra. These compounds could be classified into different chemical groups such as ethers, heterocyclic compounds, aromatic aldehydes, condensed heterocyclic compounds, ketones, alicyclic compounds, aromatics, esters, herbicides, saturated fatty acids, and unsaturated fatty acids. The use of these natural compounds seems to be a useful technological adjuvant for the control of Listeria spp. in foods.

Pseudomonas aeruginosa causes many infections worldwide. Multidrug-resistant bacteria are mostly watched in hospital-acquired infections and are linked with high mortality rates. This study aims to find a possible cure for P. aeruginosa by using an additive and synergistic combination of drugs. The Carbapenem-resistant P. aeruginosa were isolated and identified by using clinical and laboratory standards institute protocols and their antibiotic susceptibility testing was performed by using disc and well diffusion method. In computational analysis, all of the ligands and proteins were selected and docking was done using PYRX. Hundred samples were taken of isolated Gram-negative bacteria of which 25% were P. aeruginosa. Additive combinations (meropenem [MPM] + tobramycin [TOB] was 100% sensitive and imipenem + TOB was also 100% sensitive) and synergistic combinations (MPM + ciprofloxacin were 90% sensitive and amikacin and imipenem) were 100% sensitive according to CLSI protocol. In computational analysis, TOB gave the highest binding energy of −11.4, whereas MPM shows a binding energy of −9.3. In conclusion, Additive and synergistic combination of drugs showed good antibacterial activity against Pseudomonas aeruginosa. Hence it can be used as a good treatment option for P. aeruginosa.

Objective: To compare intra-operative wound irrigation with normal saline versus irrigation with Imipenem and Cilastatin solution to develop surgical site infections in open appendectomy wounds. Study Design: Quasi-experimental study. Place and Duration of Study: Department of Surgery, Combined Military Hospital, Bahawalnagar Pakistan, from Oct 2015 to Oct 2017. Methodology: Patients diagnosed with cases of acute appendicitis and planned to undergo open appendectomy were randomly divided into two equal groups; Group-A and Group-B. Group-A was subjected to intra-operative wound irrigation with 100 ml saline solution before skin closure. Group-B was irrigated with Imipenem and Cilastatin solution (500 mg diluted in 10ml of distilled water). Development of post-operative Surgical Site Infection was checked till the 30th Post-Operative Day. Results: Frequency of post-operative Surgical Side infection was comparatively less in Group-B (2.4%) as compared to GroupA (8%), which was found to be statistically significant (p-value=0.046) Conclusion: Intra-operative wound irrigation with Imipenem and Cilastatin solution was superior to normal saline irrigation regarding the development of Surgical Site Infection in cases undergoing open appendectomy.

Objective: To determine in vitro efficacy of Imipenem/Relebactam against multi-drug resistant strains. Study Design: Cross-sectional study. Place and Duration of Study: Department of Microbiology, Fauji Foundation Hospital (FFH) Rawalpindi, Pakistan from Jul to Dec 2022. Methodology: All specimens from indoor and outdoor patients with infection due to Gram-negative organisms showing resistance to Imipenem disc (10μg) were included. Cultures were inoculated on Blood and MacConkey’s agar. Imipenemresistant Gram-negative species identification was made by Gram stain, Oxidase test and commercially available identification strips Analytical profile index 10S (API-10S) (from bioMerieux, Inc.).Imipenem-resistant species were identified, showing a zone diameter of less than 23mm against10µg Imipenem disc for Enterobacterale and Non-Enterobacterales, and for Pseudomonas species, zone size is ≤19mm. These resistant organisms were tested for sensitivity against Imipenem/Relebactam by E-strip (MTSTM –MIC Test Strip) (Liofilchem, Inc., Waltham, MA). Results: Out of 160 Carbapenem-resistant Enterobacterale and Non-Enterobacterales specimens, only 14 isolates (including 02 Pseudomonas spp.) showed susceptibility to Imipenem/Relebactam combination of drug. US-FDA Imipenem/Relebactam susceptibility interpretive criteria (STIC) was used. Conclusion: In our setup, only 8.75% isolates showed sensitivity to this newer drug combination Imipenem/Relebactum. This highlights the importance of evaluating newer drugs in our population before using them empirically.

ABSTRACTCarbapenem-resistant Enterobacterales (CRE) are some of the most important pathogens causing infections, which can be challenging to treat. We identified four blaIMP-carrying CRE isolates and collected clinical data. The transferability and stability of the plasmid were verified by conjugation, successive passaging, and plasmid elimination assays. The IncC blaIMP-4-carrying pIMP4-ECL42 plasmid was successfully transferred into the recipient strain, and the high expression of traD may have facilitated the conjugation transfer of the plasmid. Interestingly, the plasmid showed strong stability in clinical isolates. Whole-genome sequencing was performed on all isolates. We assessed the sequence similarity of blaIMP -harboring plasmid from our institution and compared it to plasmids for which sequence data are publicly available. We found that four blaIMP-carrying CRE belonged to four different sequence types. The checkerboard technique and time-kill assays were used to investigate the best antimicrobial therapies for blaIMP-carrying CRE. The time-kill assay showed that the imipenem of 1× minimum inhibitory concentration (MIC) alone had the bactericidal or bacteriostatic effect against IMP-producing strains at 4–12 h in vitro. Moreover, the combination of tigecycline (0.5/1/2 × MIC) and imipenem (0.5/1 × MIC) showed a bactericidal effect against the blaIMP-26-carrying CRECL60 strain.IMPORTANCECarbapenem-resistant Enterobacterales (CRE) are an urgent public health threat, and infections caused by these microorganisms are often associated with high mortality and limited treatment options. This study aimed to determine the clinical features, molecular characteristics, and plasmid transmissible mechanisms of blaIMP carriage as well as to provide a potential treatment option. Here, we demonstrated that conjugated transfer of the IncC blaIMP-4-carrying plasmid promotes plasmid stability, so inhibition of conjugated transfer and enhanced plasmid loss may be potential ways to suppress the persistence of this plasmid. The imipenem alone or tigecycline-imipenem combination showed a good bactericidal effect against IMP-producing strains. In particular, our study revealed that imipenem alone or tigecycline-imipenem combination may be a potential therapeutic option for patients who are infected with IMP-producing strains. Our study supports further trials of appropriate antibiotics to determine optimal treatment and emphasizes the importance of continued monitoring of IMP-producing strains in the future.

The phenomenon of bacterial resistance to antibiotics, the emission and spread of these bacteria, and the genes that determine antibiotic resistance in the environment are now a major health security concern. This is especially important for anthropopressed surface waters used for recreational purposes. A particular threat is the occurrence of bacteria resistant to frequently applied pharmaceuticals, especially those used to treat persistent and complicated bacterial infections. Hence, a preliminary study of the occurrence of bacteria and genes determining resistance to selected antibiotics, ciprofloxacin and imipenem, was conducted in the bathing waters of the Great Rudnickie Lake. The research showed that the resistance to ciprofloxacin was exhibited by 28% of the total mesophilic bacteria present in water, while the resistance to imipenem was detected in 3.6% of them. It was found that 17–40% of ciprofloxacin-resistant isolates contained the fluoroquinolone-resistance gene qnrS, while the β-lactam-resistance gene blaTEM was found in all the imipenem-resistant strains. The increase in the number of bacteria resistant to the tested antibiotics in the waters of the river outflowing from the lake was observed compared to the inflowing waters, suggesting the potential of the water reservoir as a site for the spreading of drug resistance against tested antibiotics.

Abstract Background Carbapenem-resistant bacteria are an increasing problem in clinical practice; thus, it is important to identify β-lactamase inhibitors (e.g., relebactam) that can restore carbapenem susceptibility. We report analyses of relebactam enhancement of imipenem activity against both imipenem-nonsusceptible (NS) and imipenem-susceptible (S) Pseudomonas aeruginosa and Enterobacterales. Gram-negative bacterial isolates were collected for the ongoing Study for Monitoring Antimicrobial Resistance Trends global surveillance program. Clinical and Laboratory Standards Institute–defined broth microdilution minimum inhibitory concentrations (MIC) were used to determine the imipenem and imipenem/relebactam antibacterial susceptibilities of P. aeruginosa and Enterobacterales isolates. Results Between 2018 and 2020, 36.2% of P. aeruginosa (N = 23,073) and 8.2% of Enterobacterales (N = 91,769) isolates were imipenem-NS. Relebactam restored imipenem susceptibility in 64.1% and 49.4% of imipenem-NS P. aeruginosa and Enterobacterales isolates, respectively. Restoration of susceptibility was largely observed among K. pneumoniae carbapenemase-producing Enterobacterales and carbapenemase-negative P. aeruginosa. Relebactam also caused a lowering of imipenem MIC among imipenem-S P. aeruginosa and Enterobacterales isolates from chromosomal Ambler class C β-lactamase (AmpC)–producing species. For both imipenem-NS and imipenem-S P. aeruginosa isolates, relebactam reduced the imipenem MIC mode from 16 μg/mL to 1 μg/mL and from 2 μg/mL to 0.5 μg/mL, respectively, compared with imipenem alone. Conclusions Relebactam restored imipenem susceptibility among nonsusceptible isolates of P. aeruginosa and Enterobacterales and enhanced imipenem susceptibility among susceptible isolates of P. aeruginosa and isolates from Enterobacterales species that can produce chromosomal AmpC. The reduced imipenem modal MIC values with relebactam may result in a higher probability of target attainment in patients.

Abstract Background Antibiotics exert an outstanding selective pressure on bacteria, forcing their chromosomal gene mutations and drug resistance genes to spread. The objective of this study is to evaluate the expression of the New Delhi Metallo-β-Lactamase-1 gene (bla NDM−1) in the clinical isolate (Klebsiella pneumoniae TH-P12158), transformant strains Escherichia coli BL21 (DE3)-bla NDM−1, and Escherichia coli DH5α- bla NDM−1 when exposed to imipenem. Methods β-Lactamase genes (bla SHV, bla TEM−1, bla CTX−M−9, bla IMP, bla NDM−1, bla KPC, bla OXA, bla GES, and bla DHA) from randomly selected carbapenems-sensitive K.pneumoniae (n = 20) and E.coli (n = 20) strains were amplified by PCR. The recombinant plasmid of pET-28a harboring bla NDM−1 was transformed into E.coli BL21 (DE3) and E.coli DH5α by electroporation. The resistance phenotype and higher bla NDM−1 expression in K.pneumoniae TH-P12158, transformant E.coli BL21 (DE3)-bla NDM−1, and E.coli DH5α-bla NDM−1 were observed when exposed to imipenem with grade increasing, decreasing, and canceling doses, respectively. Results After being exposed to different doses of imipenem, the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of antimicrobial drugs and bla NDM−1 expression of strains increased, which was positively correlated with doses of imipenem. On the contrary, with the decrease or cancellation of imipenem doses, the bla NDM−1 expression was deteriorated, while the MIC and MBC values remained relatively stable. These results demonstrated that low doses of imipenem (˂MIC) could press bla NDM−1 positive strains producing stable drug resistance memory and altered bla NDM−1 expression. Conclusions Low doses of imipenem could press bla NDM−1 positive strains producing sustained resistance memory and altered bla NDM−1 expression. In particular, the positive correlation between the resistance genes expression and antibiotics exposure shows promising guiding significance for clinical medication.

ABSTRACT: Objective: Both ertapenem and other carbapenems, including imipenem, meropenem, and doripenem, are recommended in the treatment of extended-spectrum-β-lactamase (ESBL)-producing Enterobacterales infection. However, whether ertapenem is as effective as other carbapenems for ESBL-producing Enterobacterales remains unclear. Therefore, this meta-analysis was conducted to compare the clinical efficacy of ertapenem versus other carbapenems in the treatment of ESBL-producing Enterobacterales infection. Methods: PubMed, Web of Science, and Cochrane Library were searched from their inception to 29 November 2022. Only studies comparing ertapenem and other carbapenems in the treatment of patients with ESBL-producing Enterobacterales infections were included. Results: A total of six studies meeting selection criteria were identified. Overall, ertapenem was associated with a significantly lower 30-d mortality when compared with other carbapenems (10.7% [46/431] vs. 17.7% [104/586]; risk ratio [RR], 0.61; 95% CI: 0.40–0.91). The ertapenem group exhibited a significantly shorter length of hospital stay than the other carbapenem groups (mean differences, -6.02 d; 95% CI, -9.39 to -2.64). No significant differences were noted between ertapenem and other carbapenem groups in terms of rates of clinical cure or improvement (RR, 1.11; 95% CI: 0.97–1.25) and microbiological eradication (RR, 1.01; 95% CI: 0.97–1.06). Conclusions: Ertapenem could be as effective as other carbapenems in the treatment of patients with ESBL-producing Enterobacterales infections.

Introduction: Drug utilization evaluation (DUE) studies are designed to evaluate the rational use of drugs. Our purpose in this study is to evaluate the pattern of Imipenem, a broad-spectrum antibiotic used in different parts of Imam Khomeini and Taleghani Educational Center of Urmia. Method and material: This is a cross-sectional and retrospective study. The study was conducted by reviewing medical records of 200 admitted patients who received Imipenem during March 2016 to 2017. Results: In the study Imipenem was prescribed most frequently for intra-abdominal infection in 71 cases (35.5%), 41cases (20.5%) respiratory infection, 31 cases (15.5%) urinary tract infection, 25 cases (12.5%) skin infection, 15 (7.5%) cases septicemia infection, 7 (3.5%) cases bone and neutropenic infection, endocarditis infection were reported in 3 cases (1.5%). The highest incidence was related to intra-abdominal infections. 61% of Talehgsni hospital patients and 46% of Imam Khomeini hospital patients received Imipenem less than a week. The used dose in all patients was between one to four grams per day and the frequency of use was not correct in 7% of Taleghani hospital patients and 23% of patients in Imam Khomeini hospital. Conclusion: Some AB combination was proved to be inappropriate to the guidline consedering the indication or the microorganism to be covered. It is necessary to take action to improve prescribing habit in order to reduce the unnecessary usage of antibiotic thus enhance rational antibiotic use.

Antibiotic resistant pathogens are affecting the community and healthcare institutions all over the world. Pakistan is a developing country and resistance to drugs is the main issue and is of great importance. Current study is focused on isolation and identification of bacterial pathogens, i.e. member of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii for the evaluation of prevalence, distribution of sensitivity and antibiogram of different antibiotics and carbapenem resistance isolates with phenotypic detection of resistant gene. Total 200 samples of different sources were collected and tested for bacterial pathogens. Out of 200 samples, 83 (41.5%) were found positive for different bacterial pathogens while 117 (58.5%) were negative. Among these 83 positive samples, Urine 43 (51.8%), Pus 22 (26.5%), Blood 8 (9.8%), Tissue 3 (3.6%), wound swab 2 (2.4%), Sputum 3 (3.6%) and HVS 2 (2.4%). E. coli 37 (44.6%), Klebsiella species 23 (27.7%), Proteus vulgaris 8 (9.6%), Ps. aeruginosa 4 (4.8%), Acinetobacter baumannii 4 (4.8%), C. freundii 2 (2.4%), S. typhi 2 (2.4%), P. mirabilis 1 (1.2%), M. morganii 1 (1.2%) and member of Enterobacteriaceae 1 (1.2%) were identified. Out of 83 (41.5%) positive samples there are 17 samples which showed resistance against Imipenem (IPM) and were further processed by phenotypic method Modified Hodge Test MHT. After Modified Hoge Test (MHT) among all these 17 samples there were only 07 (39%) positive and the remaining 11 (61%) were negative, its mean there was no gene involve in 11 samples.

Antibiotic resistance is a major Public Health challenge worldwide. Mechanisms other than resistance are described as contributors to therapeutic failure. These include heteroresistance and tolerance, which escape the standardized procedures used for antibiotic treatment decision-making as they do not involve changes in minimal inhibitory concentration (MIC). Haemophilus influenzae causes chronic respiratory infection and is associated with exacerbations suffered by chronic obstructive pulmonary disease (COPD) patients. Although resistance to imipenem is rare in this bacterial species, heteroresistance has been reported, and antibiotic tolerance cannot be excluded. Moreover, development of antibiotic heteroresistance or tolerance during within-host H. influenzae pathoadaptive evolution is currently unknown. In this study, we assessed imipenem resistance, heteroresistance and tolerance in a previously sequenced longitudinal collection of H. influenzae COPD respiratory isolates. The use of Etest, disc diffusion, population analysis profiling, tolerance disc (TD)-test methods, and susceptibility breakpoint criteria when available, showed a significant proportion of imipenem heteroresistance with differences in terms of degree among strains, absence of imipenem tolerance, and no specific trends among serial and clonally related strains could be established. Analysis of allelic variation in the ftsI, acrA, acrB, and acrR genes rendered a panel of polymorphisms only found in heteroresistant strains, but gene expression and genome-wide analyses did not show clear genetic traits linked to heteroresistance. In summary, a significant proportion of imipenem heteroresistance was observed among H. influenzae strains isolated from COPD respiratory samples over time. These data should be useful for making more accurate clinical recommendations to COPD patients.

Objective: In this study, bacterial etiology, antibiotic resistance profile and clinical outcomes of foot ulcer associated amputations in persons with diabetes were analyzed. Methods: A total of 126 persons with Diabetic Foot Ulcer (DFU) admitted in surgical ward from June 2016 to May 2018 were included in this study. Foot ulcers were categorized as per Wagner's classification. Tissue samples obtained from the ulcers were processed for bacterial cultures using conventional techniques. Antibiotic sensitivity of the isolates was done by Kirby-Bauer’s Disc Diffusion method. Results: Out of 126 persons with diabetes, 74.6% of them had diabetes for 1–5 years. The minimum and maximum levels of HbA1c were 3% and 10.7%, respectively. Majority (58.7%) of the persons with diabetes had foot ulcers for less than a month. Wagner’s grade 3 ulcer was found to be high (38.1%) among the studied patients. Amputation due to foot ulcer was done in 28.6% of patients of which most of them were under insulin therapy. About 75% of amputated patients had DFU which was complicated by Gram-negative bacterial (GNB) infections. Escherichia coli (27.4%) was the predominant bacterium isolated among the GNB where as Staphylococcus aureus (13.4%) was the predominant one among Gram-positive bacteria. S. aureus isolates were highly resistant to penicillin (85%) followed by gentamicin (45.5%) and ciprofloxacin (40.9%). Enterobacteriaceae isolates showed high level of resistance to co-trimoxazole (84.4%). Imipenem was the most sensitive drug (100%) against GNB isolated from DFU. Conclusion: In this study, the Gram-negative bacteria are the major aetiological agents isolated from the amputated patients with diabetes mellitus. Incidence of multi-drug resistant bacteria associated DFU could be the major burden and limit the availability of antibiotic treatment regimens.

Abstract Background and Aim Machine learning is an important branch and supporting technology of artificial intelligence, we established four machine learning model for the drug sensitivity of Klebsiella pneumoniae to imipenem based on matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MALDI‐TOF‐MS) and compared their diagnostic effect. Methods The data of MALDI‐TOF‐MS and imipenem sensitivity of 174 cases of K. pneumoniae isolated from clinical specimens in the laboratory of microbiology department of Tianjin Haihe Hospital from 2019 January to 2020 December were collected. The mass spectrometry and imipenem sensitivity of 70 cases of imipenem‐sensitive and 70 resistant cases were randomly selected to establish the training set model, 17 cases of sensitive and 17 cases of resistant cases were randomly selected to establish the test set model. Mass spectral peak data were subjected to orthogonal partial least squares discriminant analysis (OPLS‐DA), the training set data model was established by machine learning least absolute shrinkage and selection operator (LASSO) algorithm, logistic regression (LR) algorithm, support vector machines (SVM) algorithm, neural network (NN) algorithm, the area under the curve (AUC) and confusion matrix of training set and test set model were calculated and selected by Grid search and 3‐fold Cross‐validation respectively, the accuracy of the prediction model was verified by test set confusion matrix. Results The R²Y and Q² of OPLS‐DA were 0.546 and 0.0178. The AUC of the best training set and test set models were 0.9726 and 0.9100, 1.0000 and 0.8581, 0.8462 and 0.6263, 1.0000 and 0.7180 evaluated by LASSO, LR, SVM and NN model respectively. The accuracy of the LASSO, LR, SVM and NN model were 87%, 79%, 62%, and 68% in test set, respectively. Conclusion The LASSO prediction model of K. pneumoniae sensitivity to imipenem established in this study has a high accuracy rate and has potential clinical decision support ability.

The management of postoperative wound infections is a major problem in hospitals due to the frequent ineffectiveness of antibiotic treatment. The objectives of this study are to identify the bacteria responsible for postoperative wound infections and to describe these antibiotic resistances in order to improve the management of these infections. It is a prospective study of 52 bacteriological results of postoperative wounds for a period of six months from January 2021 to June 2021 in the laboratory of the University Hospital of Befelatanana. This study showed 26 (50%) isolates of staphylococci, 17 (32.7%) isolates of enterobacteria, 6 (11.5%) isolates of streptococci and 3 (5.8%) isolates of nonfermenting gram‑negatif bacilli. Antibiotic resistance, varies from 0% (vancomycin) to 92.3% (penicillin G) for staphylococci isolates, 0% (imipenem, amikacin) to 94.1% (amoxicillin) for enterobacteria isolates, 0% (vancomycin) to 50% (penicillin G) for streptococci isolates and 33% (imipenem, amikacin) to 100% (cotrimoxazole) for the isolates of nonfermenting gram‑negatif bacilli. The knowledge of antibiotic resistance of bacteria responsible for postoperative wound infections allows better patient management.

Introduction: Antibiotic resistance in the last decade has recorded drastic changes in an increasing manner in nonfermenting bacterial groups of gram-negative bacilli including Ps. aeruginosa is a potent bacterial isolate or opportunistic nosocomial human pathogen. In recent decades, with improvements in antimicrobial therapy and diagnostic procedures have emerged multidrug resistant with beta lactamase to β-lactam antibiotics in presence of carbapenemases group of enzymes as metallo β-lactamases (MBL) are a major cause of concern. Due to its transferable character, it can hydrolyze almost all antibiotics. So, the study has conducted the detection of MBL isolates in hospital. Materials and Methods: In the study, 134 nonrepetitive clinical isolates of Pseudomonas spp. from the In Patient Department (IPD) patients attended to hospital from different clinical and isolates were confirmed in the department of microbiology and tested by the Kirby-Bauer disc diffusion method, which were screened for MBL production by disc synergy test as double-disc synergy test (DDST), combined-disc synergy test, and Modified Hodge test (MHT). The test was observed by a zone of inhibition of antibiotic with EDTA discs was ≥7 mm antibiotic disc alone as positive. MHT by the presence of a 'cloverleaf shaped' zone of inhibition was considered positive. Data were statistically analyzed and generated the graphs, whereas categorical variables (age and gender) were described in a descriptive way. Prevalence and percentage were used to establish an association of risk factors with carbapenem resistance strains. Result: A total of 134 Ps. aeruginosa was obtained from various clinical samples as 56 were found maximum in pus. Thirty nine bacterial isolates were found carbapenem resistant and in which 24 males (61.5%) were higher than 15 females (38.5%) in the 41-50 years age group. Carbapenem-resistant strains screened were for MBL production and found maximum by MHT test showed positive with meropenem (76.92%) and imipenem (71.79%). Isolates were found maximum in inpatients from surgical ward 45 (33.58%). Also, carbapenem-resistant isolates were found maximum from surgery (18). Four patients developed surgical site infections, had ulcerative lesions viz. traumatic, nondiabetic ulcer and from intensive care unit, 2 patients clinically identified as ventilated associated pneumonia (with COPD), 1 was immunocompromised with respiratory failure and COPD died in study. Discussion: Carbapenem resistant Ps. aeruginosa was found especially among critically ill patients. Isolates were found predominantly among males in the 41-50 years age group of patients. All 39 isolates were found resistant to meropenem, 32 (82.05%) bacterial isolates were resistant to both meropenem and imipenem where 7 (17.95%) isolates were found resistant to meropenem but sensitive to imipenem. MHT test was used to detect carbapenems activity but it does not give the confirmation of metal dependence of the carbapenems none of the phenotypic tests were optimal due to lower sensitivity or specificity. DDST has less channel of subjective variation, but combined-disc synergy test interprets more. The test between meropenem and meropenem with EDTA disc enhanced by diffusion method demonstrates the better synergy test (also for imipenem) and detection of carbapenem-resistant are not statistically significant [calculated P value is. 12 (P value >.05)]. The Minimum Inhibitory concentration (MIC) antibiotic susceptibility testing by E-test for imipenem and meropenem defines the use for the future. The surgical department found the highest prevalence may be due to the patient being treated by another hospital and was on third-line medication of cephalosporins. This may be due to higher comorbidity, invasive procedures, nonhealing ulcers after surgery, longer stay in the hospital, and excessive use of broad-spectrum antibiotics. The study was observed in economically weaker patients; seasonal trends of patient's admission and due to rural area tertiary healthcare centers awaiting improvement of the facility which may associate admission avoidance by the patient. Conclusion: MBL production was identified as the resistant mechanism of resistance carbapenems group of drugs including another group of antibiotics; prevalence was found similar to other studies but the resistance to another group of antibiotics was found lower. Also, disc diffusion method was reliable for screening with a correlation of DDST or MHT. Our study was focused to improve hospital infection control by the prevalence of organisms and their related risk factors, which may help in care and treatment of patients after admission. Evaluation still needs to conclude a positive association as per our study. E-test–based testing and molecular detection were not done in all isolates.

Abstract Background Enterobacter cloacae complex (ECC) is a common opportunistic pathogen and is responsible for causing various infections in humans. Owing to its inducible chromosomal AmpC β-lactamase (AmpC), ECC is inherently resistant to the 1st- and 2nd- generation cephalosporins. However, whether β-lactams antibiotics enhance ECC resistance remains unclear. Results In this study, we found that subinhibitory concentrations (SICs) of cefazolin (CFZ) and imipenem (IMP) can advance the expression of AmpC and enhance its resistance towards β-lactams through NagZ in Enterobacter cloacae (EC). Further, AmpC manifested a substantial upregulation in EC in response to SICs of CFZ and IMP. In nagZ knockout EC (ΔnagZ), the resistance to β-lactam antibiotics was rather weakened and the effect of CFZ and IMP on AmpC induction was completely abrogated. NagZ ectopic expression can rescue the induction effects of CFZ and IMP on AmpC and increase ΔnagZ resistance. More importantly, CFZ and IMP have the potential to induce the expression of AmpR's target genes in a NagZ-dependent manner. Conclusions Our findings suggest that NagZ is a critical determinant for CFZ and IMP to promote AmpC expression and resistance and that CFZ and IMP should be used with caution since they may aggravate ECC resistance. At the same time, this study further improves our understanding of resistance mechanisms in ECC.

Thanh D Dinh,1,2 Hung N Nguyen,1 Ba Hai Le,1 Thuy TT Nguyen,1 Huong TL Nguyen1 1Department of Clinical Pharmacy, Hanoi University of Pharmacy, Hanoi, Vietnam; 2Phu Tho General Hospital, Việt Trì, Phu Tho Province, VietnamCorrespondence: Huong TL Nguyen, Department of Clinical Pharmacy, Hanoi University of Pharmacy, 13, 15 – Lê Thánh Tông, Hoàn Kiếm, HàNội, 100000, Vietnam, Tel +84904308406, Email huongntl@hup.edu.vnPurpose: The purpose of this study was to characterize the population-based pharmacokinetic (POP-PK) profile of imipenem in Vietnamese adult patients and to assess the probability of target attainment (PTA) of the pharmacokinetic/pharmacodynamic (PK/PD) parameter to determine the optimal dose.Patients and Methods: A POP-PK model of imipenem was developed in patients with severe infection from a 1500-bed general hospital in Vietnam, using MONOLIX 2019. After the initial dose infusion, 6 blood samples per patient were collected to measure plasma imipenem levels. Eight covariates (eg, age, weight) were investigated to ascertain their influence on imipenem’s PK. Monte Carlo simulations were performed to determine the PTA for the time in which the total steady-state imipenem concentrations remained above the MIC (T>MIC) for 40% and 100% of the dosing interval.Results: The best fit to the PK data was a two-compartment model with inter-individual variability (IIV) in clearance (CL), central volume of distribution (Vc), intercompartmental clearance (Q), and peripheral volume of distribution (Vp). Only creatinine clearance was retained as a covariate on CL in the final model. The typical value of CL and Vc were estimated to be 4.79 L/h and 11.1 L, respectively. The between-subject variability in this population was noted to be high (> 38%, especially for IIV on Q at 110%). Prolonged or continuous infusion demonstrated efficacy (40% T>MIC) against bacteria with a MIC of 4mg/L. To achieve 100% T>MIC or bacteria with MIC> 4 mg/L, however, the number of doses must be increased while maintaining the same daily dose for the 3-hour prolonged infusion regimen.Conclusion: A population pharmacokinetic model of imipenem was developed for Vietnamese adult patients with severe illness. By using Monte Carlo simulation, the appropriate dose has been suggested based on the bacterial MIC value and the targeted PK/PD goal.Keywords: imipenem, pharmacokinetic modeling, PK/PD, Monte Carlo, carbapenem

BackgroundIncreasing reports of multidrug resistance (MDR) in clinical Pseudomonas aeruginosa have led to a necessity for new antimicrobials. Ceftazidime-avibactam (CZA) is indicated for use against MDR P. aeruginosa across a broad range of infection types and particularly those that are carbapenem resistant. This study sought to determine the molecular mechanisms of CZA and imipenem (IPM)-resistance in clinical P. aeruginosa isolates obtained from Swiss hospitals.MethodsClinical P. aeruginosa isolates were obtained from inpatients in three hospitals in Switzerland. Susceptibility was determined by either antibiotic disc testing or broth microdilution according to EUCAST methodology. AmpC activity was determined using cloxacillin and efflux activity was determined using phenylalanine-arginine β-naphthylamide, in agar plates. Whole Genome Sequencing was performed on 18 clinical isolates. Sequence types (STs) and resistance genes were ascertained using the Centre for Genomic Epidemiology platform. Genes of interest were extracted from sequenced isolates and compared to reference strain P. aeruginosa PAO1.ResultsSixteen different STs were identified amongst the 18 isolates in this study indicating a high degree of genomic diversity. No carbapenemases were detected but one isolate did harbor the ESBL blaPER-1. Eight isolates were CZA-resistant with MICs ranging from 16-64 mg/L, and the remaining ten isolates had either low/wildtype MICs (n=6; 1-2 mg/L) or elevated, but still susceptible, MICs (n=4; 4-8 mg/L). Ten isolates were IPM-resistant, seven of which had mutations resulting in truncations of OprD, and the remaining nine IPM-susceptible isolates had intact oprD genes. Within CZA-R isolates, and those with reduced susceptibility, mutations resulting in ampC derepression, OprD loss, mexAB overexpression and ESBL (blaPER-1) carriage were observed in various combinations and one harbored a truncation of the PBP4 dacB gene. Within the six isolates with wildtype-resistance levels, five had no mutations that would affect any antimicrobial resistance (AMR) genes of interest when compared to PAO1.ConclusionThis preliminary study highlights that CZA-resistance in P. aeruginosa is multifactorial and could be caused by the interplay between different resistance mechanisms including ESBL carriage, increased efflux, loss of permeability and derepression of its intrinsic ampC.

Background: Imipenem-relebactam is a new β-lactam and β-lactamase inhibitor combination to treat carbapenem-resistant gram-negative bacteria infections. However, difference in carbapenem resistant mechanisms existed with geographic variations. Objective: To evaluate the susceptibility of imipenem-relebactam to 660 carbapenem-nonsusceptible Enterobacteriaceae isolates in Taiwan and to identify the in vivo efficacy with a Caenorhabditis elegans model. Methods: 188 carbapenem-nonsusceptible Escherichia coli isolates and 472 carbapenem-nonsusceptible Klebsiella pneumoniae isolates were collected from a national surveillance study in Taiwan. The antimicrobial susceptibility profiles and carbapenemase distributions were determined. An agar dilution method was performed to evaluate the in vitro activities of imipenem monotherapy and imipenem-relebactam combination. Contributions of metallo-carbapenemase to imipenem-relebactam susceptibility was investigated via EDTA treatment. A C. elegans model was used to evaluate the in vivo efficacy of imipenem-relebactam combination. Results: 87.8% and 82.2% susceptibility to imipenem-relebactam was observed for 188 carbapenem-nonsusceptible E. coli and 472 carbapenem-nonsusceptible K. pneumoniae, respectively. However, poor activities of imipenem-relebactam was observed against 23 metallo-carbapenemase producers tested in this study. In the in vivo C. elegans model, imipenem-relebactam significantly rescued nematodes from the infection of a blaKPC-producing K. pneumoniae isolate. Conclusion: Our study supports that imipenem-relebactam is a potential therapy against carbapenem-nonsusceptible Enterobacteriaceae, and to our knowledge, this is the first report of evaluation for imipenem-relebactam efficacy against carbapenem-nonsusceptible Enterobacteriaceae in Taiwan.

Extensively drug-resistant (XDR), multidrug-resistant (MDR) and pandrug-resistant (PDR) Gram-negative microorganisms (GNBs) are considered a significant global threat. β-lactam and aminoglycoside combinations and imipenem:cyclodextrin inclusion complexes were studied for the treatment of lethal GNBs. This is because of the broad empiric coverage of the two drugs and their possession of different spectra of activity. Two cyclodextrins (β- and hydroxy propyl β-cyclodextrins) were utilized for inclusion complex formation with imipenem using the physical and kneading methods. In silico investigation using the molecular docking and Fourier-infrared spectroscopy (FTIR) were employed to estimate binding constant and confirm complex formation, respectively. The in vitro effects of amikacin and imipenem combination in comparison to the effect of imipenem-β- and hydroxy propyl β-cyclodextrin (CD) complexes against Klebsiella spp. and Acinetobacter baumannii were studied. The isolated microorganisms’ antimicrobial responsiveness to various antibiotics (19 antibiotics) was evaluated. It was found that piperacillin/tazobactam and gentamycin (resistance rates were 33.3% and 34%, respectively) were the most effective antimicrobials. The in vitro studies have been performed by the checkerboard technique and time-killing assay. The studied combination of amikacin and imipenem showed a substantial drop in bacterial count (p < 0.05). The in vitro studies demonstrated a synergism for the investigated combination. Conventional PCR was used in molecular studies to identify the resistance genes bla IMP and aac (6′)-Ib. The blaIMP and aac (6′)-Ib were recorded in 38.2% and 3.6% of the studied isolates, respectively. The in vitro studies showed synergistic effects among the tested antibiotics with FICIs of ≤0.5. Finally, the study compared the reduction in bacterial count between the tested antibiotic combinations and imipenem:CD physical and kneaded mixtures. Imipenem:CD inclusion complexes demonstrated a significant bacterial count reduction over the antibiotic combination. These results highlight the emerging role of CDs as safe biofunctional excipients in the combat against superbug bacterial resistance.

Purpose: Real-life comparison of three intravitreal drug regimens used in cases of endophthalmitis at a tertiary care center in India. Methods: In this prospective, comparative study, patients of bacterial endophthalmitis were grouped according to intravitreal antibiotic drug regimens into Group 1 (ceftazidime and vancomycin), Group 2 (piperacillin + tazobactam and vancomycin), and Group 3 (imipenem and vancomycin). Forty-eight hours after injection nonresponding/worsening patients underwent vitrectomy. Vitreous samples were subjected to microbiological and pharmacokinetic tests. Results: A total of 64 patients were included and divided into Group 1: 29, Group 2: 20, and Group 3: 15 cases. Also, 75% of patients were post-surgical endophthalmitis, whereas 25% were post-traumatic. Improvement in vision (V90-0) and vision at 3 months (V90) were comparable between the three groups. Visual recovery was poorer in post-traumatic cases. In post-surgical cases, visual recovery was poorer in those presenting beyond 72 h of onset of symptoms (P = 0.0002). Polymerase chain reaction (PCR) positivity (66%) was higher than BACTECTM (33%) and culture (14%). Antibiotic resistance was comparable amongst the three groups. Most patients (62/64) further underwent vitrectomy. Ceftazidime and vancomycin achieved vitreous concentrations more than the minimum inhibitory concentration (MIC) at 48 h after the first injection. Conclusion: The choice of antibiotics did not affect the rate of vitrectomy and final vision in a real-life scenario. Ceftazidime and vancomycin can still be used as first-line intravitreal antibiotics owing to their comparable microbial sensitivity profile and adequate ocular bioavailability.

Introduction: Carbapenem resistance due to metallo-beta-lactamase (MBL)-producing bacteria is an emerging threat worldwide. This study aimed to detect the MBL production in clinical isolates of E. coli and Klebsiella pneumoniae species in our hospital setting and to evaluate the efficiency of two phenotypic methods for the detection of MBL production. Materials and Methods: The present study was carried out in the Department of Microbiology, MGM Medical College and Hospital, Aurangabad, Maharashtra, for a period of 2 years from April 2018 to March 2020. From a total of 12,324 various clinical specimens, 393 isolates of E. coli and Klebsiella pneumoniae species were tested for MBL production. MBL was detected by two different phenotypic methods, i.e., combined disc test and E-test. Results: Out of 393 isolates, 130 (33.07%) isolates were resistant to imipenem on screening of which 71 (18.06%) were Klebsiella pneumoniae and 59 (15.01%) were E. coli. About 43.66% Klebsiella pneumoniae isolates and 40.67% E. coli isolates were MBL-positive by the combined disc test. Using the E-test, MBL production was found to be 46.47% and 45.76% in Klebsiella pneumoniae and E. coli, respectively. Conclusion: Routine screening of MBL-producing organisms should be performed in diagnostic laboratories to control the spread of resistance and for the proper management of antibiotic therapy. E-test is better than the combined disc test for the detection of MBL-producing gram-negative bacilli.

Yilin Xiong,1,&ast; Yuqiao Han,1,&ast; Zinan Zhao,1,&ast; Wenting Gao,2 Yong Ma,2 Shiyu Jiang,1 Mengyao Wang,1 Qingqing Zhang,3 Yun Zhou,4 Yang Chen1 1Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian, People’s Republic of China; 2Institute of Genome Engineered Animal Models for Human Disease, Dalian Medical University, Dalian, People’s Republic of China; 3Laboratory of Pathogenic Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, People’s Republic of China; 4Department of Clinical Nutrition, Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang ChenDepartment of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, 9 West Section of Lvshun South Road, Dalian, 116044, People’s Republic of ChinaTel/Fax +86 411 86110350Email yangchen@dmu.edu.cnYun ZhouDepartment of Clinical Nutrition, Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116023, People’s Republic of ChinaTel +86 411 84690722Fax +86 411 84672130Email dmu_yunzhou@yeah.netPurpose: Antibiotic resistance is a growing health crisis that is further complicated by treatment failures caused by bacteria that exhibit heterogeneous susceptibility to antibiotics. The aim of this study was to describe imipenem (IPM)-heteroresistant strains among multidrug-resistant (MDR) ESBL/AmpC-producing Klebsiella pneumoniae clinical isolates, investigate their molecular phenotypic characteristics, and elucidate the outcome of antibiotic treatment in mice infected with the heteroresistant isolates.Materials and Methods: Antimicrobial susceptibility of K. pneumoniae isolates was determined by the disk diffusion and E-test methods. Heteroresistance to IPM was confirmed by population analysis profile (PAP) assays. PCR and sequencing were employed to detect MDR determinants. Molecular differences between the susceptible and resistant subpopulations were evaluated by sequencing and quantitative real-time reverse transcription PCR (qRT-PCR) analysis. The effect of the carbapenem-heteroresistant strains on antibiotic treatment was assessed using a mouse model of peritonitis with heteroresistant K. pneumoniae and subsequent treatment with IPM.Results: In total, 37 MDR ESBL/AmpC-producing clinical isolates of K. pneumoniae were identified between September 2018 and December 2019. These strains were notably resistant to conventional antimicrobials other than carbapenems. Among the isolates, three strains exhibited heteroresistance to IPM and carried several ESBL and/or AmpC genes. Mice infected with a lethal dose of any of the three heteroresistant isolates were unable to survive in the presence of IPM treatment, as the percentage of the IPM-resistant subpopulation of each strain was increased in the peritoneum of these mice at 24 h after infection. The resistant subpopulation of the strains presented pulsed-field gel electrophoresis (PFGE) profiles that were identical to those of the susceptible subpopulation, but ompK36 porin showed a reduction in gene expression (0.09- to 0.50-fold) in the resistant subpopulation.Conclusion: Carbapenem-heteroresistant strains were present among the MDR K. pneumoniae isolates producing ESBL/AmpC β-lactamases, and these heteroresistant strains failed IPM therapy in experimentally infected mice.Keywords: Enterobacteriaceae, imipenem, heterogeneous susceptibility, treatment failure, OmpK porin, in vivo

Plasmodiophora brassicae causes a serious threat to cruciferous plants including radish (Raphanus sativus L.). Knowledge on the pathogenic regularity and molecular mechanism of P. brassicae and radish is limited, especially on the metabolism level. In the present study, clubroot-susceptible and clubroot-resistant cultivars were inoculated with P. brassicae Race 4, root hairs initial infection of resting spores (107 CFU/mL) at 24 h post-inoculation and root galls symptom arising at cortex splitting stage were identified on both cultivars. Root samples of cortex splitting stage of two cultivars were collected and used for untargeted metabonomic analysis. We demonstrated changes in metabolite regulation and pathways during the cortex splitting stage of diseased roots between clubroot-susceptible and clubroot-resistant cultivars using untargeted metabonomic analysis. We identified a larger number of differentially regulated metabolites and heavier metabolite profile changes in the susceptible cultivar than in the resistant counterpart. The metabolites that were differentially regulated in both cultivars were mostly lipids and lipid-like molecules. Significantly regulated metabolites and pathways according to the P value and variable important in projection score were identified. Moreover, four compounds, including ethyl α-D-thioglucopyranoside, imipenem, ginsenoside Rg1, and 6-gingerol, were selected, and their anti-P. brassicae ability and effects on seedling growth were verified on the susceptible cultivar. Except for ethyl α-D-thioglucopyranoside, the remaining could inhibit clubroot development of varing degree. The use of 5 mg/L ginsenoside Rg1 + 5 mg/L 6-gingerol resulted in the lowest disease incidence and disease index among all treatments and enhanced seedling growth. The regulation of pathways or metabolites of carbapenem and ginsenoside was further explored. The results provide a preliminary understanding of the interaction between radish and P. brassicae at the metabolism level, as well as the development of measures for preventing clubroot.

Introduction: Non Fermentative Gram Negative Bacilli (NFGNB), which are saprophytic in nature, have emerged as important pathogens. They have been associated with infections such as septicaemia, meningitis, pneumonia, Urinary Tract Infection (UTI) and surgical site infections. They exhibit resistance to beta lactams and also to other groups of antibiotics and carbapenems. Aim: To identify and isolate NFGNB from various clinical samples and to know their antimicrobial susceptibility pattern. Materials and Methods: The present study was a crosssectional study done in the Department of Microbiology, Rangaraya Medical College, Kakinada, Andhra Pradesh, India, from July 2018 to August 2019. The study was done on 204 clinical samples that were inoculated on different growth media. The non fermenters were identified by conventional methods and isolates that were not identified, were subjected to automated system (MicroScan autoSCAN-4 system). The susceptibility testing was done by Kirby-Bauer disc diffusion method. Data was entered in Microsoft Excel sheet 10 and all analysis was performed by Statistical Package for the Social Sciences (SPSS) 24.0. Results: A total of 100 NFGNB were isolated from 204 clinical samples. Pseudomonas aeruginosa (P. aeruginosa) was the most common non-fermenter (49%), followed by Acinetobacter baumannii (A. baumannii) (19%), P. fluorescens (17%), Acinetobacter lwoffii (A. lwoffii) (4%), Alcaligenes faecalis (A. faecalis) (4%), Burkholderia cepacia (B. cepacia) (3%), Pseudomonas putida (P. putida) (2%) and Stenotrophomonas maltophilia (S. maltophilia) (2%). The NFGNB showed good sensitivity to imipenem (97%), amikacin (53%) , and 92% resistance to cefipime, 75%, 73%, 49%, and 48%, resistance to ceftazidime, ticarcillin, ciprofloxacin, piperacillin, respectively. Conclusion: P. aeruginosa and A. baumannii were the common NFGNB isolated in the present study from surgical site infections, urinary tract infections, bacteraemia, and ventilator associated pneumonia. The different species of NFGNB have shown a varied sensitivity pattern. All NFGNB showed higher rate of resistance to cefipime and ceftazidime and good sensitivity to imipenem, and amikacin.

Abstract Background The appropriate dosing of imipenem for critically ill AKI patients undergoing CRRT remains scarce. Purpose This study aimed to (1) gather the available published pharmacokinetic studies conducted in septic patients receiving continuous renal replacement therapy (CRRT) and (2) to define the optimal imipenem dosing regimens in these populations via Monte Carlo simulations. Methods The databases of PubMed, Embase, and ScienceDirect were searched from inception to May 2020. We used the Medical Subject Headings of “Imipenem,” “CRRT,” and “pharmacokinetics” or related terms or synonym to identify the studies for systematic reviews. A one-compartment pharmacokinetic model was conducted to predict imipenem levels for the initial 48 h of therapy. The pharmacodynamic target was 40% of free drug level above 4 times of the MIC (40% fT > 4 MIC). The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. Results Eleven articles were identified and included for our systematic review. The necessary pharmacokinetic parameters such as the volume of distribution and the CRRT clearance were mentioned in 100 and 90.9%, respectively. None of the current studies reported the complete necessary parameters. A regimen of 750 mg q 6 h was the optimal dose for the predilution-CVVH and CVVHD modality with two effluent rates (25 and 35 mL/kg/h) for the pharmacodynamic target of 40% fT > 4MIC. Conclusions None of the current studies showed the complete necessary pharmacokinetic parameters for drug dosing. Pharmacodynamic target significantly contributed to imipenem dosing regimens in these patients. Different effluent rates and types of CRRT had minimal impact on dosing regimens. Clinical validation of the recommendation is necessary.

Leilei Wang,1,2 Yuancheng Chen,1– 3 Renru Han,1,2 Zhiwei Huang,1– 3 Xuefei Zhang,1,2 Fupin Hu,1,2 Fan Yang1,2 1Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, People’s Republic of China; 3Phase I Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Fan Yang; Fupin HuInstitute of Antibiotics, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Shanghai, 200040, People’s Republic of ChinaTel +86 21 52888193Email fanyang9@fudan.edu.cn; hufupin@fudan.edu.cnPurpose: To evaluate in vitro activities of β-lactam antibiotics alone and in combination with sulbactam at different ratios against Acinetobacter baumannii clinical strains from China.Methods: A total of 300 clinical isolates of A. baumannii were collected from 29 hospitals across China in 2018. Susceptibility to common antibiotics was assessed, and β-lactamase genes were detected. In vitro activity of ampicillin, cefoperazone and imipenem was tested alone and in combination with sulbactam at the ratios of 2:1, 1:1, 1:1.5, 1:2, 1:2.5 and 1:3.Results: High resistant rates for common antibiotics were observed except tigecycline and polymyxin B. Among carbapenem-resistant A. baumannii, 97.3% isolates harbored blaOXA-23. MIC50 and MIC90 values for sulbactam were 32 mg/L and 64 mg/L, respectively. High resistant rates for ampicillin, cefoperazone and imipenem were observed (92.3%, 93% and 85.3%, respectively). A stepwise increase in the ratio of sulbactam to partner β-lactam antibiotics led to a stepwise decrease in the MICs and a stepwise increase in the susceptible rates. The susceptible rates for imipenem-sulbactam 1:3, ampicillin-sulbactam 1:3 and cefoperazone-sulbactam 1:3 reached 16.3%, 58.3% and 91%, respectively.Conclusion: The increasing proportion of sulbactam could enhance antimicrobial activities of imipenem-sulbactam, ampicillin-sulbactam and cefoperazone-sulbactam combinations against A. baumannii clinical strains in China, with cefoperazone-sulbactam as the most potent compound.Keywords: sulbactam, ampicillin, cefoperazone, imipenem, Acinetobacter baumannii

Objective. To evaluate in vitro activity of biapenem and other clinically available carbapenems against Russian clinical isolates of Enterobacterales, Pseudomonas aeruginosa и Acinetobacter spp., including isolates with acquired fermentative mechanisms of resistance to β-lactams. Materials and Methods. A total of 3139 Enterobacterales isolates, 793 P. aeruginosa isolates and 634 Acinetobacter spp. isolates from hospitalized patients in 63 hospitals from 35 Russian cities were included in the study during 2018-2019. Minimal inhibitory concentrations (MIC) for biapenem and other antimicrobials were determined in accordance with ISO 20776-1:2006. Carbapenemases genes were detected by commercially available real-time PCR kits AmpliSens® MDR KPC/OXA-48-FL and AmpliSens® MDR MBL-FL (Central Research Institute of Epidemiology, Russia). Data analysis and reporting was performed using AMRcloud online platform (www.amrcloud.net). Results. For all tested Escherichia coli isolates MIC50/90 were 0.06/0.125 mg/l for biapenem, 0.125/0.25 mg/l for imipenem, and 0.06/0.06 mg/l for meropenem. When MIC50/90 for ertapenem (0.015/0.125 mg/l for all isolates tested) were comparable to those of biapenem, a greater number of nosocomial E. coli isolates had MIC >4 mg/l for ertapenem (3.6%) than for biapenem (2.6%). MIC50/90 of Klebsiella pneumoniae for biapenem were 0.5/16 mg/l, for both imipenem and meropenem – 0.5/32 mg/l, for ertapenem – 2/32 mg/l. Resistance to oxyimino-β-lactams had no significant influence on activity of biapenem against Enterobacterales isolates. For 321 carbapenemase-producing K. pneumoniae isolates (ОХА-48 – 63.9%, NDM – 27.7%) biapenem has shown no advantages over imipenem and meropenem. МПК50/90 for nosocomial and community-acquired P. aeruginosa isolates were 8/64 mg/l and 0,5/16 mg/l for biapenem, 8/128 mg/l and 1/16 mg/l – for imipenem, 16/64 mg/l and 0,5/32 mg/l – for meropenem. All carbapenems, including biapenem, had very low in vitro activity against carbapenemaseproducing P. aeruginosa isolates. МПК50/90 of Acinetobacter spp. were 64/128 mg/l for biapenem, 64/128 mg/l – for imipenem, and 128/128 mg/l – for meropenem. Conclusions. According to the MIC distributions and MICs50/90 values independently of the presence of fermentative mechanisms of resistance to β-lactams, in vitro activity of biapenem against Russian clinical isolates of Enterobacterales, P. aeruginosa and Acinetobacter spp. was comparable to those of imipenem and meropenem.

ABSTRACT In the absence of a molecule that would collectively inhibit both metallo-β-lactamases and serine-reactive carbapenemases, containment of their genes is the main weapon currently available for confronting carbapenem resistance in hospitals. Cost-effective methodologies rapidly detecting carbapenemase-producing enterobacteria (CPE) would facilitate such measures. Herein, a low-cost CPE detection method was developed that was based on the direct colorimetry of the yellow shift caused by the accumulation of diketopiperazines—products of the acid-catalyzed imipenem oligomerization—induced by carbapenemase action on dense solutions of imipenem/cilastatin. The reactions were studied by spectrophotometry in the visible spectrum using preparations of β-lactamases from the four molecular classes. The effects of various buffers on reaction mixtures containing the potent carbapenemases NDM-1 and NMC-A were monitored at 405 nm. Optimal conditions were used for the analysis of cell suspensions, and the assay was evaluated using 66 selected enterobacteria, including 50 CPE as well as 16 carbapenemase-negative strains overexpressing other β-lactamases. The development of the yellow color was specific for carbapenemase-containing enzyme preparations, and the maximum intensity was achieved in acidic or unbuffered conditions in the presence of zinc. When applied on bacterial cell suspensions, the assay could detect CPE with 98% sensitivity and 100% specificity, with results being comparable to those obtained with the Carba NP technique. Direct colorimetry of carbapenemase-induced imipenem decomposition required minimum reagents while exhibiting high accuracy in detecting CPE. Therefore, it should be considered for screening purposes after further clinical evaluation. IMPORTANCE Currently, the spread of multidrug-resistant (MDR) carbapenemase-producing enterobacteria (CPE), mostly in the clinical setting, is among the most pressing public health problems worldwide. In order to effectively control CPE, use of reliable and affordable methods detecting carbapenemase genes or the respective β-lactamases is of vital importance. Herein, we developed a novel method, based on a previously undescribed phenomenon, that can detect CPE with few reagents by direct colorimetry of bacterial suspensions and imipenem/cilastatin mixtures.

Abstract The current study was aimed at investigating the prevalence of the mutations upstream of the oprD coding region and its promoters among imipenem-resistant and sensitive Pseudomonas aeruginosa isolated from educational hospitals in Yazd City, Iran. All isolates were identified by the conventional biochemical tests. Then, the antibiotic resistance of these isolates was determined using the disk diffusion method according to the CLSI guidelines. Also, the E.test was performed to determine the minimum inhibitory concentrations (MIC) of imipenem. The mutations of this gene were recognized by the amplification of this region and subsequently sequenced. Sequencing of the genomic region upstream of oprD these regions were done in the 29 clinical strains. Statistical analysis was done by the statistical software SPSS-18. Seventy (77.7%) of isolates had MIC ≥ 16 and were resistant to imipenem. Mutations of the upstream of the oprD gene and its promoters were seen in 25 (86.2%) isolates and 4 isolates had no mutation. One isolate had a base substitution A→Cat nt 25 in the coding region and this isolate had a point mutation leading to an amino acid change at positions 9 (I→L). Our study results indicated that none of the strains had mutation in Shine-Dalgarno and the point mutations were the most common mutations upstream of the oprD coding region among P. aeruginosa isolates. Mutations were observed in imipenem-resistant isolates and it seems this mechanism is effective in resistance of isolates to imipenem and this confirmed that the indiscriminate use of antibiotic should be controlled.

Salmonella Typhimurium is an important zoonotic food borne pathogen and the second most widely studied pathogen in relation to antimicrobial resistance studies in Nigeria. Its resistance to β-lactam antibiotics is on the rise globally due to persistent exposure and production of Extended Spectrum Beta-lactamase enzymes (ESBLs) which is barely reported to occur among food producing animals in Nigeria. This poses a threat to the successful therapy of salmonellosis infections and raises concern on food safety. Further complicating these challenges is the lack of strict laws mitigating antibiotic usage in Nigeria. The study was conducted in the Microbiology laboratory of Nasarawa State University, Keffi, Nigeria. A total of 300 samples each of poultry droppings, flesh, feeds, human hand swabs and stool were randomly collected following ethical approval and screened for ESBL- producing S. Typhimurium using standard Microbiological methods of isolation and identification. Antibiotic susceptibility testing, phenotypic ESBL detection and interpretation were carried out as described by the Clinical Laboratory and Standard Institute (CLSI) guideline. The bla genes were identified using polymerase chain reaction (PCR) method. A total of 106 S.Typhimurium were isolated with the following resistance profile; Ampicillin 99(93.4%), Augmentin 104(98.1%), Ceftriaxone 74(69.8%), Ceftazidime 50(47.2%), Imipenem 1(1.0%). The antibiotic resistance of S. Typhimurium in the study is significant (P = 0.01). The Multiple Antibiotic Resistance (MAR) Index was > 0.2. Out of 106 isolates, 32 distinct antimicrobial resistant phenotypes were observed and 62 (81.6%) were confirmed ESBL producers having 19 distinct phenotypes. The bla genes were identified among 38.7% (24/62) isolates; 100% blaSHV (24/24), 87.5 %(21/24)blaTEM with 54.2% (13/24) co-carriage of blaTEM-SHV. The blaCTX-M was not detected. Poultry is therefore an important reservoir and source of transmission of ESBL- producing S.Typhimurium, which is a major public health concern. The high MAR index suggests frequent antibiotic usage within our study area, thus calls for antibiotic stewardship in animal production in Nigeria.

The World Health Organization in 2017 listed carbapenem resistant Enterobacteriaceae (CRE) with critical priority for research. A research to assess carbapenem resistant Escherichia coli (CREc) in coliuria among the outpatients and inpatients of a tertiary health institution was carried out using conventional methods, polymerase chain reaction, Sanger sequencing, and bioinformatics. There were 39 positive coliuria cases from the urine samples collected from a total of 126 patients with various genitourinary diseases. The E. coli enumeration (log10 CFU/mL) revealed that 82.1% (n = 32) of the samples showed significant coliuria, 12.8% (n = 5) showed non-significant coliuria while 5.1% (n = 2) showed indeterminate coliuria even when repeated. Significantly higher numbers (p > 0.05) of the sampled inpatients yielded positive coliuria (57.9%) than the outpatients. Though there were significantly more (P > 0.05) urology female patients (n = 77) than male (n = 49), coliuria was more prevalent in sampled male patients (34.9%) than female (28.6%). Highest prevalence of coliuria was observed among the age range (18–30) years. Selected CREc that was sequenced and the sequences submitted to GenBank of National Center for Biotechnological Information (NCBI) were Escherichia coli AYO-WINI111 and Escherichia coli AYO-WINI112 with accession number MT735391 and MT735392, respectively. High resistance was observed against ertapenem (53%), imipenem (62%), meropenem (48%), and doripenem (47%), while 7%–22% of the isolates showed phenotypic intermediate carbapenem resistance. Critically dangerous CREc are harboured by large number urology patients in the study area, depicting the need for more attention in the management of the condition, as CREc are close to achieving totally antibiotic resistance.

The study aimed to investigate the factors affecting the stability of imipenem and cilastatin sodium for injection (IMI/CIL) to improve the quality and stability in IMI/CIL preparation. In this study, the effects of headspace oxygen (HO), water content, particle shape, and particle size on the stability of IMI/CIL were investigated. IMI/CIL was purged with air, premixed oxygen/nitrogen gas (5%/95%), or high-purity nitrogen (99.999%) at 20, 5, or 2% oxygen levels to prepare IMI/CIL with different HO levels. IMI/CIL was stored at 30, 45, and 75% relative humidity for 30 days to prepare IMI/CIL with different water contents. High-performance liquid chromatography method was used for analysis. The results showed that oxygen, water, particle shape, and particle size had significant effects on the stability of IMI/CIL, and free water content is a better predictor of the safety and stability of imipenem and cilastatin sodium than the total water content. The optimization scheme of the above parameters is proposed, which significantly improves the stability of IMI/CIL. This study led to a better understanding of the degradation mechanism of imipenem and cilastatin sodium, and could provide a reference for the selection and control of IMI/CIL process conditions. This study would contribute to the development of IMI/CIL with improved stability.

Correction: In the Article of Activity of imipenem/relebactam on Klebsiella pneumoniae with different mechanisms of imipenem non-susceptibility DOI: https://doi.org/10.18502/ijm.v13i6.8080 Volume 13 Number 6 (December 2021) 785-792 The first author`s name was Mervat El-Seyed Mashaly, it should be corrected as Mervat Mashaly and also the affilations were: 1Department of Clinical Pathology, Clinical Microbiology Unit, School of Medicine, Mansoura University, Mansoura, Egypt 2Department of Medical Microbiology and Immunology, School of Medicine, Mansoura University, Mansoura, Egypt they should be corrected as : 1Department of Clinical Pathology, Clinical Microbiology Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt 2Department of Medical Microbiology and Immunology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Imipenem (IMP) possesses a broad spectrum of antibacterial activity; however, nephrotoxicity limits its clinical application in patients with renal insufficiency. In our previous studies, a dipeptide, JBP485, a dipeptide with the chemical structure cyclo-trans-4-L-hydroxyprolyl-L-serine, was found to attenuate drug-induced kidney injury. The current study aimed to explore whether JBP485 could relieve IMP-induced kidney injury and clarify the potential molecular pharmacokinetic mechanism. The effects of JBP485 on IMP nephrotoxicity were evaluated in rabbits and human kidney 2 (HK-2) cells. Drug-drug interactions (DDIs) mediated by organic anion transporters (OATs) and dehydropeptidase-I (DHP-I) were explored through pharmacokinetic studies in rats, metabolism assays in the kidney, and uptake studies in OAT-over-expressing cells. The results revealed that JBP485 significantly ameliorated IMP-induced nephrotoxicity in rabbits. Further, incubation of HK-2 cells with JBP485 or cilastatin markedly improved the cell survival rate, inhibited apoptosis and attenuated mitochondrial damage by improving the stability of IMP and reducing its intracellular accumulation. This suggests that DHP-I and OATs might be involved in the protective effect of JBP485. Furthermore, coadministration with JBP485 significantly increased the IMP’s plasma concentration as well as the area under the plasma concentration-time curve (AUC), while decreasing IMP renal clearance and cumulative urinary excretion. Moreover, JBP485 reduced IMP uptake in kidney slices and OAT1/3-human embryonic kidney 293 (HEK293) cells. At the same time, the metabolism of IMP by DHP-I was inhibited by JBP485 with an IC50 value of 12.15 ± 1.22 μM. Finally, the molecular docking assay revealed a direct interaction between JBP485 and OAT1/3 or DHP-I. In conclusion, JBP485 protected against IMP nephrotoxicity in rabbits and HK-2 cells by improving IMP stability and reducing its intracellular accumulation via simultaneous inhibition of renal OATs and DHP-I. JBP485 is a promising renoprotective agent and could serve as an effective supplement to reduce IMP-induced adverse renal reactions in the clinical setting.

Background: Superinfection is a new isolate pathogen after 48 h of antibiotic treatment or within one week of treatment discontinuation. In many studies carbapenem and piperacillin–tazobactam were associated with high risk of superinfection. Aim: To evaluate the rate of superinfections during carbapenem and piperacillin/tazobactam treatment. Also, to identify risk factors for superinfections. Methods: A Retrospective observational study was conducted in King Abdulaziz Medical City. Approval from the institutional Review Board was obtained. The study included all adult patient treated with carbapenem or piperacillin/tazobactam for more than 72 h. Univariate and multivariate analysis was conducted to compare piperacillin/tazobactam versus carbapenems and to identify the associated risk factor to develop superinfection. Finding: 507 patients were included in this study. The mean age of the patients was 61 years ± 19.33. Of these, 278 received carbapenems and 229 received piperacillin/tazobactam. In univariate analysis superinfections were significantly higher with carbapenems compared with piperacillin–tazobactam (28.77% versus 20.96%; P value = 0.044). After adjustment of cofounders in multivariate analysis, presence of tracheostomy, endotracheal ventilation, foley catheter and duration of antibiotic were associated with higher risk to developed superinfection adjusted odd ratio (aOR) 3.23 (95% CI,1.39–7.52) P < 0.01, aOR 2.556 (95% CI,1.30–5.02) P < 0.01, aOR 2.20 (95% CI,1.35–3.61) P < 0.001, aOR 1.051(95% CI,1.02–1.08) P < 0.001 respectively, but not carbapenems use aOR 1.052 (95% CI,0.657–1.685). Conclusions: The use of carbapenems were not associated with higher risk to developed superinfection. The most important risk factors associated with superinfection were presence of tracheostomy, endotracheal mechanical ventilation, Foley catheter and the duration of antibiotics.

Genital infections and subsequent vaginosis diagnosed through high vaginal swab in women is caused due to fungi or bacteria. The presented study focused on determining the types, numbers and antibacterial susceptibility pattern of aerobic bacteria causing vaginosis in 147 female patients attending infertility centre in Chennai, Tamil Nadu, India. Candida spp. caused 17% of infections with 15.7% of vaginosis caused by E.coli, Klebsiella spp., Acinetobacter spp., Citrobacter spp. and Gram positive cocci – Methicillin Sensitive Staphylococcus aureus (MSSA), Coagulase Negative Staphylococci(CONS), Staphylococcus aureus and Enterococcus spp. causing 12.9% of vaginitis in the study population. A total of 20 different antibiotics – cell wall inhibitors, protein synthesis inhibitors and nucleic acid synthesis inhibitors; were tested to determine the response of bacterial isolates by Kirby-Bauer disc diffusion method. The study result determined that the most effective drug for treating Gram positive bacterial vaginitis as per CLSI guidelines based on susceptibility pattern as: Linezolid(100%), Gentamycin(91.6%), Amikacin(87.5%),Erythromycin(79.2%), Co-Trimoxazole(72.2%), Ciprofloxacin(65.6%) and least Chloramphenicol(44.3%). High level gentamycin(83.3%) was found to be effective in treating Enterococci. The descending order of susceptibility of Gram negative aerobacteria causing vaginitis as per CLSI guidelines are: Amikacin(87.5%), Gentamycin(82.5%), Cefoperazone sulbactam (76.3%), Ciprofloxacin(68.5%), Ceftazidime(62.5%) and least Amoxyclav(25%).All Gram negative bacteria tested were susceptible to– Imipenem and Meropenem as well as Chloramphenicol. Ceftriaxone (87.5%) and Nitrofurantoin(72.3%) among other antibiotics was effective against Gram negative bacteria while all Enterobacteriaceae members were found to be resistant to tetracycline.

Background: Gram-negative rods are one of the most commonly isolated bacteria within human infections. These microorganisms are typically opportunistic pathogens that pose a serious threat to public health due to the possibility of transmission in the human population. Resistance to carbapenems is one of the most important antimicrobial resistance mechanisms amongst them. The aim of this study was to evaluate ceftolozane–tazobactam in vitro activity against carbapenem-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae clinical strains. Information on the antimicrobial activity of this antimicrobial against Gram-negative rods was also supplemented with a brief review of the relevant literature. Methods: The research involved 316 strains of Gram-negative rods: P. aeruginosa—206 and K. pneumoniae—110. Results: Of the tested strains, 86.0% P. aeruginosa and 30.0% K. pneumoniae remained susceptible to ceftolozane–tazobactam. Conclusions: Therefore, ceftolozane–tazobactam might be a good option in the treatment of infections caused by carbapenem-resistant P. aeruginosa strains, including those in ICU patients. Meanwhile, due to dissemination of ESBLs among K. pneumoniae strains, infections with this etiology should not be treated with the ceftolozane–tazobactam combination.

Klebsiella pneumoniae (K. pneumoniae) is an opportunistic bacterium that has drawn attention due to its resistance to carbapenem antibiotics. The treatment of patients with severe infections has been challenging. Thus, silver nanoparticles (AgNPs) have been applied for their antimicrobial effects. This work aims to analyze the synergistic effect of the carbapenem antibiotic Imipenem with AgNPs against different susceptibility clinical profiles of K. pneumoniae. The silver nanoparticles were synthesized by bottom-up methodology and capped with alpha-lipoic acid. Susceptibility tests were performed using four K. pneumoniae strains with different susceptibility profiles to Imipenem. The strains were induced to form a biofilm for 48 h. Crystal violet and Resazurin assays were performed to determine biofilm formation and minimal inhibitory concentration, respectively. The reduction in Imipenem concentration with the association of nanoparticles was found in all strains studied in planktonic form, and the synergism between silver nanoparticles and Imipenem was demonstrated through the analysis of the fractional inhibitory concentration index. The viability percentage was reduced at rates ≥80% in the biofilm analysis, characterized by the minimal biofilm inhibitory concentration. The study’s proposed association resulted in inhibitory effects on different K. pneumoniae profiles, both in planktonic forms and biofilm, with peculiar behavior in the Imipenem-resistant profile.

Bacteroides fragilis is a commonly investigated commensal bacterium for its protective role in host diseases. Here, we aimed to develop a reproducible antibiotic-based model for conditioning the gut microbiota and engrafting B. fragilis into a conventional murine host. Initially, we selected different combinations of antibiotics, including metronidazole, imipenem, and clindamycin, and investigated their efficacy in depleting the mouse Bacteroides population. We performed 16S rRNA sequencing of DNA isolated from fecal samples at different time points. The α-diversity was similar in mice treated with metronidazole (MET) and differed only at weeks 1 (p = 0.001) and 3 (p = 0.009) during metronidazole/imipenem (MI) treatment. Bacteroides compositions, during the MET and MI exposures, were similar to the pre-antibiotic exposure states. Clindamycin supplementation added to MET or MI regimens eliminated the Bacteroides population. We next repeated metronidazole/clindamycin (MC) treatment in two additional independent experiments, followed by a B. fragilis transplant. MC consistently and reproducibly eliminated the Bacteroides population. The depleted Bacteroides did not recover in a convalescence period of six weeks post-MC treatment. Finally, B. fragilis was enriched for ten days following engraftment into Bacteroides-depleted mice. Our model has potential use in gut microbiota studies that selectively investigate Bacteroides’ role in diseases of interest.

Ebrahim M Abda,1 Zenebe Adugna,2 Adugna Assefa2 1Department of Biotechnology, College of Biological and Chemical Engineering, Addis Ababa Science and Technology University, Addis Ababa, Ethiopia; 2Department of Biology, College of Natural and Computational Sciences, University of Gondar, Gondar, EthiopiaCorrespondence:Ebrahim M AbdaDepartment of Biotechnology, College of Biological and Chemical Engineering, Addis Ababa Science and Technology University, P.O. Box.16417, Addis Ababa, EthiopiaTel +251966917654Email ebrexmama@gmail.comBackground: The frequent identification of resistant bacteria in hospitals constantly presents antimicrobial therapy with a challenge. Imipenem, once considered an extremely powerful antibiotic against multidrug-resistant bacterial infections, is losing its effectiveness. Its use in empirical therapy with inadequate or nonexistent antimicrobial stewardship programs has further triggered bacterial resistance in low-income countries. Therefore, this study aimed at identifying imipenem-resistant Gram-negative bacteria from patients who were referred to health centers in North Gondar, Ethiopia.Methods: A total of 153 sputum samples were used to isolate Gram-negative bacteria. The isolates, which were resistant to imipenem, were identified by standard biochemical tests and 16S rRNA sequencing. The Kirby-Bauer disk diffusion method was used to determine the sensitivity or resistance of the isolate to diverse antimicrobial agents.Results: The study identified 79 imipenem-resistant bacterial isolates from eight genera with clinically relevant microorganisms, including Acinetobacter baumannii (20.77%), Klebsiella pneumoniae (19.48%), Pseudomonas aeruginosa (16.88%), and Serratia marcescens (14.28%). Overall, imipenem-resistant bacterial isolates were detected in 31 samples (20.26%). Additionally, a remarkably high level of resistance to most antibiotics was observed among isolates of Klebsiella pneumoniae and Acinetobacter baumannii. Gentamycin is the most active antibiotic against many of the isolates, while β-lactams appear to be less effective.Conclusion: The study indicated that many Gram-negative bacteria were resistant to imipenem with parallel resistances to other antimicrobials. Hence, the prescription of imipenem within the region should be according to the antibiotic resistance profiles of the multi-drug resistant bacteria.Keywords: Gram-negative bacteria, imipenem, North Gondar, 16S rRNA sequencing

Patients with Acinetobacter baumannii bacteremia treated with antipseudomonal cephalosporins showed higher 14-day mortality than patients treated with antipseudomonal carbapenems. We hypothesized that the bacterial membrane vesicles (BMVs) induced by antipseudomonal cephalosporins are more virulent than BMVs induced by antipseudomonal carbapenems. To simulate the clinical condition with inadequate antimicrobial treatment, carbapenem-resistant A. baumannii was treated with ceftazidime (an antipseudomonal cephalosporin) or imipenem (an antipseudomonal carbapenem) at 1/2 the minimum inhibitory concentration. BMVs and BMV-carried lipopolysaccharide were measured by nanoparticle tracking analysis and western blotting, respectively. Cytokine expression in RAW264.7 macrophages or mice serum induced by the BMVs was determined by ELISA, fluorescent bead-based immunoassay or western blotting. The virulence of the BMVs was assessed in mice. Liquid chromatography tandem-mass spectrometry was used to determine the protein contents of the BMVs. We found that ceftazidime induced a higher number of BMVs (CAZ-BMV), which carried more LPS, and induced higher expression levels of iNOS, IL-1β, and IL-6 in macrophages, higher expression of many cytokines in mice, more neutrophil infiltration in lung interstitium, and higher mortality in mice than imipenem-induced BMVs (IMP-BMV). When adjusted to same amount of LPS, CAZ-BMV still led to higher mortality than IMP-BMV. Proteomic analysis revealed different protein contents in CAZ-BMV and IMP-BMV. In conclusion, A. baumannii BMVs induced by ceftazidime are more virulent than BMVs induced by imipenem.