Multidrug-resistant Gram-negative Infections Research Articles

First three Escherichia coli isolates harbouring mcr-1 in Uruguay.

This report described the first Escherichia coli (E. coli) isolates harbouring mcr-1 in Uruguay. Three E. coli isolates were obtained from blood, urine and rectal swabs from different patients in two hospitals. Extended-spectrum β-lactamases (ESBL), plasmid-encoded (pAmpC) β-lactamases, plasmid-mediated quinolone resistance (PMQR) genes, class 1 integrons, and mcr-1, mcr-2 and mcr-3 were sought and characterised in three E. coli isolates. Transfer of resistance determinants was assessed by conjugation. Clonality was analysed by multilocus sequence typing. All isolates were categorised as being colistin-resistant and the mcr-1 gene was detected. Two isolates were also resistant to oxyimino cephalosporins: one on account of blaCMY-2 and the other due to blaCTX-M-15, the latter also harbouring transferable quinolone-resistance genes (aac(6')Ib-cr and qnrB). All mcr-1 genes were transferred by conjugation to recipient strains. The mcr-1-bearing isolates belonged to sequence types ST10, ST93 and ST5442. ST10 is considered as a high-risk clone worldwide. This type of mcr-1-harbouring clone is a major concern for human and animal health and must be under close surveillance. This study detected the presence of mcr-1 for the first time in Uruguay, albeit in an allodemic manner, associated with different antibiotic-resistance genes and from diverse clinical contexts. Considering that colistin is often the last therapeutic option available for multidrug-resistant Gram-negative bacilli infections, it is important to maximise precautions to avoid dissemination of isolates carrying mcr-1.

In vitro activity of Protegrin-1, alone and in combination with clinically useful antibiotics, against Acinetobacter baumannii strains isolated from surgical wounds.

In the past few years the increasing incidence of hospital infections with Acinetobacter baumannii, especially in immunocompromised patients, and its proneness to develop multidrug resistance have been raising considerable concern. This study examines the antimicrobial and antibiofilm activity of protegrin 1 (PG-1), an antimicrobial peptide from porcine leukocytes, against A. baumannii strains isolated from surgical wounds. PG-1 was tested both alone and combined with the antibiotics commonly used in clinical settings. Its antimicrobial activity was evaluated by determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), checkerboard assays, and time-kill experiments. Its effects on biofilm inhibition/eradication were tested with crystal violet staining. The strains were grown in subinhibitory or increasing PG-1 concentrations to test the development of resistance. Mammalian cell toxicity was tested by XTT assays. PG-1 MICs and MBCs ranged from 2 to 8µg/ml. PG-1 was most active and demonstrated a synergistic interaction with colistin, a last resort antibiotic. Interestingly, antagonism was never observed. In time-kill experiments, incubation with 2 × MIC for 30min suppressed all viable cells. PG-1 did not select resistant strains and showed a limited effect on cell viability, but it did exert a strong activity against multidrug-resistant A. baumannii. In contrast, in our experimental conditions it had no effect on biofilm inhibition/eradication. PG-1 thus seems to be a promising antimicrobial agent against multidrug-resistant Gram-negative infections.

Evaluation of risk factors for colistin resistance among uropathogenic isolates of Escherichia coli and Klebsiella pneumoniae: a case-control study.

The last few years have seen the emergence of multi-drug resistant (MDR) Gram-negative infections, which are associated with high morbidity and mortality. The indiscriminate use of colistin has led to the development of resistance, which can be diagnosed effectively by broth microdilution. Studies from India are limited, and this study was conducted in order to determine the prevalence and risk factors associated with colistin resistance. Urine samples from patients admitted with urinary tract infection (UTI), growing MDR Escherichia coli and Klebsiella pneumoniae, were tested for the minimum inhibitory concentration (MIC) of colistin by broth microdilution. Isolates with an MIC >2 µg ml-1 (resistant) were subjected to polymerase chain reaction (PCR) for the mcr1, mcr2 and mgrB genes. A case-control study with 21 cases (resistant) and 42 matched controls (sensitive) was designed to evaluate risk factors and outcomes (recurrent UTI, readmission and hospital stay >2 weeks). Two hundred and fifty MDR isolates (E. coli=142/2319 and K.pneumoniae=108/775) from 216 patients were selected from the 25 046 isolates screened. Twenty-five isolates (20 K.pneumoniae and 5 E. coli) were resistant to colistin, with a prevalence of 3.52 % in E. coli and 18.5 % in K. pneumoniae among the MDR isolates. PCR for the mcr1 and mcr2 genes was negative. Multivariate regression showed that multiple episodes of hospitalization, hospital stay >2 weeks, exposure to >three antibiotic classes and abnormality/surgery of the lower urinary tract were the significant risk factors for colistin resistance. Previous use of colistin and colistin resistance had a significant effect on all outcomes. K. pneumoniae show six times higher prevalence of colistin resistance than E. coli, and the emergence of resistant organisms has led to an increase in morbidity in infected patients.

Can Nebulised Colistin Therapy Improve Outcomes in Critically Ill Children with Multi-Drug Resistant Gram-Negative Bacterial Pneumonia?

In the past decade, multidrug-resistant (MDR) gram-negative bacteria have become a major problem, especially for patients in intensive care units. Recently, colistin became the last resort therapy for MDR gram-negative bacteria infections. However, nebulised colistin use was limited to adult patients. Thus, we investigated the efficacy and safety of nebulised colistin treatment against MDR microorganisms in the paediatric intensive care unit (PICU). Data of all patients admitted for various critical illnesses (January 2016 to January 2019) were reviewed. Differences between groups (with and without a history of nebulised colistin) were compared. Of 330 patients, 23 (6.97%) used nebulised colistin. Significant relationships were found between nebulised colistin usage and several prognostic factors (inotropic drug use (p = 0.009), non-invasive mechanical ventilation (p ≤ 0.001), duration in PICU (p ≤ 0.001), and C-reactive protein level (p = 0.003)). The most common microorganism in tracheal aspirate and sputum cultures was Pseudomonas aeruginosa (13 patients). The most common underlying diagnosis was cystic fibrosis, noted in 6 patients. No serious nephrotoxicity and neurotoxicity occurred. This study showed that colistin can be safely used directly in the airway of critically ill children. However, nebulised colistin use did not have a positive effect on mortality and prognosis.

Antimicrobial Susceptibility Testing for Polymyxins: Challenges, Issues, and Recommendations.

Polymyxins, including polymyxin B and polymyxin E (colistin), are now increasingly being used worldwide to treat patients with multidrug-resistant (MDR) Gram-negative bacterial infections. This necessitates that laboratories employ an accurate and reliable method for the routine performance of polymyxin susceptibility testing. A number of reasons have accounted for the difficulties with susceptibility testing for the polymyxins, including their multicomponent composition, poor diffusion in the agar medium, adsorption to microtiter plates, the lack of a reliable susceptibility test, the lack of a specific breakpoint from professional organizations, the synergistic effect of polysorbate 80, and the development of heteroresistance. This minireview discusses such problems that impact the results of currently available susceptibility testing methods. We also provide emerging concepts on mechanisms of polymyxin resistance, including chromosomally and plasmid-mediated mcr-related resistance. Broad-range investigations on such critical issues in relation to polymyxins can be beneficial for the implementation of effective treatment against MDR Gram-negative bacterial infections.

Teaching an Old Class New Tricks: A Novel Semi-Synthetic Aminoglycoside, Plazomicin.

The emergence of multi-drug resistant (MDR) Gram-negative pathogens has become a serious worldwide health concern. Gram-negative bacteria such as Enterobacteriaceae (Klebsiella pneumoniae, Escherichia coli, Enterobacter spp.,) Acinetobacter spp., and Pseudomonas aeruginosa have rendered most antibiotics inactive, leaving aminoglycosides and polymyxins. Plazomicin (formerly ACHN-490), is a neoglycoside with unique structural modifications to the aminoglycoside pharmacophore that impart activity against many MDR Gram-negative organisms. ACHN-490 was recently approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections caused by MDR Enterobacteriaceae. In this era of increasing Gram-negative resistance, it is imperative to critically evaluate new antibiotics so that we understand how to use them optimally. The objective of this article is to discuss available data detailing plazomicin’s biochemistry, pharmacokinetic/pharmacodynamic characteristics, in-vitro activity and current progress in clinical trials. In addition, plazomicin’s potential role in therapy for the treatment of MDR Gram-negative infections will be discussed.

Characteristics and clinical outcome of patients treated in the respiratory ICU of Abbassia Chest Hospital

BackgroundAdmission to the respiratory ICU (RICU) is based upon the nature and severity of the patient’s acute medical illness, their need for ICU intervention(s) or monitoring, and the likelihood that such interventions and ICU management will improve outcome. Knowledge of patients’ characteristics and outcome reflects the level of care in a given ICU and helps improve performance.AimThe aim was to study the characteristics and clinical outcomes of patients admitted to the respiratory ICU of Abbassia Chest Hospital.Settings and designA prospective analytical study was conducted.Patients and methodsThe study was conducted on patients admitted to RICU of Abbassia Chest Hospital in the period from February 2017 to July 2017. The following data were collected: admission diagnosis, co-morbidities, simplified acute physiology ‘simplified acute physiology score (SAPS)’ II score, vital data, mechanical ventilation management, laboratory tests including microbiological, length of stay, final diagnosis, complications during stay in ICU and outcome at discharge including mortality, morbidities, and area of transfer.Statistical analysisThe data were entered and analyzed using SPSS 23. For each test, P value less than 0.05 was considered significant.ResultsA total of 407 patients were admitted over the study period. Mean age of the patients was 55.45±17.88 years. Overall, 249 of them were males and 158 females. Most of the patients were referred from the emergency room. Of them, 206 patients were admitted owing to an exacerbation of underling chest disease and 201 were admitted owing to an acute insult, which caused respiratory failure (RF). Moreover, 281 (69.05%) had RF type II, whereas 126 (30.95%) had RF type I. Chronic obstructive pulmonary disease was the main underlying respiratory disease in 141 (34.64%), and pneumonia was the main acute event, which caused RF, in 138 (33.91%). The mean value of SAPS II score was 27.95 ±13.28, with nonsurvivors having higher SAPS II score of 33.8 compared with survivors of 20.94 (P<0.001). Mean length of ICU stay (LOS) was 5.889±5.96 days, with a significant correlation between LOS and mortality rate. Overall, 69.8% of the patients required mechanical ventilation (MV). The mean MV duration was 4.7±4.8 days. MV was associated with longer stay in ICU and a higher mortality. No complications were reported in 327 (80.3%) of patients, whereas 10.5% developed different complications. Klebsiella spp. was the most frequently isolated organism followed by Candida and Acinetobacter. Multidrug-resistant bacteria represented 7% of isolates. Colistin was the most effective in-vitro antibiotic. Levofloxacin was the most frequent empirically prescribed antibiotic.ConclusionRespiratory ICU at Abbassia Chest Hospital serves a large number of patients with diverse respiratory critical illnesses. Most patients were males, in sixth decade of life, and had chronic obstructive pulmonary disease. Mechanical ventilation was applied to most patients and was associated with longer LOS and a higher mortality. MDR gram-negative infections were not infrequent. SAPS II score did not correlate well with the survival in the present study.

Molecular Mechanisms of Colistin-Induced Nephrotoxicity

The emergence of multidrug resistant (MDR) infections and the shortage of new therapeutic options have made colistin, a polymyxin antibiotic, the main option for the treatment of MDR Gram-negative bacterial infections in the last decade. However, the rapid onset of renal damage often prevents the achievement of optimal therapeutic doses and/or forces the physicians to interrupt the therapy, increasing the risk of drug resistance. The proper management of colistin-induced nephrotoxicity remains challenging, mostly because the investigation of the cellular and molecular pharmacology of this drug, off the market for decades, has been largely neglected. For years, the renal damage induced by colistin was considered a mere consequence of the detergent activity of this drug on the cell membrane of proximal tubule cells. Lately, it has been proposed that the intracellular accumulation is a precondition for colistin-mediated renal damage, and that mitochondria might be a primary site of damage. Antioxidant approaches (e.g., ascorbic acid) have shown promising results in protecting the kidney of rodents exposed to colistin, yet none of these strategies have yet reached the bedside. Here we provide a critical overview of the possible mechanisms that may contribute to colistin-induced renal damage and the potential protective strategies under investigation.

Multidrug resistant Gram-negative infections in neonatology.

Multidrug resistant Gramnegative (MDRGN) infections are an increasing problem in neonatal intensive care units. The objective of this study was to establish the epidemiological, clinical, microbiological, and evolutionary characteristics of carbapenem-resistant MDRGN infections and the risk factors for them at the Division of Neonatology of a tertiary care hospital. A retrospective cohort study was done in this Division in patients with a documented MDRGN infection between 4/24/2013 and 4/29/2015. Twenty-one patients were included. Their median gestational age and birth weight were 35 weeks and 2070 g, respectively. Eighteen patients (86 %) had a positive blood culture; the most commonly isolated microorganism was Acinetobacter baumannii (17 patients, 81 %), followed by carbapenemase-producing Klebsiella pneumoniae (3 patients, 14 %) and Enterobacter cloacae (1 patient, 5 %).The median age at diagnosis was 28 days and all patients had risk factors for infection, including surgery, assisted mechanical ventilation, parenteral nutrition, central venous line, and antibiotics. The definite antibiotic therapy included colistin in all cases; in combination, in 84 %. Five patients (24 %) died due to the infection. Prematurity and a birth weight < 2000 g were statistically significant risk factors associated with mortality (p = 0.03 and 0.01, respectively). MDRGN infections were observed in patients with predisposing factors. Acinetobacter baumannii was the main etiologic agent. Mortality was high and related to prematurity and a low birth weight.

Colistin Use in Patients with Extreme Renal Function: From Dialysis to Augmented Clearance

Background and objectives: Colistin is used for the treatment of multidrug-resistant (MDR) Gram-negative bacteria infection in critically ill patients. It is recommended to adjust the dose in cases of renal impairment but not in cases of augmented renal clearance (ARC). The aim of this study was to determine colistin use pattern in patients with different renal functional states. Materials and Methods: Adult patients admitted to intensive care units of single Latvian hospitals in the years 2015–2017 with an MDR Gram-negative bacterial infection and at least 72 h colistin therapy were included in this study. Data were collected retrospectively from medical notes. Colistin use pattern and outcomes were analyzed in patients with different renal function prior to colistin therapy: normal, ARC, impaired, and on renal replacement therapy (RRT). Results: 100 cases of colistin use met the inclusion criteria. The study group was heterogeneous, and patients had different renal function states prior to colistin therapy-from continuous RRT (18 cases) to ARC (16 cases). The standard colistin dose of 9 million units (MU) daily was the most common dose among the patients. In many cases (43%), colistin dose adjustment did not follow the recent recommendations of drug manufacturers-this was mainly in patients with renal impairment prior to colistin therapy. Eighteen cases of colistin acute kidney injury (AKI) were detected, mostly (10 cases) in patients with normal renal function and without ARC prior to colistin therapy. No patients with colistin AKI needed RRT. Conclusions: Colistin doses varied greatly among patients, and in patients with renal function impairment it was commonly not in accordance with the summary of product characteristics (SPC). Patients with ARC mostly received a standard colistin daily dose of 9 MU daily, but the cumulative dose had a tendency to be higher and duration of colistin therapy was longer in comparison with other patient groups. ARC’s role in the development of colistin nephrotoxicity is still unclear.

A Decision Tree Using Patient Characteristics to Predict Resistance to Commonly Used Broad-Spectrum Antibiotics in Children With Gram-Negative Bloodstream Infections.

As rates of multidrug-resistant gram-negative infections rise, it is critical to recognize children at high risk of bloodstream infections with organisms resistant to commonly used empiric broad-spectrum antibiotics. The objective of the current study was to develop a user-friendly clinical decision aid to predict the risk of resistance to commonly prescribed broad-spectrum empiric antibiotics for children with gram-negative bloodstream infections. This was a longitudinal retrospective cohort study of children with gram-negative bacteria cared for at a tertiary care pediatric hospital from June 2009 to June 2015. The primary outcome was a bloodstream infection due to bacteria resistant to broad-spectrum antibiotics (ie, cefepime, piperacillin-tazobactam, meropenem, or imipenem-cilastatin). Recursive partitioning was used to develop the decision tree. Of 689 episodes of gram-negative bloodstream infections included, 31% were resistant to broad-spectrum antibiotics. The decision tree stratified patients into high- or low-risk groups based on prior carbapenem treatment, a previous culture with a broad-spectrum antibiotic resistant gram-negative organism in the preceding 6 months, intestinal transplantation, age ≥3 years, and ≥7 prior episodes of gram-negative bloodstream infections. The sensitivity for classifying high-risk patients was 46%, and the specificity was 91%. A decision tree offers a novel approach to individualize patients' risk of gram-negative bloodstream infections resistant to broad-spectrum antibiotics, distinguishing children who may warrant even broader antibiotic therapy (eg, combination therapy, newer β-lactam agents) from those for whom standard empiric antibiotic therapy is appropriate. The constructed tree needs to be validated more widely before incorporation into clinical practice.

Clinical relevance of in vitro synergistic activity of antibiotics for multidrug-resistant Gram-negative infections: A systematic review.

The aim of this review was to investigate the outcomes of patients infected with multidrug-resistant (MDR) or extensively drug-resistant (XDR) Gram-negative bacteria following synergy-guided antibiotic combination therapy (SGACT). A systematic review of PubMed and Scopus databases was performed. Published studies of any design reporting outcomes of patients with MDR Gram-negative bacteria treated with SGACT were included. Two reviewers independently assessed the relevancy and quality of the retrieved articles and extracted the available data. Nineteen reports (530 patients) were included. Eleven case reports/series described 26 cases of systemic infection due to MDR Gram-negative bacteria treated with SGACT. Five deaths were reported, two of which were attributed to the infection. Six studies (including one randomised controlled trial) provided comparative data for patients treated with SGACT and those treated with unguided combination therapy (UCT) or active monotherapy. In the pooled analysis of unadjusted data from these studies (504 patients), there was no difference between SGACT and UCT or monotherapy (OR=0.47, 95% CI 0.21-1.04; I2=52%). Analysis of adjusted data showed that SGACT was significantly associated with survival (OR=0.44, 95% CI 0.20-0.98; I2=54%). These limited but promising findings warrant further investigation of SGACT in the outcome of patients with MDR Gram-negative infections in well-designed trials.

Colistin Resistant A. baumannii: Genomic and Transcriptomic Traits Acquired Under Colistin Therapy.

Even though colistin-based treatment represents the antimicrobial-regimen backbone for the management of multidrug-resistant Gram-negative infections, colistin resistance is still rare, at least as a full resistance, in Acinetobacter baumannii (Ab). We investigated the genomics and transcriptomics of two clinical Extensively Drug Resistance (XDR) colistin-susceptible/resistant (COL-S/R) Ab strain-pairs in which COL-resistance was developed after exposure to colistin therapy. The molecular characterization of the strains showed that all strains belonged to PFGE-A, ST-281, OXA-23 producers, Global Clone-II, and were resistant to imipenem, meropenem, ampicillin/sulbactam, ciprofloxacin, gentamicin, amikacin, trimethoprim/sulfamethoxazole, and susceptible to tigecycline, in agreement with NGS-acquired resistome. COL-R vs. COL-S Ab comparative genomics, mapping on Ab ATCC 17978 and Ab ACICU Reference Genomes, revealed a closely related genomic phylogeny, especially between strain-pair isolates, and distinctive common genomic non-synonymous SNPs (nsSNPs) in COL-R Ab strains. Furthermore, pmrB and pmrC nsSNPs were found. Notably we recovered, for the first time, lpxC and lpxD nsSNPs previously described only in “in-vitro” mutants and associated with colistin resistance in a clinical COL-R Ab. COL-R vs. COL-S Ab comparative transcriptomics evidenced a strain-dependent response to the colistin resistance onset highly variable among the single COL-R strains vs. their COL-S parents and merely seven common over-expressed transcripts, i.e. the PgaB lipoprotein for biofilm-matrix production, the diacylglycerol kinase for the lipid recycling in the membrane-derived oligosaccharide cycle, a membrane non-ribosomal peptide synthetase, the Lipid A phosphoethanol aminotransferase PmrC, and three hypothetical proteins. The transcript analysis of the “COL-R related genes” and the RNA-seq data confirmed pmrCAB over-expression responsible for a greater positive net cell-charge, and lpxACD under-expression in COL-R causing a decreased LPS production, as main mechanisms of colistin resistance. Our study reports the COL-R Ab genomic and transcriptomic signatures reflecting the interplay between several direct and indirect potential adaptations to antimicrobial pressure, including the occurrence of SNP accumulation hotspot loci in genes related to intrinsic or adaptive colistin resistance, surface adhesion proteins and porins, and over-expressed genes involved in different pathways, i.e. biofilm production, oxidative stress response, extensive drug and COL resistance.

Rapid screening of colistin-resistant Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa by the use of Raman spectroscopy and hierarchical cluster analysis.

Colistin is recognized as the last therapeutic option for multidrug-resistant Gram-negative bacteria infection. In addition, bacterial resistance to colistin could be transmitted between different species through plasmid-mediated mcr-1 gene transfer. Therefore, rapid screening of colistin-resistant isolates will play a key role in controlling the spread of resistance and improving patient outcomes. We developed a rapid method for the detection of colistin-resistance in Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa bacteria based on Raman spectroscopy and hierarchical cluster analysis. Bacteria were incubated with and without colistin using CAMHB as the liquid culture medium. They were then centrifuged and dried on a glass slide. Five Raman spectra of each of the samples were recorded and analyzed by the hierarchical cluster analysis method to determine whether the bacteria were resistant. To evaluate this method, 123 clinical bacterial isolates (42 isolates of E. coli, 41 isolates of A. baumannii and 40 isolates of P. aeruginosa) were tested. The detection sensitivity and specificity were 90.9% and 91.1%, respectively, compared with the reference broth microdilution method. The screening is easy to perform and can be completed in 1.5 h, suggesting that it holds great potential to be an initial screening method in countries and areas where colistin becomes the last resort antibiotic.

Multidrug-resistant Gram-negative infection in solid organ transplant recipients: implications for outcome and treatment.

Solid organ transplantation (SOT) is the best therapeutic option for both acute and chronic end-stage diseases. The development of more potent and safer immunosuppressants and the improvement of prophylactic practices have significantly diminished the morbidity and mortality associated with rejection and opportunistic infections. However, infections produced by multidrug-resistant (MDR) Gram-negative bacilli (GNB) have recently emerged as a significant threat. The Spanish Society of Transplantation (SET), the Group for Study of Infection in Transplantation of the Spanish Society of Infectious Diseases and Clinical Microbiology (GESITRA-SEIMC) and the Spanish Network for Research in Infectious Diseases (REIPI) have recently published their recommendations concerning the management of MDR GNB infections in SOT recipients. We review this guideline, and also the most recent available evidence, focusing on donor-derived infections, colonized recipients and therapeutic approaches. Overall, donor and recipient colonization is associated with an increased risk of infection by MDR GNB, although none of these circumstances constitutes an absolute contraindication to transplantation. SOT recipients with risk factors for MDR GNB infection should receive an empirical treatment which includes potentially active antibiotics. Targeted therapy should be adjusted according to antimicrobial susceptibility testing and severity of infection.

Evaluation of bactericidal and anti-biofilm activities of silver nanoparticles against multidrug-resistant Gram-negative bacilli isolated from burn wound infections

Background: The emergence and spread of multidrug-resistant Gram-negative bacilliin burn wound infections related to biofilm formation, which lend to challenge in treatment with conventional antibiotics andprompting to search for novel antimicrobial agents to control the infections.Silver nanoparticles (AgNPs) have wide spectrum biological properties with different mechanisms of action and less toxicity towards human cells.&#x0D; Objective:The goal of this study was to evaluated the anti-bacterial and anti-biofilm activities of AgNPs alone and in combination with aminoglycoside (Amikacin) and β-lactam (Ampicillin) antibiotics against multidrug resistant Gram-negative bacilli (Pseudomonas aeruginosa, Escherichia coli, klebsiellapneumoniae) isolated from burn wound infections. Type of the study: Cross –sectional study.&#x0D; Methods: 70 clinical isolates of GNBtested for susceptibility tests by disk diffusion method against 10 antibiotics. The minimum inhibitory concentrations (MICs) of AgNPs and antibiotics were carried out according to the standard broth microdilution method, while synergistic interactions were evaluated by time kill-kinetic assays. Calgary method was applied for anti-biofilm activity.&#x0D; Results:Pseudomonas aeruginosa represented the majority of GNBisolated from burn wound infections 34 (48.5 %)followed by Klebsiella pneumonia 21 (30 %) and Escherichia coli 15 (21.5 %). Silver nanoparticles showed remarkable antibacterial activity against GNB that isolated from burn wound infections with the MICs between 25- 75 µg/ml. Aztreonam, amikacin and cefepime were the most effective antimicrobial drugagainst GNB isolates.Synergistic bactericidal effects were observed in two-drug combinations of AgNPswith broad-spectrum aminoglycoside (Amikacin) and β-lactam (Ampicillin) antibiotics against multidrug resistant GNB. In addition,AgNPsalone or in combination with ampicillin inhibited biofilm activity about 60 % – 75 % ofGNB,while combination of AgNPs withamikacin exhibited a powerful anti-biofilm activity and inhibition biofilm formation by 75% to 80%.&#x0D; Conclusion: The results confirmed a synergistic bactericidal effects and significant enhancing of anti-biofilm activity of AgNPs in combination with antibiotics (amikacin and ampicillin) against multidrug resistant GNB isolated from burn wound infections. These data suggest that AgNPs could beapplied as nanodrug for treatment of burn wound infections

Cefiderocol in context

New antibiotics reaching clinical development are scarce, although bacterial plasmids encoding antibiotic resistance genes seem to be everywhere. 1 Madec JY Haenni M Ponsin C et al. Sequence type 48 Escherichia coli carrying the blaCTX-M-1 IncI1/ST3 plasmid in drinking water in France. Antimicrob Agents Chemother. 2016; 60: 6430-6432 Crossref PubMed Scopus (28) Google Scholar Thus, the first clinical trial of cefiderocol, a siderophore cephalosporin active against multidrug-resistant Gram-negative pathogens, 2 Kohira N West J Ito A et al. In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Antimicrob Agents Chemother. 2016; 60: 729-734 Crossref PubMed Scopus (172) Google Scholar reported by Simon Portsmouth and colleagues in The Lancet Infectious Diseases, 3 Portsmouth S van Veenhuyzen D Echols R et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Diseases. 2018; (published online Oct 25.)http://dx.doi.org/10.1016/S1473-3099(18)30554-1 Summary Full Text Full Text PDF PubMed Scopus (198) Google Scholar represents an eagerly-awaited development in the field. The definitive mechanism of action of cefiderocol is not novel; once inside the bacterial cell, it interrupts the synthesis of peptidoglycan, a key component of the bacterial cell wall. What is novel is its manner of getting inside to do the job—no easy task in the era of increasing efflux pump overproduction and porin mutations. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trialIntravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration. Clinical trials of hospital-acquired pneumonia and carbapenem-resistant infections are ongoing. Full-Text PDF Cefiderocol for treatment of complicated urinary tract infections – Author's replyThe enormous efforts of investigators and trial participants in the premarket development of cefiderocol should be neither disregarded nor underestimated: thanks to their work,1 this drug might soon be accessible to patients who might benefit from it. Nonetheless, a drug tested on only a few hundred people and for a few narrow indications will always require additional, postmarket development. As I have stated,2 because we, the public, have demanded an accelerated path to approval, novel antibiotics are now entering the market on the basis of very thin clinical experience. Full-Text PDF Cefiderocol for treatment of complicated urinary tract infectionsWe were pleased to read the generally positive Comment1 regarding our Article,2 published in The Lancet Infectious Diseases. However, we would like to respond to some of the points raised. Full-Text PDF

Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial

Carbapenem-resistant Gram-negative bacteria represent the highest priority for addressing global antibiotic resistance. Cefiderocol (S-649266), a new siderophore cephalosporin, has broad activity against Enterobacteriaceae and non-fermenting bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii, including carbapenem-resistant strains. We assessed the efficacy and safety of cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infection in patients at risk of multidrug-resistant Gram-negative infections. We did a phase 2, multicentre, double-blind, parallel-group non-inferiority trial at 67 hospitals in 15 countries. Adults (≥18 years) admitted to hospital with a clinical diagnosis of complicated urinary tract infection with or without pyelonephritis or those with acute uncomplicated pyelonephritis were randomly assigned (2:1) by an interactive web or voice response system to receive 1 h intravenous infusions of cefiderocol (2 g) or imipenem-cilastatin (1 g each) three times daily, every 8 h for 7-14 days. Patients were excluded if they had a baseline urine culture with more than two uropathogens, a fungal urinary tract infection, or pathogens known to be carbapenem resistant. The primary endpoint was the composite of clinical and microbiological outcomes at test of cure (ie, 7 days after treatment cessation), which was used to establish non-inferiority (15% and 20% margins) of cefiderocol versus imipenem-cilastatin. The primary efficacy analysis was done on a modified intention-to-treat population, which included all randomly assigned individuals who received at least one dose of study drug and had a qualifying Gram-negative uropathogen (≥1 × 105 colony-forming units [CFU]/mL). Safety was assessed in all randomly assigned individuals who received at least one dose of study drug, according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02321800. Between Feb 5, 2015, and Aug 16, 2016, 452 patients were randomly assigned to cefiderocol (n=303) or imipenem-cilastatin (n=149), of whom 448 patients (n=300 in the cefiderocol group; n=148 in the imipenem-cilastatin group) received treatment. 371 patients (n=252 patients in the cefiderocol group; n=119 patients in the imipenem-cilastatin group) had qualifying Gram-negative uropathogen (≥1 × 105 CFU/mL) and were included in the primary efficacy analysis. At test of cure, the primary efficacy endpoint was achieved by 183 (73%) of 252 patients in the cefiderocol group and 65 (55%) of 119 patients in the imipenem-cilastatin group, with an adjusted treatment difference of 18·58% (95% CI 8·23-28·92; p=0·0004), establishing the non-inferiority of cefiderocol. Cefiderocol was well tolerated. Adverse events occurred in 122 (41%) of 300 patients in the cefiderocol group and 76 (51%) of 148 patients in the imipenem-cilastatin group, with gastrointestinal disorders (ie, diarrhoea, constipation, nausea, vomiting, and abdominal pain) the most common adverse events for both treatment groups (35 [12%] patients in the cefiderocol group and 27 [18%] patients in the imipenem-cilastatin group). Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration. Clinical trials of hospital-acquired pneumonia and carbapenem-resistant infections are ongoing. Shionogi & Co Ltd, Shionogi Inc.

Incidence and outcomes of multidrug-resistant gram-negative bacteria infections in intensive care unit from Nepal- a prospective cohort study

BackgroundInfections caused by multi-drug resistant gram-negative bacterial infections are the principle threats to the critically ill patients of intensive care units. Increasing reports of these infections from the Nepalese intensive care unit underline the clinical importance of these pathogens. However, the impact of these infections on the patient’s clinical outcome has not yet been clearly evaluated. The objective of our study was to determine the incidence and associated clinical outcome of multi-drug resistant gram-negative bacterial infections in intensive care unit from a tertiary care center of Nepal.MethodsA prospective cohort study was conducted among adult patients admitted in intensive care unit of B. P Koirala Institute of Health Sciences from July to December 2017. Patients infected with multi-drug resistant gram-negative bacteria, non-multi-drug resistant gram-negative bacteria and those without infection were included. Identification of gram-negative bacteria and their antibiotic susceptibility pattern was performed with standard microbiological methods. Demographic, clinical profiles and outcomes (in-hospital-mortality, intensive care unit and hospital length of stay) were documented.ResultsThe incidence rate of multi-drug resistant gram-negative bacteria infections was 47 per 100 admitted patients (64/137) with 128 episodes. Acinetobacter species (41%, 52/128) was the commonest followed by Klebsiella pneumoniae (28%, 36/128) and Pseudomonas spp (21%, 27/128). Patients with multi-drug resistant gram-negative bacteria in comparison to non-multi-drug resistant gram-negative bacteria had high healthcare-associated infections (95%, 61/64 versus 20%, 2/10; p = < 0.001). In-hospital-mortality was 38% (24/64), 20% (2/10) and 10% (4/41) in multi-drug resistant, non-multi-drug resistant and uninfected group respectively (p = 0.007). After adjustment for independent risk factors, compared to uninfected patients, the odds ratio (CI) for in-hospital-mortality in multi-drug resistant and non-multi-drug resistant group was (4.7[1.4–15.5], p = 0.01) and 2.60 [0.38–17.8], p = 0.32) respectively. Multi-drug resistant patients also had longer intensive care unit and hospital stay, however, it was statistically insignificant.ConclusionThe incidence of multi-drug resistant gram-negative bacterial infections was remarkably high in our intensive care unit and showed a significant association with healthcare-associated infections and in-hospital-mortality.

Predictive factors for multidrug-resistant gram-negative bacteria among hospitalised patients with complicated urinary tract infections

BackgroundPatients with complicated urinary tract infections (cUTIs) frequently receive broad-spectrum antibiotics. We aimed to determine the prevalence and predictive factors of multidrug-resistant gram-negative bacteria in patients with cUTI.MethodsThis is a multicenter, retrospective cohort study in south and eastern Europe, Turkey and Israel including consecutive patients with cUTIs hospitalised between January 2013 and December 2014. Multidrug-resistance was defined as non-susceptibility to at least one agent in three or more antimicrobial categories. A mixed-effects logistic regression model was used to determine predictive factors of multidrug-resistant gram-negative bacteria cUTI.ResultsFrom 948 patients and 1074 microbiological isolates, Escherichia coli was the most frequent microorganism (559/1074), showing a 14.5% multidrug-resistance rate. Klebsiella pneumoniae was second (168/1074) and exhibited the highest multidrug-resistance rate (54.2%), followed by Pseudomonas aeruginosa (97/1074) with a 38.1% multidrug-resistance rate. Predictors of multidrug-resistant gram-negative bacteria were male gender (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.20–2.29), acquisition of cUTI in a medical care facility (OR, 2.59; 95%CI, 1.80–3.71), presence of indwelling urinary catheter (OR, 1.44; 95%CI, 0.99–2.10), having had urinary tract infection within the previous year (OR, 1.89; 95%CI, 1.28–2.79) and antibiotic treatment within the previous 30 days (OR, 1.68; 95%CI, 1.13–2.50).ConclusionsThe current high rate of multidrug-resistant gram-negative bacteria infections among hospitalised patients with cUTIs in the studied area is alarming. Our predictive model could be useful to avoid inappropriate antibiotic treatment and implement antibiotic stewardship policies that enhance the use of carbapenem-sparing regimens in patients at low risk of multidrug-resistance.