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This study aimed to conduct a retrospective Middle East systematic review and meta-analysis on the prevalence and antibiotic susceptibility pattern for this microorganism isolated from cystic fibrosis patients. We searched MEDLINE, the Cochrane Library, SCOPUS, and Web of Science (ISI) to identify studies that reported the prevalence of Pseudomonas aeruginosa isolated from cystic fibrosis (CF) patients, and antibiotic resistance patterns. To assess the quality of publications was used of a checklist provided by the Joanna Briggs Institute. Finally, the data was analyzed by comprehensive meta-analysis software. The studied populations comprised children and young, and adult CF patients. Patients were aged between 3 months-65 years. A higher percentage of CF patients were males. Pseudomonas aeruginosa frequency varied between 5.9 and 76.2% in the studies included. The combined prevalence of P aeruginosa was reported 34.3%. The lowest level resistance of P aeruginosa was toward colistin (0%-l3.3%) and ticarcillin (3.9%-24%). Our study showed the prevalence of P aeruginosa and antibiotic resistance are almost high, while colistin and ticarcillin are the best antibiotics to decrease postantibiotic effects (PAEs) in CF patients from the Middle East. Therefore, physicians should pay more attention to therapeutic protocols to prevent further resistance. [ABSTRACT FROM AUTHOR]

Background Fosfomycin is gaining increasing attention for its activity against MDR or XDR pathogens. Currently, IV fosfomycin is a potential option for treating various infections, including urinary tract infections, pneumonia and skin infections when first-line treatments fail. Objectives To evaluate the demographic, clinical, microbiological and treatment modality of children received IV fosfomycin to treat infections caused by MDR pathogens since there are few data on the use of fosfomycin in children. Methods This study was conducted retrospectively with patients under 18 years of age who were treated with IV fosfomycin for at least 72 h due to infections caused by MDR pathogens between January 2019 and October 2023 at Marmara University Pendik Training and Research Hospital, İstanbul, Türkiye. Data on demographic and clinical features, microbiological findings, treatment modalities and side effects were evaluated. Results Twenty-five children, for a total of 32 cases of infection episodes, with a mean age of 11.4 ±   3.92 years who received IV fosfomycin were included. The most frequent comorbidity was chronic pulmonary diseases, and the most common infection needed for IV fosfomycin was MDR Pseudomonas aeruginosa pneumonia. In all cases, fosfomycin was administered in combination with other antibiotics, mainly meropenem–colistin (68.7%) or meropenem (15.6%). Twenty-two (71.9%) cases had favourable clinical responses at the end of therapy. Conclusions Our results suggest that IV fosfomycin may be an effective treatment option for MDR pathogens in the paediatric population. Nevertheless, careful stewardship is necessary to maintain efficacy and reduce antimicrobial resistance selection risk. [ABSTRACT FROM AUTHOR]

Pharmaceutical drugs, including antibiotics and hormonal agents, pose a significant threat to environmental and public health due to their persistent presence in aquatic environments. Colistin (KOL), fluoxetine (FLUO), amoxicillin (AMO), and 17-alpha-ethinylestradiol (EST) are pharmaceuticals (PhCs) that frequently exceed regulatory limits in water and wastewater. Current removal methods are mainly ineffective, necessitating the development of more efficient techniques. This study investigates the use of synthetic zeolite (NaP1_FA) and zeolite-carbon composites (NaP1_C), both derived from fly ash (FA), for the removal of KOL, FLUO, AMO, and EST from aquatic environments. Batch adsorption experiments assessed the effects of contact time, adsorbent dosage, initial concentration, and pH on the removal efficiency of the pharmaceuticals. The results demonstrated that NaP1_FA and NaP1_C exhibited high removal efficiencies for all tested pharmaceuticals, achieving over 90% removal within 2 min of contact time. The Behnajady-Modirshahla-Ghanbary (BMG) kinetic model best described the adsorption processes. The most effective sorption was observed with a sorbent dose of 1–2 g L−1. Regarding removal efficiency, the substances ranked in this order: EST was the highest, followed by AMO, KOL, and FLUO. Sorption efficiency was influenced by the initial pH of the solutions, with optimal performance observed at pH 2–2.5 for KOL and FLUO. The zeolite-carbon composite NaP1_C, due to its hydrophobic nature, showed superior sorption efficiency for hydrophobic pharmaceuticals like FLUO and EST. The spectral analysis reveals that the primary mechanism for immobilizing the tested PhCs on zeolite sorbents is mainly due to physical sorption. This study underscores the potential of utilizing inexpensive, fly ash-derived zeolites and zeolite-carbon composites to remove pharmaceuticals from water effectively. These findings contribute to developing advanced materials for decentralized wastewater treatment systems, directly addressing pollution sources in various facilities. [ABSTRACT FROM AUTHOR]

Background: The increased incidence of infections due to multidrug-resistant Gram-negative bacteria has led to the renewed interest in the use of 'forgotten' antibiotics such as colistin. In this work, we studied the chromosomal colistin resistance mechanisms among laboratory-induced colistin-resistant Escherichia coli isolates. Methods: Three colistin-susceptible (ColS) clinical isolates of E. coli assigning to ST131, ST405, and ST361 were exposed to successively increasing concentrations of colistin. The nucleotide sequences of pmrA, pmrB, pmrD, phoP, phoQ, and mgrB genes were determined. The fitness burden associated with colistin resistance acquisition was determined by measuring the in vitro growth rate. Results: Colistin resistance induction resulted in 16–64 times increase in colistin MICs in mutants (n = 8) compared with parental isolates. Analysis of chromosomal genes in colistin-resistant mutants compared with those of ColS ancestors revealed genetic alterations confined to PmrAB two-component system and included PmrA G53R/R81S/L105P and PmrB E121K/E121A/A159P/A159V/G302E changes. The PmrB E121 was found as a critical position for colistin resistance development being altered in three mutants with different ancestors. The acquired colistin-resistance phenotype was stable following 10 consecutive passages in the absence of selective pressure of colistin and it did not alter the susceptibility of mutants to other antimicrobial agents. All mutants exhibited growth rates similar to their respective ColS ancestors, except for one isolate, which revealed a significant growth defect. Conclusion: Our results revealed that colistin resistance in E. coli was more related to PmrAB alterations, which did not impose a fitness cost in most cases. [ABSTRACT FROM AUTHOR]

Background: Gram-negative bacteria (GNB) are becoming increasingly resistant to a wide variety of antibiotics. There are currently limited treatments for GNB, and the combination of antibiotics with complementary mechanisms has been reported to be a feasible strategy for treating GNB infection. The inability to cross the GNB outer membrane (OM) is an important reason that a broad spectrum of Gram-positive only class of antibiotics (GPOAs) is lacking. Polymyxins may help GPOAs to permeate by disrupting OM of GNB. Objective: To identify what kind of GPOAs can be aided to broaden their anti-GNB spectrum by polymyxins, we systematically investigated the synergy of eight GPOAs in combination with colistin (COL) and polymyxin B (PMB) against GNB in vitro. Methods: The synergistic effect of COL or PMB and GPOAs combinations against GNB reference strains and clinical isolates were determined by checkerboard tests. The killing kinetics of the combinations were assessed using time-kill assays. Results: In the checkerboard tests, polymyxins-GPOAs combinations exert synergistic effects characterized by species and strain specificity. The synergistic interactions on P. aeruginosa strains are significantly lower than those on strains of A. baumannii, K. pneumoniae and E. coli. Among all the combinations, COL has shown the best synergistic effect in combination with dalbavancin (DAL) or oritavancin (ORI) versus almost all of the strains tested, with FICIs from 0.16 to 0.50 and 0.13 to < 0.28, respectively. In addition, the time-kill assays demonstrated that COL/DAL and COL/ORI had sustained bactericidal activity. Conclusions: Our results indicated that polymyxins could help GPOAs to permeate the OM of specific GNB, thus showed synergistic effects and bactericidal effects in the in vitro assays. In vivo combination studies should be further conducted to validate the results of this study. [ABSTRACT FROM AUTHOR]

More than 70% of bacteria are resistant to all or nearly all known antimicrobials, creating the need for the development of new types of antimicrobials or the use of "last-line" antimicrobial therapies for the treatment of multi-resistant bacteria. These antibiotics include Glycopeptide (Vancomycin), Polymyxin (Colistin), Lipopeptide (Daptomycin), and Carbapenem (Meropenem). However, due to the toxicity of these types of molecules, it is necessary to develop new rapid methodologies to be used in Therapeutic Drug Monitoring (TDM). TDM could improve patient outcomes and reduce healthcare costs by enabling a favorable clinical outcome. In this way, personalized antibiotic therapy emerges as a viable option, offering optimal dosing for each patient according to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Various techniques are used for this monitoring, including high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), and immunoassays. The objective of this study is the development and characterization by ELISA of specific polyclonal antibodies for the recognition of the antibiotics Vancomycin (glycopeptide), Colistin (polymyxin), Daptomycin (lipopeptide), and Meropenem (carbapenem) for future applications in the monitoring of these antibiotics in different fluids, such as human plasma. The developed antibodies are capable of recognizing the antibiotic molecules with good detectability, showing an IC50 of 0.05 nM for Vancomycin, 7.56 nM for Colistin, 183.6 nM for Meropenem, and 13.82 nM for Daptomycin. These antibodies offer a promising tool for the precise and effective therapeutic monitoring of these critical antibiotics, potentially enhancing treatment efficacy and patient safety. [ABSTRACT FROM AUTHOR]

Fungi and bacteria coexist in many polymicrobial communities, yet the molecular basis of their interactions remains poorly understood. Here, we show that the fungus Candida albicans sequesters essential magnesium ions from the bacterium Pseudomonas aeruginosa. To counteract fungal Mg2+ sequestration, P. aeruginosa expresses the Mg2+ transporter MgtA when Mg2+ levels are low. Thus, loss of MgtA specifically impairs P. aeruginosa in co-culture with C. albicans, but fitness can be restored by supplementing Mg2+. Using a panel of fungi and bacteria, we show that Mg2+ sequestration is a general mechanism of fungal antagonism against gram-negative bacteria. Mg2+ limitation enhances bacterial resistance to polymyxin antibiotics like colistin, which target gram-negative bacterial membranes. Indeed, experimental evolution reveals that P. aeruginosa evolves C. albicans-dependent colistin resistance via non-canonical means; antifungal treatment renders resistant bacteria colistin-sensitive. Our work suggests that fungal–bacterial competition could profoundly impact polymicrobial infection treatment with antibiotics of last resort. Interactions between fungi and bacteria can both suppress and promote bacterial fitness. This study uncovers a widespread form of antagonism, in which fungi like Candida albicans sequester magnesium to lower the fitness of gram-negative bacteria like Pseudomonas aeruginosa, which however renders the bacteria more resistant to last-resort antibiotics like colistin. [ABSTRACT FROM AUTHOR]

Background: Due to its rapid resistance development and ability to form biofilms, treatment of Pseudomonas aeruginosa infections is becoming more complicated by the day. Drug combinations may help reduce both resistance and biofilm formation. Methods: Using the microtiter plate assay, we investigated the in vitro inhibition of biofilm formation and the disruption of preformed biofilms in multidrug-resistant and extensively drug-resistant clinical isolates of P. aeruginosa in the presence of peak plasma levels of eight antipseudomonal antibiotics alone and in combination with fosfomycin: ceftazidime, piperacillin/tazobactam, cefepime, imipenem, gentamicin, amikacin, ciprofloxacin and colistin. Results: Combination therapy was significantly superior to monotherapy in its inhibition of biofilm formation. The highest inhibition rates were observed for combinations with colistin, cefepime and ceftazidime. Conclusion: Our results support fosfomycin combination therapy as an enhanced prophylactic option. Moreover, combinations with β-lactam antibiotics and colistin demonstrated a more potent inhibition effect on biofilm formation than protein synthesis inhibitors. [ABSTRACT FROM AUTHOR]

Bacteriophage (phage) therapy is a promising anti-infective option to combat antimicrobial resistance. However, the clinical utilization of phage therapy has been severely compromised by the potential emergence of phage resistance. Although certain phage resistance mechanisms can restore bacterial susceptibility to certain antibiotics, a lack of knowledge of phage resistance mechanisms hinders optimal use of phages and their combination with antibiotics. Genome-wide transposon screening was performed with a mutant library of Klebsiella pneumoniae MKP103 to identify phage pKMKP103_1-resistant mutants. Phage-resistant phenotypes were evaluated by time-kill kinetics and efficiency of plating assays. Phage resistance mechanisms were investigated with adsorption, one-step growth, and mutation frequency assays. Antibiotic susceptibility was determined with broth microdilution and population analysis profiles. We observed a repertoire of phage resistance mechanisms in K pneumoniae , such as disruption of phage binding (fhuA ::Tn and tonB ::Tn), extension of the phage latent period (mnmE ::Tn and rpoN ::Tn), and increased mutation frequency (mutS ::Tn and mutL ::Tn). Notably, in contrast to the prevailing view that phage resistance re-sensitizes antibiotic-resistant bacteria, we observed a bidirectional steering effect on bacterial antibiotic susceptibility. Specifically, rpoN ::Tn increased susceptibility to colistin while mutS ::Tn and mutL ::Tn increased resistance to rifampicin and colistin. Our findings demonstrate that K pneumoniae employs multiple strategies to overcome phage infection, which may result in enhanced or reduced antibiotic susceptibility. Mechanism-guided phage steering should be incorporated into phage therapy to better inform clinical decisions on phage-antibiotic combinations. [Display omitted] [ABSTRACT FROM AUTHOR]

Healthcare-associated central nervous system infections are a significant complication for patients undergoing neurosurgical interventions. We present a case of a 6-year-old patient with an embryonal tumor of the central nervous system. Following a craniotomy for the resection of the tumor, an external ventricular drainage was placed. Several weeks after surgery, she developed signs of meningism. Cerebrospinal fluid cultures were positive for pan-drug resistant Acinetobacter baumannii. Several revisions with the insertion of new external valves were done. She was treated with intravenously meropenem and vancomycin combined with colistin administrated intraventricularly. Significant improvement was seen clinically with negative cultures after 2 weeks. The synergistic action of colistin administrated locally combined with systemic antibiotics may be a promising option for critically ill patients with pan-drug resistant A. baumannii central nervous system infection. [ABSTRACT FROM AUTHOR]

Background Metallo-β-lactamase (MBL)–producing Enterobacterales are increasing worldwide. Our aim was to describe clinical features, treatments, and outcomes of infections by MBL-Enterobacterales. Methods A prospective observational study conducted in the Pisa University Hospital (January 2019 to October 2022) included patients with MBL-producing Enterobacterales infections. The primary outcome measure was the 30-day mortality rate. Multivariable Cox regression analysis was performed to identify factors associated with that mortality rate, and adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated. Results The study's 343 patients included 15 with Verona integron-encoded MBL (VIM)- and 328 with New Delhi MBL (NDM)–producing Enterobacterales infections; there were 199 patients (58%) with bloodstream infections, 60 (17.5%) with hospital-acquired or ventilator-associated pneumonia, 60 (17.5%) with complicated urinary tract infections, 13 (3.8%) with intra-abdominal infections, and 11 (3.2%) with skin and soft-tissue infections. The 30-day mortality rate was 29.7%. Of 343 patients, 32 did not receive in vitro active antibiotic therapy, 215 (62.7%) received ceftazidime-avibactam plus aztreonam, 33 (9.6%) received cefiderocol-containing regimens, 26 (7.6%) received colistin-containing regimens, and 37 (10.8%) received other active antibiotics. On multivariable analysis, septic shock (aHR, 3.57 [95% CI, 2.05–6.23]; P <.001) and age (1.05 [1.03–1.08]; P <.001) were independently associated with the 30-day mortality rate, while in vitro active antibiotic therapy within 48 hours after infection (0.48 [.26–.8]; P =.007) and source control (0.43 [.26–.72]; P =.001) were protective factors. Sensitivity analysis showed that ceftazidime-avibactam plus aztreonam, compared with colistin, was independently associated with a reduced 30-day mortality rate (aHR, 0.39 [95% CI,.18–.86]; P =.02). Propensity score analyses confirmed these findings. Conclusions MBL-producing carbapenem-resistant Enterobacterales infections are associated with high 30-day mortality rates. Patients with MBL-producing Enterobacterales infections should receive early active antibiotic therapy. [ABSTRACT FROM AUTHOR]

Background: Multiple randomized controlled studies have compared numerous antibiotic regimens, including new, recently commercialized antibiotics in the treatment of nosocomial pneumonia (NP). The objective of this Bayesian network meta-analysis (NMA) was to compare the efficacy and the safety of different antibiotic treatments for NP. Methods: We conducted a systematic search of PubMed, Medline, Web of Science, EMBASE and the Cochrane Library databases from 2000 through 2021. The study selection included studies comparing antibiotics targeting Gram-negative bacilli in the setting of NP. The primary endpoint was 28 day mortality. Secondary outcomes were clinical cure, microbiological cure and adverse events. Results: Sixteen studies encompassing 4993 patients were included in this analysis comparing 13 antibiotic regimens. The level of evidence for mortality comparisons ranged from very low to moderate. No significant difference in 28 day mortality was found among all beta-lactam regimens. Only the combination of meropenem plus aerosolized colistin was associated with a significant decrease of mortality compared to using intravenous colistin alone (OR = 0.43; 95% credible interval [0.17–0.94]), based on the results of the smallest trial included. The clinical failure rate of ceftazidime was higher than meropenem with (OR = 1.97; 95% CrI [1.19–3.45]) or without aerosolized colistin (OR = 1.40; 95% CrI [1.00–2.01]), imipemen/cilastatin/relebactam (OR = 1.74; 95% CrI [1.03–2.90]) and ceftazidime/avibactam (OR = 1.48; 95% CrI [1.02–2.20]). For microbiological cure, no substantial difference between regimens was found, but ceftolozane/tazobactam had the highest probability of being superior to comparators. In safety analyses, there was no significant difference between treatments for the occurrence of adverse events, but acute kidney failure was more common in patients receiving intravenous colistin. Conclusions: This network meta-analysis suggests that most antibiotic regimens, including new combinations and cefiderocol, have similar efficacy and safety in treating susceptible Gram-negative bacilli in NP. Further studies are necessary for NP caused by multidrug-resistant bacteria. Registration PROSPERO CRD42021226603 [ABSTRACT FROM AUTHOR]

Bacterial resistance surveillance is one of the main outputs of microbiological laboratories and its results are important part of antimicrobial stewardship (AMS). In this study, the susceptibility of specific bacteria to selected antimicrobial agents was tested. The susceptibility of 90 unique isolates of pathogens of critical priority obtained from clinically valid samples of ICU patients in 2017–2021 was tested. 50% of these fulfilled difficult-to-treat resistance (DTR) criteria and 50% were susceptible to all antibiotics included in the definition. 10 Enterobacterales strains met DTR criteria, and 2 (20%) were resistant to colistin (COL), 2 (20%) to cefiderocol (FCR), 7 (70%) to imipenem/cilastatin/relebactam (I/R), 3 (30%) to ceftazidime/avibactam (CAT) and 5 (50%) to fosfomycin (FOS). For Enterobacterales we also tested aztreonam/avibactam (AZA) for which there are no breakpoints yet. The highest MIC of AZA observed was 1 mg/l, MIC range in the susceptible cohort was 0.032–0.064 mg/l and in the DTR cohort (incl. class B beta-lactamase producers) it was 0.064–1 mg/l. Two (13.3%) isolates of Pseudomonas aeruginosa (15 DTR strains) were resistant to COL, 1 (6.7%) to FCR, 13 (86.7%) to I/R, 5 (33.3%) to CAT, and 5 (33.3%) to ceftolozane/tazobactam. All isolates of Acinetobacter baumannii with DTR were susceptible to COL and FCR, and at the same time resistant to I/R and ampicillin/sulbactam. New antimicrobial agents are not 100% effective against DTR. Therefore, it is necessary to perform susceptibility testing of these antibiotics, use the data for surveillance (including local surveillance) and conform to AMS standards. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effect of commonly prescribed antibiotics on sperm parameters in breeding roosters. Twenty adult subjects were divided on the basis of their response to the dorso-abdominal massage into four experimental groups (G1: 30 mg/kg of ampicillin, G2: 10 mg/kg of enrofloxacin, G3: 2.5 mg/kg of colistin, and G4: 140 mg/kg of a sulfonamides association (sulphaquinoxaline sodium 150 mg, sulphamethazine sodium 70 mg, sulphadiazine sodium 70 mg). The measurements were performed at (T0) (before treatment), (T3 and T9) (representing 3 and 9 days of treatment) by Computer Aided Sperm Analysis (CASA). All antibiotics did not affect ejaculate color, pH, seminal fluid viscosity, and agglutination. Ampicillin increased slightly sperm volume at T3 (0.31±0.19) with no significant change at T9 (0.30±0.15). No significant effect was observed at T3 on sperm count (224.05±41.9), viability (94±2.08), and total motility (TM) (57%). However, progressive motility (PM) deceased slightly on T3 (36.92%). Enrofloxacin and colistin induced a significant decrease in sperm volume (0.40±0.10, 0.16±0.08), count (2.13±0.27, 0.65±0.33), viability (81.33±5.45, 37.33±18.67), TM (54.95%, 46.91%), and PM (31.24%, 23%) on T3. On T9 some parameters were improved to be closer to those observed at T0. Ampicillin, colistin, and enrofloxacin decreased significantly all (CASA) kinematic parameters. The highest impact was observed on the third day of treatment (T3). Sulfonamides decreased sperm volume and gametes concentration but enhanced significantly sperm viability, total motility TM, progressive motility PM, and all kinematic parameters. [ABSTRACT FROM AUTHOR]

Background and Objectives: Over the last decade, hospital-acquired infections, particularly in the critical care setting, have become more common, with Gram-negative bacterial infections having the highest prevalence. This study aims to determine the prevalence and antibiotic susceptibility pattern of Pseudomonas species to WHO's, aware class of antibiotics, which are commonly prescribed across various ICU's, medical and surgical wards of our tertiary care teaching hospital. Materials and Methods: This prospective study conducted from January 2021 to June 2022 at a tertiary care centre of central India identified Pseudomonas species from clinical samples using standard procedures and antimicrobial susceptibility testing performed as per Clinical Laboratory Standards Institute (CLSI) guidelines (M100; 32th Edition). Results: A total of 1490 non duplicate Pseudomonas species isolates were grown from 21,019 culture positive clinical samples, of which 1247 were Pseudomonas aeruginosa. Out of these 1247 Pseudomonas aeruginosa 384 were MDR (30.7%). Pseudomonas aeruginosa were most commonly isolated from the pus samples (85%). ICU isolates were significantly more resistant to antibiotics than those from other units. P. aeruginosa strains from ICUs showed the highest rates of resistance to ceftazidime (93.9%). Reserve drug colistin showed good susceptibility (98.2%). All the 18 colistin resistant strains were found to be negative for plasmid mediated mcr-1,2,3 genes. Conclusion: The study shall help to generate and disseminate the data so that proper antibiotic policy can be made for judicious use of Access, Watch and Reserve antibiotics and antibiotic de-escalation plan can be put forth. [ABSTRACT FROM AUTHOR]

Introduction: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections commonly cause hospital-acquired infections. The study aimed to compare the outcomes of CRKP infections between patients receiving ceftazidime avibactam +/− aztreonam and polymyxins in a hospital setting with a high prevalence of New Delhi Metallo Beta Lactamase production. Methods: We conducted a retrospective cohort study from January 2020 to September 2022 in critically ill adult patients admitted to a non-COVID-19 medical intensive care unit with CRKP infection. The patients were followed up for a total of 30 days or death, whichever was later. Results: Of a total of 106 patients included in the study, 65 patients received polymyxins and 41 patients received ceftazidime–avibactam +/− aztreonam. Higher 30-day mortality was noted in the polymyxin group (56.9% vs. 29.2%, P = 0.005). The mean time to event (mortality) in ceftazidime–avibactam +/− aztreonam was 23.9 + 1.5 days which was significantly higher compared to polymyxins (17.9 + 1.2 days, p = 0.006). On Cox regression analysis, after adjusting for the covariates, the hazard ratio for time to event with the use of polymyxin was 2.02 (95% CI: 1.03–3.9). Conclusion: Ceftazidime–avibactam + aztreonam is possibly associated with better clinical outcomes in patients infected with CRKP. [ABSTRACT FROM AUTHOR]

Neonatal sepsis is a leading cause of morbidity and mortality in neonates, particularly in low- and middle-income countries. The emergence of antimicrobial resistance is a rapidly growing global problem. A significant proportion of the pathogens that commonly cause neonatal sepsis are resistant to multiple antibiotics. Therefore, for the empirical treatment of neonatal sepsis, the repurposing of older antibiotics that are effective against multidrug-resistant pathogens is being investigated. This review aims to provide an overview of current research and experience using the repurposed antibiotics colistin and fosfomycin for the empirical treatment of neonatal sepsis. Based on current knowledge, colistin and fosfomycin may be potentially helpful for the empirical treatment of sepsis in neonates due to their efficacy against a wide range of pathogens and acceptable safety profile. [ABSTRACT FROM AUTHOR]

Surgical emergencies in patients with hemophilia A represent a major risk of mortality without proper multidisciplinary management and require prompt and effective treatment to prevent complications and improve patient outcomes. We present a short number of cases that were hospitalized in the I–II Surgery Clinic of the Emergency County Hospital "St. Spiridon" from Iasi, Romania, with hemophilia A requiring surgical emergencies. The timing of surgical intervention is very important, so the indication for surgical intervention must be made judiciously and without delay. Consequently, it is vital to ensure access to hemostatic support so surgery can be performed on these patients, ultimately saving their lives. [ABSTRACT FROM AUTHOR]

This article discusses the challenges of developing new antibiotics, particularly for the gram-negative bacteria Pseudomonas aeruginosa. The lack of therapeutic options for this bacteria is concerning, as it is classified as a "serious threat" by the CDC and has high rates of antibiotic resistance. The article presents permeation guidelines for P. aeruginosa, which can help in designing small molecules that can effectively penetrate the bacteria and gain intracellular access. These guidelines differ from those for another gram-negative bacteria, Escherichia coli, and provide insights into the physiological differences between the two bacteria. The article suggests that these permeation guidelines can aid in the development of new antibiotics by enhancing the accumulation of candidate drugs. [Extracted from the article]

The emergence of Klebsiella (K.) pneumoniae as a leading cause of nosocomial infections in Southeast Asia is of concern. Vietnam has an outstanding position with regard to antimicrobialresistant (AMR) pathogens and is a hotspot for carbapenem-resistant K. pneumoniae. In the current study, 19 clinical K. pneumoniae strains isolated from patients in Vietnam were tested for antibiotic susceptibility, and their genome sequences were analyzed to investigate potential resistance profiles, genotypes, AMR determinants, and virulence-associated genes. More than half of the isolates were multidrug-resistant (MDR), displaying resistance to ciprofloxacin, levofloxacin, chloramphenicol, piperacillin, cefotaxime, ceftazidime, and cefepime. Carbapenem- resistance was detected in 47% (n=9) of isolates. Five isolates were assigned to sequence type (ST) 23 by multi-locus sequence typing (MLST). These ST23 strains exhibited determinants characteristic of hypervirulent strains and were sensitive to all antibiotics tested except for one strain, which was resistant to chloramphenicol and trimethoprim/sulfamethoxazole. All isolates had AMR determinants that conferred resistance to aminoglycosides and ß-lactams. Single nucleotide variants of oqxA and oqxB conferring resistance to phenicol/quinolone, ompK37 and ompA conferring resistance to beta-lactams, and lptD conferring resistance to rifamycin, were found in all isolates. Additionally, 95% of the isolates (n=18) carried fosA genes; however, only two were resistant to fosfomycin. Five isolates carried genes conferring resistance to colistin; only one carried mcr-1.1 and showed resistance to colistin. One hundred thirty virulence-associated genes were identified. The current study demonstrated an inverse relationship between the number of detected virulence determinants and antibiotic resistance. Several well-known resistance genes have been identified but did not mediate resistance, which could be due to insufficient levels or lack of expression. A comprehensive study of the genotypic findings of AMR determinants and virulence with phenotypic data is required. The presence of hypervirulent K. pneumoniae carrying specific virulomes is a growing problem, and monitoring of virulence characteristics of K. pneumoniae is important. [ABSTRACT FROM AUTHOR]

The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial fitness and this cost correlates with lipid A perturbation. However, the exact molecular mechanism remains unclear. Here, we identified the MCR-1 M6 variant carrying two-point mutations that conferred co-resistance to β-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe disturbance in lipid A, resulting in up-regulation of L, D-transpeptidases (LDTs) pathway, which explains co-resistance to β-lactams. Moreover, we show that a lipid A loading pocket is localized at the linker domain of MCR-1 where these 2 mutations are located. This pocket governs colistin resistance and bacterial membrane permeability, and the mutated pocket in M6 enhances the binding affinity towards lipid A. Based on this new information, we also designed synthetic peptides derived from M6 that exhibit broad-spectrum antimicrobial activity, exposing a potential vulnerability that could be exploited for future antimicrobial drug design. This study shows that a variant of the colicin resistance gene mcr-1 exhibits co-resistance towards β-lactam antibiotics. This MCR-1 variant contains a potential lipid A binding cavity which may explain the costs of carrying this resistance gene, and a peptide derived from this mutant itself displays broad-spectrum antimicrobial activity". [ABSTRACT FROM AUTHOR]

Background: Carbapenem-resistant enterobacteriaceae (CRE) is associated with high mortality in critically ill patients, with limited treatment options. This study aims to compare clinical response, microbiological response, and mortality in patients treated with ceftazidime--avibactam with or without aztreonam (CAZ-AVI + AZT) and colistin or polymyxin B (polymyxins) in CRE infections. Materials and methods: This single-center prospective observational study included adult patients with CRE infections treated with CAZ-AVI+AZT or polymyxins between January 2022 and December 2022 at a Tertiary Care Medical Center in India. The clinical response, microbiological response, and mortality were compared between the two groups using a Cox multivariate regression model adjusted for the baseline SOFA score and comorbidities. Results: A total of 89 patients were enrolled, with 59 (66%) patients receiving CAZ-AVI + AZT and 30 receiving polymyxins. Baseline demographics and clinical characteristics were similar between the two groups. The Cox multivariate regression analysis showed a statistically significant difference in clinical failure on day 14 with the CAZ-AVI + AZT group vs polymyxins (HR = 0.78, 95% CI 0.63-0.95, p = 0.018). There was no difference in microbiological failure (HR = 1.08, 95% CI 0.66-1.77, p = 0.76), microbiological relapse (HR = 0.75, 95% CI 0.36-3.02, p = 0.62), and hospital mortality (HR = 1.04, 95% CI 0.75-1.43, p = 0.796) between the two groups. Conclusion: Treatment with ceftazidime--avibactam with or without aztreonam for CRE infections associated with a better clinical response compared with polymyxins monotherapy but without any difference in microbiological response or mortality. [ABSTRACT FROM AUTHOR]

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Polymyxin' E' (Colistin) is considered the last resort therapy against Multidrug resistance (MDR) bacteria, mainly Klebsiella peumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli and play a critical role in causing life-threatening infection, and their prevalence is increasing as a big concern globally. Apart from immunological adaptation, chromosomal mutations and plasmid-mediated genes are mostly associated with this resistance at the molecular level. Therefore, the current review extensively focused on Colistin as a drug in 21st-century antibiotics, the activities spectrum with diverse resistance mechanisms of bacteria against Colistin, and emerging approaches of Colistin from discovery to tackling MDR. In the study, we got to know about the challenges and new developments with old weapons like phage therapy as well as new approaches like Phage display and drug repurposing, in addition to the chromosomal and plasmid-mediated genes that play a role in antimicrobial resistance (AMR). The present study would provide insight into the prognostic aspect of combating MDR. [ABSTRACT FROM AUTHOR]

More than 70% of bacteria are resistant to all or nearly all known antimicrobials, creating the need for the development of new types of antimicrobials or the use of “last-line” antimicrobial therapies for the treatment of multi-resistant bacteria. These antibiotics include Glycopeptide (Vancomycin), Polymyxin (Colistin), Lipopeptide (Daptomycin), and Carbapenem (Meropenem). However, due to the toxicity of these types of molecules, it is necessary to develop new rapid methodologies to be used in Therapeutic Drug Monitoring (TDM). TDM could improve patient outcomes and reduce healthcare costs by enabling a favorable clinical outcome. In this way, personalized antibiotic therapy emerges as a viable option, offering optimal dosing for each patient according to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Various techniques are used for this monitoring, including high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), and immunoassays. The objective of this study is the development and characterization by ELISA of specific polyclonal antibodies for the recognition of the antibiotics Vancomycin (glycopeptide), Colistin (polymyxin), Daptomycin (lipopeptide), and Meropenem (carbapenem) for future applications in the monitoring of these antibiotics in different fluids, such as human plasma. The developed antibodies are capable of recognizing the antibiotic molecules with good detectability, showing an IC50 of 0.05 nM for Vancomycin, 7.56 nM for Colistin, 183.6 nM for Meropenem, and 13.82 nM for Daptomycin. These antibodies offer a promising tool for the precise and effective therapeutic monitoring of these critical antibiotics, potentially enhancing treatment efficacy and patient safety.

ABSTRACT Turnercyclamycin A and B lipopeptides exhibit Gram-negative bacteria-specific toxicity. This includes CDC urgent threat organisms such as multidrug-resistant Acinetobacter baumannii. Like the last-line agent colistin, turnercyclamycins interact with the lipopolysaccharide (LPS) pathway, but they remain active against clinical isolates that are colistin resistant. Here, we aimed to determine why turnercyclamycins A and B show little cross-resistance with colistin despite some potential mechanistic and structural similarities. The outer membrane was important in the actions of all three agents, since the deletion of lpxC that synthesizes LPS and the addition of exogenous LPS led to resistance to turnercyclamycins and colistin. Even so, it was much more difficult to generate resistance to turnercyclamycin A than turnercyclamycin B. In Escherichia coli, disruption of the mlaA gene, which is involved in outer membrane homeostasis, resulted in resistance to turnercyclamycin B. However, mlaA disruption blocked neither turnercyclamycin A nor colistin activity. This activity was recapitulated in A. baumannii, where transposon mutants were more resistant to turnercyclamycin B. Moreover, the common A. baumannii colistin resistance gene mcr-1 blocked colistin activity in E. coli but did not affect turnercyclamycins. These results demonstrate a unique resistance profile for turnercyclamycins A and B, in addition to suggesting differences in the mechanism of action. Further, turnercyclamycin A was effective in a mouse model of A. baumannii infection, indicating that this compound class may have potential promise in treating drug-resistant infections. IMPORTANCE Bacterial resistance to antibiotics is a crisis. Acinetobacter baumannii is among the CDC urgent threat pathogens in part for this reason. Lipopeptides known as turnercyclamycins are produced by symbiotic bacteria that normally live in marine mollusks, where they may be involved in shaping their symbiotic niche. Turnercyclamycins killed Gram-negative pathogens including drug-resistant Acinetobacter, but how do the mechanisms of resistance compare to other lipopeptide drugs? Here, we define resistance from a truncation of MlaA, a protein involved in regulating bacterial membrane phospholipids. Intriguingly, this resistance mechanism only affected one turnercyclamycin variant, which differed only in two atoms in the lipid tail of the compounds. We could not obtain significant resistance to the second turnercyclamycin variant, which was also effective in an infection model. This study reveals an unexpected subtlety in resistance to lipopeptide antibiotics, which may be useful in the design and development of antibiotics to combat drug resistance.

Introduction: The access, watch, and reserve (AWaRe) classification of antibiotics was developed in 2019 by the WHO Expert Committee on the Selection and Use of Essential Medicines as a tool to support antibiotic stewardship efforts at local, national, and global levels. The objectives of this study were to assess the availability of antibiotics as per WHO AWaRe classification at community pharmacies located around a tertiary care hospital in Lalitpur and to compare these antibiotics with the national essential medicine list of Nepal. Method: The cross-sectional study was conducted at community pharmacies located within a two-kilometer radius of a teaching hospital from August to November 2022. A total of 82 community pharmacies registered with the Nepal Chemist and Druggists Association and the Department of Drug Administration were studied. Data was collected using a standard proforma containing the names of the antibiotics classified as per the WHO's AWaRe classification. Results: Access group of antibiotics, Ampicillin, (82;100%), Amoxycillin, (82;100%), Flucloxacillin, (82;100%), and Metronidazole, (82;100%) were available in all community pharmacies. Results from the watch group showed that Azithromycin, (80; 97.6%) was available in all pharmacies followed by Cefixime, (80; 97.6%), Ciprofloxacin, (73; 89%), Levofloxacin, (74; 90.2%)and Ofloxacin, (74; 90.2%). Linezolid, (24; 29.3%) was the most common antibiotics available from the reserve group of antibiotics. Colistin was the second commonly available antibiotic. The most available antibiotic from the not recommended group were Ampicillin/Cloxacillin (82; 100%), followed by Piperacillin/Sulbactam, (39; 47.6%). There were differences in the classification of antibiotics between the WHO AWaRe list and the Essential Medicines list of Nepal in terms of numbers of antibiotics listed. Conclusion: Antibiotics from the not recommended and reserve groups were commonly available in community pharmacies. The implementation of antibiotic guidelines should be emphasized along with strict monitoring of the sale of antibiotics without a prescription in community pharmacy settings. [ABSTRACT FROM AUTHOR]

Background: The spread of antibiotic resistance and the emergence of MDR strains, especially in gram-negative bacteria, has led to combining antibiotics to treat infections caused by these bacteria. The study aimed to evaluate some antibiotics' synergistic effect on multidrug-resistant Pseudomonas aeruginosa isolates isolated from clinical samples between thyroid dysfunction and asymptomatic bacteriuria in women of reproductive and postmenopausal age. Materials and Methods: P. aeruginosa was isolated from Rasht city hospitals (North of Iran) clinical specimens with multiple antibiotic resistance. The antibiotic resistance of isolates was determined by the disk diffusion method. The screening checklist evaluated the synergistic effects of ciprofloxacin, colistin, meropenem, and gentamicin. Results: The combination of meropenem and colistin in four isolates was additive, and in two isolates was indifferent. The combined effect of ciprofloxacin and colistin was also incremental in 4 isolates and indifferent in 2 isolates. The combined effect of gentamicin and colistin was indifferent in all selected strains. Conclusion: Results of this study showed that combinations of colistin with ciprofloxacin and colistin with meropenem were successful against resistant isolates, while a combination of gentamicin and colistin showed no synergistic effect. Since the characteristics of each clinical isolate differ from the other isolates, more study with more isolates is recommended to make any precise and definite recommendation. [ABSTRACT FROM AUTHOR]

Recent studies have revealed that colistin dependence frequently develops in colistin-susceptible Acinetobacter baumannii isolates. Despite resistance in parental strains, colistin-dependent mutants showed increased susceptibility to several antibiotics, which suggests the possibility of developing strategies to eliminate multidrug-resistant (MDR) A. baumannii. We investigated in vitro and in vivo efficacy of combinations of colistin and other antibiotics using MDR A. baumannii strains H08-391, H06-855, and H09-94, which are colistin-susceptible but develops colistin dependence upon exposure to colistin. An in vitro time-killing assay, a checkerboard assay, and an antibiotic treatment assay using Galleria mellonella larvae were performed. Although a single treatment of colistin at a high concentration did not prevent colistin dependence, combinations of colistin with other antibiotics at subinhibitory concentrations, especially amikacin, eradicated the strains by inhibiting the development of colistin dependence, in the in vitro time-killing assay. Only 40% of G. mellonella larvae infected by A. baumannii survived with colistin treatment alone; however, all or most of them survived following treatment with the combination of colistin and other antibiotics (amikacin, ceftriaxone, and tetracycline). Our results suggest the possibility of the combination of colistin and amikacin or other antibiotics as one of therapeutic options against A. baumannii infections by eliminating colistin-dependent mutants. [ABSTRACT FROM AUTHOR]

Objective: Antibiotics resistance in bacteria is an important public health problem recently. Resistance rates vary from country to country, from region to region, and even from hospital to hospital. Recently, tigecycline and colistin have been widely used due to increasing multi-resistance in Gram-negative bacteria. The aim of the study was to investigate the changes in colistin and tigecycline intrinsic-resistant bacteria ratio and the effects of these drugs on the hospital flora throughout the hospital due to the widespread use of these drugs. Materials and Methods: In our microbiology laboratory, clinical samples were processed according to the general microbiology procedure. Bacterial identification and antibiogram susceptibility tests were performed with VITEK®2 Compact, MALDI-TOF mass spectrometry (bioMérieux, France). Results were evaluated according to CLSI and EUCAST criteria. The data were scanned retrospectively between the years 2012 and 2019. Chi-square test was used in statistical analysis. Significance was evaluated at the p<0.05 level. Results: While the number of Escherichia coli isolates decreased over the years, an increase was detected in Klebsiella spp. tigecycline intrinsic-resistant bacteria, Proteus spp., Providencia spp., and Pseudomonas spp. When evaluated with the general number of bacteria isolated over the years, Pseudomonas spp., a three-fold increase was found in 2018 and 2019 and in colistin intrinsic-resistant bacteria, Morganella spp., Proteus spp., Providencia spp., Yersinia spp., Burkholderia spp., and Eliseabethkingea spp. No statistically significant increase was detected. A significant increase was detected in Serratia spp. Conclusion: Changes were detected in intrinsic-resistant bacteria and in antibiotic distribution. The antibiotic drugs used affect the entire flora, including the microbiota. The importance of patient care and antibiotic management should be emphasized, targeted therapies treatments should be made that the microbiota will not change, or fecal transplantation methods, which are new methods to replace microbiota, should be investigated. [ABSTRACT FROM AUTHOR]

This study was devoted to the comparison of the probiotic effect of compound probiotics to antibiotics as a feed additive for chicken. Two hundred and seventy newly hatched yellow-feather broilers were randomly divided into three groups: the control group (Con), probiotics (Pb), and antibiotics group (Ab). The Pb group received compound probiotics (Bifidobacterium, Lactobacillus acidophilus, Streptococcus faecalis, and yeast) via drinking water for 24 days. The Ab group received antibiotics (zinc bacitracin and colistin sulfate) in their diet for 24 days. All broilers were slaughtered on day 42. Compared with the Con group, the body weight was significantly increased on days 13, 28, and 42 in the Pb group (p < 0.05), and markedly increased on day 28 in the Ab group (p < 0.05). Compared with the Ab group, the body weight of the broilers in the Pb group increased significantly on day 13 (p < 0.05). Compared to the Con and Pb groups, the antibiotics treatment reduced the feed intake (p < 0.05), but there was no significant difference in the feed conversion ratio between the Ab and Pb groups (p > 0.05). The feed conversion ratio of the broilers treated with antibiotics or probiotics significantly decreased compared to the Con group (p < 0.05). The depth of duodenum, jejunum, and ileum crypts in the Pb group decreased significantly compared to the Con and Ab group (p < 0.05). The ratio of the villi length to crypt depth of duodenum, jejunum, and ileum epithelium was significantly increased in the Pb group compared to the Con group (p < 0.05). The genera Bacteroides and Barnesiella were the most significantly enriched bacteria in the Ab and Pb groups, respectively (p < 0.05). The expression of the genes related to antibiotic resistance was significantly decreased in the Pb group compared to the Ab group (p < 0.05). Although both compound probiotics and antibiotics can improve growth performance, antibiotics increased the abundance of harmful bacteria and drug-resistant genes, while probiotics increased Barnesiella abundance, which is related to a decrease in the drug-resistant gene expression. Moreover, the probiotics treatment improved small intestinal morphology and fecal emissions, while antibiotics have no significant effect on these indicators, indicating a bright future for probiotics as an alternative to feed antibiotics in the yellow-feather broiler industry. [ABSTRACT FROM AUTHOR]

Globally, antibiotic-resistant Klebsiella spp. cause healthcare-associated infections with high mortality rates, and the rise of hypervirulent Klebsiella pneumoniae (hvKp) poses a significant threat to human health linked to community-acquired infections and increasing non-susceptibility. We investigated the phenotypic and genetic features of 36 Klebsiella isolates recovered from invasive infections at Hospital Central of Maputo in Mozambique during one year. The majority of the isolates displayed multidrug resistance (MDR) (29/36) to cephalosporins, gentamicin, ciprofloxacin, and trimethoprim–sulfamethoxazole but retained susceptibility to amikacin, carbapenems, and colistin. Most isolates were ESBLs-producing (28/36), predominantly carrying the blaCTX-M-15 and other beta-lactamase genes (blaSHV, blaTEM-1, and blaOXA-1). Among the 16 genomes sequenced, multiple resistance genes from different antibiotic classes were identified, with blaCTX-M-15, mostly in the ISEcp1-blaCTX-M-15-orf477 genetic environment, co-existing with blaTEM-1 and aac(3)-IIa in five isolates. Our results highlight the presence of polyclonal MDR ESBL-producing K. pneumoniae from eight sequence types (ST), mostly harbouring distinct yersiniabactin within the conjugative integrative element (ICE). Further, we identified susceptible hvKp ST23, O1-K1-type isolates carrying yersiniabactin (ybt1/ICEKp10), colibactin, salmochelin, aerobactin, and hypermucoid locus (rmpADC), associated with severe infections in humans. These findings are worrying and underline the importance of implementing surveillance strategies to avoid the risk of the emergence of the most threatening MDR hvKp. [ABSTRACT FROM AUTHOR]

Beyond the development of resistance, the effects of antibiotics on bacteria and microbial communities are complex and far from exhaustively studied. In the context of the current global antimicrobial resistance crisis, understanding the adaptive and physiological responses of bacteria to antimicrobials is of paramount importance along with the development of new therapies. Bacterial dependence on antibiotics is a phenomenon in which antimicrobials instead of eliminating the pathogens actually provide a boost for their growth. This trait comprises an extreme example of the complexities of responses elicited by microorganisms to these drugs. This compelling evolutionary trait was readily described along with the first wave of antibiotics use and dependence to various antimicrobials has been reported. Nevertheless, current molecular characterizations have been focused on dependence on vancomycin, linezolid and colistin, three critically important antibiotics frequently used as last resource therapy for multi resistant pathogens. Outstanding advances have been made in understanding the molecular basis for the dependence to vancomycin, including specific mutations involved. Regarding linezolid and colistin, the general physiological components affected by the dependence, namely ribosomes and membrane function respectively, have been established. Nonetheless the implications of antibiotic dependence in clinically relevant features, such as virulence, epidemics, relationship with development of resistance, diagnostics and therapy effectiveness require clarification. This review presents a brief introduction of the phenomenon of bacterial dependence to antibiotics and a summary on early and current research concerning the basis for this trait. Furthermore, the available information on the effect of dependence in key clinical aspects is discussed. The studies performed so far underline the need to fully disclose the biological and clinical significance of this trait in pathogens to successfully assess its role in resistance and to design adjusted therapies. [ABSTRACT FROM AUTHOR]

Background Antimicrobial resistance (AMR) data in the pediatric population are limited, particularly in developing countries. This study assessed the AMR profile and key resistance phenotypes and genotypes for Gram-negative bacteria (GNB) isolates collected as part of the Antimicrobial Testing Leadership and Surveillance program from pediatric patients in Latin America, Africa-Middle East, and Asia in 2016–2020 versus 2011–2015. Methods Minimum inhibitory concentrations by broth microdilution methodology were interpreted per the Clinical and Laboratory Standards Institute. European Committee on Antimicrobial Susceptibility Testing breakpoints were used for interpreting colistin activity. β-lactamase genes were screened by polymerase chain reaction and sequencing. Results For Acinetobacter baumannii , low susceptibility (<60.0%) was observed for all antimicrobials, except colistin (≥92.9%), across regions and year periods. Ceftazidime-avibactam, amikacin, colistin, and meropenem were mostly active (78.6%–100.0%) against Enterobacter cloacae , Escherichia coli , and Klebsiella pneumoniae. For Pseudomonas aeruginosa , susceptibility to ceftazidime-avibactam, amikacin, and colistin was ≥85.9%. Among resistance phenotypes, carbapenem-resistant (CR, ≥44.8%) and difficult-to-treat resistant (DTR, ≥37.1%) rates were the highest in A. baumannii. A consistent increase in CR and DTR K. pneumoniae was noted across regions over time. Extended-spectrum β-lactamases (ESBL)-producing K. pneumoniae (32.6%–55.6%) were more frequent than ESBL-producing E. coli (25.3%–37.1%). CTX-M was the dominant ESBL among Enterobacterales. NDM-positive Enterobacterales species and VIM-positive P. aeruginosa were identified across regions. Conclusions This study identified high susceptibility to few agents for key GNB in pediatric patients. Continued surveillance of resistance phenotypes and genotypes at regional levels may help to guide appropriate treatment decisions. [ABSTRACT FROM AUTHOR]

Neuromeningeal infections caused by carbapenemase-secreting Enterobacteriaceae are a serious complication with a high mortality rate. The management of carbapenemase encephalitis/meningitis is complicated by the limited therapeutic options available, due to pan-resistance to antibiotics and their poor distribution in cerebrospinal fluid. Carbapenemase- secreting Klebsiella pneumoniae has recently become endemic, posing a global public health problem, and several - still rare - cases of meningitis caused by this germ have been reported. We describe a case of post-craniectomy nosocomial meningitis caused by K. pneumoniae carbapenemase-secreting New Delhi metallo-betalactamase (NDM), described for the first time in the literature. treated effectively with intrathecal polymyxin E. [ABSTRACT FROM AUTHOR]

Resistance of Acinetobacter baumannii to multiple clinically important antimicrobials has increased to very high rates in Greece, rendering most of them obsolete. The aim of this study was to determine the molecular epidemiology and susceptibilities of A. baumannii isolates collected from different hospitals across Greece. Single-patient A. baumannii strains isolated from blood cultures (n = 271), from 19 hospitals, in a 6-month period (November 2020–April 2021) were subjected to minimum inhibitory concentration determination and molecular testing for carbapenemase, 16S rRNA methyltransferase and mcr gene detection and epidemiological evaluation. 98.9% of all isolates produced carbapenemase OXA-23. The vast majority (91.8%) of OXA-23 producers harbored the armA and were assigned mainly (94.3%) to sequence group G1, corresponding to IC II. Apramycin (EBL-1003) was the most active agent inhibiting 100% of the isolates at ≤16 mg/L, followed by cefiderocol which was active against at least 86% of them. Minocycline, colistin and ampicillin-sulbactam exhibited only sparse activity (S <19%), while eravacycline was 8- and 2-fold more active than minocycline and tigecycline respectively, by comparison of their MIC50/90 values. OXA-23-ArmA producing A. baumannii of international clone II appears to be the prevailing epidemiological type of this organism in Greece. Cefiderocol could provide a useful alternative for difficult to treat Gram-negative infections, while apramycin (EBL-1003), the structurally unique aminoglycoside currently in clinical development, may represent a highly promising agent against multi-drug resistant A. baumanni infections, due to its high susceptibility rates and low toxicity. [ABSTRACT FROM AUTHOR]

Colistin heteroresistance has been identified in several bacterial species, including Escherichia coli and Klebsiella pneumoniae, and may underlie antibiotic therapy failures since it most often goes undetected by conventional antimicrobial susceptibility tests. This study utilizes population analysis profiling (PAP) and time–kill assay for the detection of heteroresistance in K. pneumoniae and for evaluating the association between in vitro regrowth and heteroresistance. The mechanisms of colistin resistance and the ability of combination therapies to suppress resistance selection were also analysed. In total, 3 (18%) of the 16 colistin-susceptible strains (MIC ≤ 2 mg/L) were confirmed to be heteroresistant to colistin by PAP assay. In contrast to the colistin-susceptible control strains, all three heteroresistant strains showed regrowth when exposed to colistin after 24 h following a rapid bactericidal action. Colistin resistance in all the resistant subpopulations was due to the disruption of the mgrB gene by various insertion elements such as ISKpn14 of the IS1 family and IS903B of the IS5 family. Colistin combined with carbapenems (imipenem, meropenem), aminoglycosides (amikacin, gentamicin) or tigecycline was found to elicit in vitro synergistic effects against these colistin heteroresistant strains. Our experimental results showcase the potential of combination therapies for treatment of K. pneumoniae infections associated with colistin heteroresistance. [ABSTRACT FROM AUTHOR]

Background: We investigated the presence of heteroresistance against both tigecycline and colistin in Acinetobacter baumannii and then evaluated the effectiveness of combined antibiotic treatment given the existence of discrete tigecycline- and colistin-resistant subpopulations. Methods: We performed population analysis profiling (PAP) to evaluate the degree of composite heteroresistance in A. baumannii isolates, with the extent of this resistance quantified using subsequent antibiotic susceptibility testing. We then evaluated the amino acid sequence of PmrBAC and the relative mRNA expression levels of pmrB. Finally, we investigated the combined antibiotic efficacy of tigecycline and colistin in multiple-heteroresistant isolates using dual PAP and in vitro time-killing assays. Results: All tigecycline-heteroresistant A. baumannii isolates, with the exception of one colistin-resistant isolate, were also heteroresistant to colistin. Evaluations of the colistin-resistant subpopulations revealed amino acid alterations in PmrA and PmrB and increased expression of pmrB. All tigecycline-resistant subpopulations were susceptible to colistin, and all colistin-resistant subpopulations were susceptible to tigecycline. Dual PAP analysis using tigecycline and colistin showed no heteroresistance, and in vitro time-killing assays revealed that a combination of these two antibiotics effectively eliminated the bacterial cells. Conclusion: Our results suggest that multiple heteroresistance to tigecycline and colistin is highly prevalent among A. baumannii clinical isolates and that these resistant subpopulations exist independently in single multiple heteroresistant isolates. Therefore, our findings may explain the success of combined antibiotic therapies in these infections. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance has become a significant public health problem globally with multidrug resistant Gram negative (MDR-GN) bacteria being the main representatives. The emergence of these pathogens in neonatal settings threatens the well-being of the vulnerable neonatal population given the dearth of safe and effective therapeutic options. Evidence from studies mainly in adults is now available for several novel antimicrobial compounds, such as new β-lactam/β-lactamase inhibitors (e.g., ceftazidime–avibactam, meropenem–vaborbactam, imipenem/cilastatin–relebactam), although old antibiotics such as colistin, tigecycline, and fosfomycin are also encompassed in the fight against MDR-GN infections that remain challenging. Data in the neonatal population are scarce, with few clinical trials enrolling neonates for the evaluation of the efficacy, safety, and dosing of new antibiotics, while the majority of old antibiotics are used off-label. In this article we review data about some novel and old antibiotics that are active against MDR-GN bacteria causing sepsis and are of interest to be used in the neonatal population. [ABSTRACT FROM AUTHOR]

Evidence-based, standard antibiotic therapy for ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) is a relevant unmet clinical need in the intensive care unit (ICU). We aimed to evaluate the effectiveness of first-line therapy with old and novel CRAB active antibiotics in monomicrobial VAP caused by CRAB. A prospective, observational study was performed in a mixed non-COVID-19 ICU. The primary outcome measure was clinical failure upon first-line targeted therapy. Features independently influencing failure occurrence were also investigated via Cox proportional multivariable analysis. To account for the imbalance in antibiotic treatment allocation, a propensity score analysis with an inverse probability treatment weighting approach was adopted. Of the 90 enrolled patients, 34 (38%) experienced clinical failure. Compared to patients who experienced a clinical resolution of VAP, those who had clinical failure were of an older age (median age 71 (IQR 64–78) vs. 62 (IQR 52–69) years), and showed greater burden of comorbidities (median Charlson comorbidity index 8 (IQR 6–8) vs. 4 (IQR 2–6)), higher frequency of immunodepression (44% vs. 21%), and greater clinical severity at VAP onset (median SOFA score 10 (IQR 9–11) vs. 9 (IQR 7–11)). Lower rates of use of fast molecular diagnostics for nosocomial pneumonia (8.8% vs. 30.3%) and of timely CRAB active therapy administration (65% vs. 89%), and higher rates of colistin-based targeted therapy (71% vs. 46%) were also observed in patients who failed first-line therapy. Overall, CRAB active iv regimens were colistin-based in 50 patients and cefiderocol-based in 40 patients, both always combined with inhaled colistin. According to the backbone agent of first-line regimens, clinical failure was lower in the cefiderocol group, compared to that in the colistin group (25% vs. 48%, respectively). In multivariable Cox regression analysis, the burden of comorbid conditions independently predicted clinical failure occurrence (Charlson index aHR = 1.21, 95% CI = 1.04–1.42, p = 0.01), while timely targeted antibiotic treatment (aHR = 0.40, 95% CI = 0.19–0.84, p = 0.01) and cefiderocol-based first-line regimens (aHR = 0.38, 95% CI = 0.17–0.85, p = 0.02) strongly reduced failure risk. In patients with VAP caused by CRAB, timely active therapy improves infection outcomes and cefiderocol holds promise as a first-line therapeutic option. [ABSTRACT FROM AUTHOR]

The increasing antibiotic resistance in bacteria is an alarming phenomenon all around the world. Certain strains have developed resistance against multiple antimicrobial molecules, in which cases, the final option is to use a last-resort drug. These drugs, however, are last-resort for a reason: they can pose serious risk on vital organ functions in the patient. To mitigate the risk of severe side-effects and to reduce the rate of bacterial mutation, co-administration with other molecules that increase their efficacy seems to be the only suitable option. This leads to a reduced dose while maintaining the same level of antibiotic activity within the body. In this study, the effect of heparin derivatives on the antibiotic activity of colistin and their interactions were studied by ion mobility, mass spectrometry, and bacterium growth assays. The results show that during the association of colistin and heparin, they retain their structure while higherstoichiometry complexes can form. When long-chain heparin is co-administered, multiple colistin molecules can associate with it, which increases the antibiotic activity by ~40% relative to the sole administration of colistin. [ABSTRACT FROM AUTHOR]

There is a crucial need for novel antibiotics to stem the tide of antimicrobial resistance, particularly against difficult to treat gram-negative pathogens like Acinetobacter baumannii-calcoaceticus complex (ABC). An innovative approach to addressing antimicrobial resistance may be pathogen-targeted development programs. Sulbactam-durlobactam (SUL-DUR) is a β-lactam/β-lactamase inhibitor combination antibiotic that is being developed to specifically target drug-resistant ABC. The development of SUL-DUR culminated with the Acinetobacter Treatment Trial Against Colistin (ATTACK) trial, a global, randomized, active-controlled phase 3 clinical trial that compared SUL-DUR with colistin for treating serious infections due to carbapenem-resistant ABC. SUL-DUR met the primary noninferiority endpoint of 28-day all-cause mortality. Furthermore, SUL-DUR had a favorable safety profile with a statistically significant lower incidence of nephrotoxicity compared with colistin. If approved, SUL-DUR could be an important treatment option for infections caused by ABC, including carbapenem-resistant and multidrug-resistant strains. The development program and the ATTACK trial highlight the potential for pathogen-targeted development programs to address the challenge of antimicrobial resistance. [ABSTRACT FROM AUTHOR]

Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) is one of the top-priority pathogens for new antibiotic development. Unlike other antibiotic-resistant threats, none of the available therapies have been shown to consistently reduce mortality or improve patient outcomes in clinical trials. Antibiotic combination therapy is routinely used in clinical practice; however, the preferred combination has not been defined. This narrative review focuses on evidence-based solutions for the treatment of invasive CRAB infections. We dissect the promise and perils of traditional agents used in combination, such as colistin, sulbactam, and the tetracyclines, and offer clinical pearls based on our interpretation of the available data. Next, we investigate the merits of newly developed β-lactam agents like cefiderocol and sulbactam-durlobactam, which have demonstrated contrasting results in recent randomized clinical trials. The review concludes with the authors' perspective on the evolving treatment landscape for CRAB infections, which is complicated by limited clinical data, imperfect treatment options, and a need for future clinical trials. We propose that effective treatment for CRAB infections requires a personalized approach that incorporates host factors, the site of infection, pharmacokinetic-pharmacodynamic principles, local molecular epidemiology of CRAB isolates, and careful interpretation of antibiotic susceptibility testing results. In most clinical scenarios, a dose-optimized, sulbactam-based regimen is recommended with the addition of at least one other in vitro active agent. Should sulbactam-durlobactam receive regulatory approval, recommendations will need to be re-evaluated with the most recent evidence. [ABSTRACT FROM AUTHOR]

Understanding the mechanisms and kinetics of membrane damage is of interest to researchers in several overlapping fields of biology. In this study, we describe the development and validation of a simple 32 PO 4 3 − release radioassay used to track nanometer-scale damage to the bacterial cell membrane. Nanoscale membrane damage will result in the release of small cytoplasmic molecules, such as amino acids, sugars, and osmolytes. Our radioassay tracks the release of these molecules using the release of cytoplasmic 32 PO 4 3 − as a proxy. Our assay can both detect 32 PO 4 3 − release and track release kinetics in the order of minutes. We demonstrate the use of our radioassay using A. baumannii treated with colistin and Ω 76 : two agents known to cause membrane damage. Our assay tracks greater membrane damage in A. baumannii treated with both these agents, compared to an untreated control. Our assay fills a niche that is not covered by traditional 51 Cr release radioassays and fluorescent staining techniques. Furthermore, our assay can potentially be used to track membrane damage in other membrane systems such as lipid vesicles, animal cells, and organelles. [ABSTRACT FROM AUTHOR]

Antimicrobial misuse is a worldwide issue, and antimicrobial resistance is considered the most challenging aspect of health care. It has been reported that as much as 30–50% of antimicrobials prescribed in hospitals are deemed unnecessary or inappropriate. Antibiotic stewardship programs (ASPs) include policies that apply continuous management of judicious anti-infectious treatment in the clinical setting. Therefore, the objectives of this study were to evaluate the effect of ASPs on antibiotic consumption, the costs of antibiotic expenditure, and the sensitivity of antimicrobials. A retrospective, quasi-experimental study was performed to assess the effect of ASP at An-Najah National University Hospital, a tertiary care hospital in the West Bank, Palestine, over a period of 20 months before and 17 months after the implementation of the ASP. Data on antibiotic consumption were reported monthly as days of therapy per 1000 patient-days and monthly costs (USD/1000 patient-days). A total of 2367 patients who received one or more of the targeted antibiotics (meropenem, colistin and tigecycline) during their hospital stay were included in the study. They have split into two groups: 1710 patients in the pre-ASP group, and 657 patients in the post ASP group. The most significant reduction in DOT per 1000 patient-days was seen with tigecycline, with a percentage of change of − 62.08%. Furthermore, the mean cost of the three antibiotics decreased significantly by 55.5% in the post-ASP phase compared to the pre-ASP phase. After the implementation of ASP, there was a statistically significant increase in susceptibility to meropenem, piperacillin and piperacillin/tazobactam with respect to Pseudomonas aeruginosa. However, changes in mortality rates were not statistically significant (p = 0.057). ASP positively reduced costs and antimicrobial consumption, with no statistically significant effect on the overall mortality rate. However, a long-term evaluation of the ASP's impact is needed to conclude its lasting impact on infection-related mortality and antimicrobial susceptibility pattern. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae is one of the leading pathogens contributing to antimicrobial resistance. The emergence of carbapenem-resistant K. pneumoniae (CRKP) has put the use of clinical antimicrobial agents in a dilemma. In particular, CRKP exhibiting resistance to ceftazidime/avibactam, tigecycline and colistin have raised great clinical concern, as these are the last-resort antibiotics for the treatment of CRKP infections. Within-host evolution is a survival strategy closely related to the emergence of antimicrobial resistance, while little attention has been paid to the in vivo genetic process of conversion from antibiotic-susceptible to resistant K. pneumoniae. Here we have a literature review regarding the in vivo evolution of resistance to carbapenems, ceftazidime/avibactam, tigecycline, and colistin in K. pneumoniae during antibacterial therapy, and summarized the detailed resistance mechanisms. In general, acquiring blaKPC and blaNDM harboring-plasmid, specific mutations in blaKPC, and porin genes, such as ompK35 and ompK36, upregulation of blaKPC, contribute to the development of carbapenem and ceftazidime/avibactam resistance in vivo. Overexpression of efflux pumps, acquiring plasmid-carrying tet (A) variants, and ribosomal protein change can lead to the adaptive evolution of tigecycline resistance. Specific mutations in chromosomes result in the cationic substitution of the phosphate groups of lipid A, thus contributing to colistin resistance. The resistant plasmid might be acquired from the co-infecting or co-colonizing strains, and the internal environment and antibiotic selection pressure contribute to the emergence of resistant mutants. The internal environment within the human host could serve as an important source of resistant K. pneumoniae strains. [ABSTRACT FROM AUTHOR]

Introduction: Antimicrobial resistance and the rapid spread of multiresistant bacteria represent one of the main public health problem in limited resources countries. This issue is significantly worsening since the COVID-19 pandemic due to the unreasonably increased antibiotics prescription to patients with confirmed SARS-CoV-2 infection. The aim of this study was to examine whether COVID-19 pandemic (2020, 2021) was associated with increased antibiotic consumption in inpatient and outpatient settings in the middle size urban region (Republic of Srpska/Bosnia and Herzegovina) in comparison to period before the pandemic (2019). Additionally, we aimed to determine antimicrobial resistance and the presence of multiresistant bacteria in the regional hospital ("Saint Apostol Luka" Hospital Doboj) in 2021. Methodology: The consumption of antibiotics in inpatient was calculated as Defined Daily Dose per one hundred of patient-days. The consumption of antibiotics in outpatient was calculated as Defined Daily Dose per thousand inhabitants per day. Resistance of bacteria to antibiotics is expressed as a rates and density for each observed antibiotic. The rate of resistance was calculated as a percentage in relation to the total number of isolates of individual bacteria. The density of resistance of isolated bacteria against a specific antibiotic was expressed as the number of resistant pathogens/1000 patient days. Results: Antibiotic consumption in hospital setting registered during 2019, 2020 and 2021 was as follows: carbapenems (meropenem: 0.28; 1.91; 2.33 DDD/100 patient-days, respectively), glycopeptides (vancomycin: 0.14; 1.09, 1.54 DDD/100 patient-days, respectively), cephalosporins (ceftriaxone: 6.69; 14.7; 14.0 DDD/100 patient-days, respectively) and polymyxins (colistin: 0.04; 0.25; 0.35 DDD/100 bed-days, respectively). Consumption of azithromycin increased drastically in 2020, and dropped significantly in 2021 (0.48; 5.61; 0.93 DDD/100 patientdays). In outpatient setting, an increase in the consumption of oral forms of azithromycin, levofloxacin and cefixime, as well as parenteral forms of amoxicillinclavulanic acid, ciprofloxacin and ceftriaxone, was recorded. In 2021, antimicrobial resistance to reserve antibiotics in hospital setting was as follows: Acinetobacter baumanii to meropenem 66.0%, Klebsiella spp to cefotaxime 67.14%, Pseudomonas to meropenem 25.7%. Conclusion: Recent COVID-19 pandemic was associated with increased antibiotic consumption in inpatient and outpatient settings, with characteristic change of pattern of azithromycin consumption. Also, high levels of antimicrobial resistance to reserve antibiotics were registered in hospital setting with low prevalence of identified pathogen-directed antimicrobial prescription. Strategies toward combat antimicrobial resistance in the Doboj region are urgently needed. [ABSTRACT FROM AUTHOR]

In this work, we show that the addition of thiourea (TU) initiated broad‐spectrum antimicrobial activity of otherwise inactive D‐maltose‐capped gold nanoclusters (AuNC‐Mal). For example, AuNC‐Mal/TU was effective against multidrug‐resistant Pseudomonas aeruginosa with a minimum inhibitory concentration (MIC) of 1 μg mL−1 (2.5 μM [Au]) while having 30–60 times lower in vitro cytotoxicity against mammalian cells. The reaction of AuNC‐Mal and TU generated the antimicrobial species of [Au(TU)2]+ and smaller AuNCs. TU increased the accumulation of Au in bacteria and helped maintain the oxidation state as AuI (vs. AuIII). The modes of action included the inhibition of thioredoxin reductase, interference with the CuI regulation and depletion of ATP. Moreover, the antimicrobial activity did not change in the presence of colistin or carbonyl cyanide 3‐chlorophenylhydrazone, suggesting that AuNC‐Mal/TU was indifferent to the outer membrane barrier and to bacterial efflux pumps. [ABSTRACT FROM AUTHOR]

Snakebite envenomation (SBE) is a life-threatening medical emergency with a high mortality rate. Common secondary complications following SBE, such as wound infections, are significant due to their impact on worsening local tissue damage and causing systemic infection. Antivenoms are not effective to treat wound infections following SBE. Moreover, in several rural clinical settings, broad-spectrum antibiotics are often used without clear guidelines or based on limited laboratory data, resulting in undesirable side effects and exacerbated treatment costs. Therefore, robust antibiotic strategies should be developed to tackle this critical issue. Currently, there is limited information available on the bacterial profiles of SBE-induced infections and antibiotic susceptibility. Hence, it is essential to improve the knowledge of bacterial profiles and their antibiotic sensitivity in SBE victims to develop better treatment strategies. This study aimed to address this issue by examining the bacterial profiles of SBE victims with a specific focus on Russell's viper envenomation. The most frequently found bacteria in the bites of SBE victims were Staphylococcus aureus, Klebsiella sp., Escherichia coli, and Pseudomonas aeruginosa. Linezolid, clindamycin, colistin, meropenem, and amikacin were some of the most effective antibiotics for commonly grown bacteria in SBE victims. Similarly, ciprofloxacin, ampicillin, amoxiclave, cefixime, and tetracyclin were the least effective antibiotics for common bacteria found in the wound swabs of SBE victims. These data provide robust guidance for infection management following SBE and offer useful insights to aid in designing effective treatment protocols for SBE with serious wound infections in rural areas where laboratory facilities may not be readily available. [ABSTRACT FROM AUTHOR]