Pan-resistant Strains Research Articles

Identifying virulence determinants of multidrug-resistant Klebsiella pneumoniae in Galleria mellonella.

ABSTRACTInfections caused by Klebsiella pneumoniae are a major public health threat. Extensively drug-resistant and even pan-resistant strains have been reported. Understanding K. pneumoniae pathogenesis is hampered by the fact that murine models of infection offer limited resolution for non-hypervirulent strains which cause the majority of infections. The insect Galleria mellonella larva is a widely used alternative model organism for bacterial pathogens. We have performed genome-scale fitness profiling of a multidrug-resistant K. pneumoniae ST258 strain during infection of G. mellonella, to determine if this model is suitable for large-scale virulence factor discovery in this pathogen. Our results demonstrated a dominant role for surface polysaccharides in infection, with contributions from siderophores, cell envelope proteins, purine biosynthesis genes and additional genes of unknown function. Comparison with a hypervirulent strain, ATCC 43816, revealed substantial overlap in important infection-related genes, as well as additional putative virulence factors specific to ST258, reflecting strain-dependent fitness effects. Our analysis also identified a role for the metalloregulatory protein NfeR (YqjI) in virulence. Overall, this study offers new insight into the infection fitness landscape of K. pneumoniae, and provides a framework for using the highly flexible and easily scalable G. mellonella infection model to dissect molecular virulence mechanisms of bacterial pathogens.

A Diverse Panel of Clinical Acinetobacter baumannii for Research and Development.

Over the past two decades, Acinetobacter baumannii has emerged as a leading cause of nosocomial infections worldwide. Of particular concern are panresistant strains, leading the World Health Organization (WHO) to designate carbapenem-resistant A. baumannii as a priority 1 (critical) pathogen for research and development of new antibiotics. A key component in supporting this effort is accessibility to diverse and clinically relevant strains for testing. Here, we describe a panel of 100 diverse A. baumannii strains for use in this endeavor. Whole-genome sequencing was performed on 3,505 A. baumannii isolates housed at the Multidrug-Resistant Organism Repository and Surveillance Network. Isolates were cultured from clinical samples at health care facilities around the world between 2001 and 2017. Core-genome multilocus sequence typing and high-resolution single nucleotide polymorphism (SNP)-based phylogenetic analyses were used to select a final panel of 100 strains that captured the genetic diversity of the collection. Comprehensive antibiotic susceptibility testing was also performed on all 100 isolates using 14 clinically relevant antibiotics. The final 100-strain diversity panel contained representative strains from 70 different traditional Pasteur scheme multilocus sequence types, including major epidemic clones. This diversity was also reflected in antibiotic susceptibility and antimicrobial resistance (AMR) gene content, with phenotypes ranging from pansensitive to panresistant, and over 100 distinct AMR gene alleles identified from 32 gene families. This panel provides the most diverse and comprehensive set of A. baumannii strains for use in developing solutions for combating antibiotic resistance. The panel and all available metadata, including genome sequences, will be available to industry and academic institutions and federal and other laboratories free of charge.

A Tractable Drosophila Cell System Enables Rapid Identification of Acinetobacter baumannii Host Factors.

Acinetobacter baumannii is an important causative agent of nosocomial infections worldwide. The pathogen also readily acquires resistance to antibiotics, and pan-resistant strains have been reported. A. baumannii is widely regarded as an extracellular bacterial pathogen. However, accumulating evidence demonstrates that the pathogen can invade, survive or persist in infected mammalian cells. Unfortunately, the molecular mechanisms controlling these processes remain poorly understood. Here, we show that Drosophila S2 cells provide several attractive advantages as a model system for investigating the intracellular lifestyle of the pathogen, including susceptibility to bacterial intracellular replication and limited infection-induced host cell death. We also show that the Drosophila system can be used to rapidly identify host factors, including MAP kinase proteins, which confer susceptibility to intracellular parasitism. Finally, analysis of the Drosophila system suggested that host proteins that regulate organelle biogenesis and membrane trafficking contribute to regulating the intracellular lifestyle of the pathogen. Taken together, these findings establish a novel model system for elucidating interactions between A. baumannii and host cells, define new factors that regulate bacterial invasion or intracellular persistence, and identify subcellular compartments in host cells that interact with the pathogen.

Improving effectiveness of microbiological diagnostics in patients with surgical infection of soft tissues.

Recently, there has been a steady tendency towards increase in the resistance of microorganisms to antibacterial drugs, which is due to the lack of development of new antibiotics, their uncontrolled administration, total use in animal husbandry, etc. leads to fatal outcomes, unsatisfactory results of treatment, rise in cost of treatment, formation of hospital pan-resistant strains. The increasing ability of microorganisms to cooperate in biofilms, production and improvement of resistance mechanisms in symbiosis are intractable issues in the treatment of patients with surgical infection of soft tissues. In patients with surgical infection of soft tissues, surgical treatment of a purulent focus and antibiotic therapy are fundamental doctrinal, determining the success of treatment.The choice of an antibacterial drug in most cases is based on the results of an antibioticogram. A study of wounds by smear technique and biopsy samples of wound tissues in 81 patients was performed. The quantitative and qualitative composition of wound microflora of patients was evaluated during the study of biopsy samples and standard culture from the wound surface. When examining the biopsy samples, 86 strains were isolated, and 110 – in the material from the wound surface. There was no growth on the wound surface in 11 cases (13.5%), against 20 (almost 25%) in biopsy samples. One species of flora was isolated from 37 wound surfaces (about 46%), biopsy samples of wounds with monoculture – in 61 samples (75%). Associations (two or more) are present in 33 (41%) wound samples, and only in 21 biopsy samples (26%). Thus, the conducted studies confirm the fact that wound surface is more contaminated by foreign microflora than biopsy samples. The data obtained allow us to recommend the method of wound biptates instead of a smear, as more specific and sensitive in patients with surgical infection of soft tissues.

A phage-based decolonisation strategy against pan-resistant enterobacterial strains

A phage-based decolonisation strategy against pan-resistant enterobacterial strains

Determining the susceptibility of carbapenem resistant Klebsiella pneumoniae and Escherichia coli strains against common disinfectants at a tertiary hospital in China

BackgroundCarbapenem-resistant Enterobacteriaceae (CRE) infections have become a global health threat. Controlling CRE transmission in hospitals is increasingly dependent on the use of disinfectants to restrict the risk of infection. Here, the susceptibility of patient-derived carbapenem resistant Klebsiella pneumoniae (CRKP) and Escherichia coli (CREC) strains against three common disinfectants and the determinants of resistance to disinfectants were investigated.MethodsThe minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs) of three common chemical disinfectants: chlorhexidine, trichloroisocyanuric (TCCA) acid and Povidone iodine (PVP-I) against 50 CRE strains were measured. The drug-resistance genes -qacEΔ1, qacA/B and cepA-were determined using polymerase chain reaction.ResultsA total of 36 CRKP and 14 CREC strains were collected in our hospital from 2016 to 2018. The MIC ranges of 36 CRKP strains against chlorhexidine, TCCA and PVP-I were 8~512 mg/L, 64~128 mg/L and 8~128 mg/L, respectively. For 14 CREC strains, the MIC ranges against chlorhexidine, TCCA and PVP-I were 4~128 mg/L, 64~128 mg/L and 4~128 mg/L, respectively. Moreover, against chlorhexidine and PVP-I, the MIC90 of 36 CRKP strains was higher than that of 50 CSKP strains. The qacE△1 gene was detected in 15 isolates among 36 CRKP strains (41.7%), and 8 isolates among 14 CREC strains (57.1%); while the qacA/B gene was not detected. Specifically, the cepA gene was much more prevalent than the qacEΔ1; it reached over 80% among CRKP strains. Compared to the CSKP strains, the presence of the qacEΔ1 and cepA genes was significantly higher among the CRKP strains (p < 0.05).ConclusionCRE strains collected from patients in our hospital exhibit various degree of resistance to the commonly used chemical disinfectants. It is of great help to keep monitoring the tendency of the reduced susceptibility of the pan-resistant strains against disinfectants, in order to effectively control and prevent the spread of the super resistant bacteria.

A cross-sectional study on antibiotic prescription in a teaching hospital in Ghana.

IntroductionAntibiotic misuse is the paramount factor for antibiotic resistance. Tamale Teaching Hospital (TTH), located in Ghana’s Northern Region, is the biggest tertiary hospital in the Northern half of the country and consequently one of the biggest prescribers of antibiotics. Understanding the use of antibiotics in the TTH and providing information that could be inferred to develop strategies for antibiotic prescription is of extreme importance in this era of multiple and pan-resistant strains of pathogenic microorganisms.MethodsA cross-sectional study on the use of antibiotics at TTH in the Northern region of Ghana was performed. Data were collected by reviewing 10% of patients’ files from January to June 2015 and then assessed for its appropriateness against the criteria based on the British National Formulary (BNF) 2015 and BNF children 2013-2014. Results were expressed in frequencies and percentages.ResultsA total of 617 patients’ records were included in this study. Up to 385 cases of different antibiotic misuse were found, comprising of 335 errors in prescriptions and 50 non-completed treatments. The most common prescription error was made on treatment duration (29.6%). The potential interactions were 16.7%.ConclusionThe study revealed a high burden of antibiotics misuse in TTH. This suggests a need for the development of an antibiotic stewardship programme for the hospital.

Faktori rizika za nastanak bolničkih infekcija uzrokovanih Pseudomonas aeruginosa rezistentnim na cefepim

Introduction: The increasing resistance of Pseudomonas aeruginosa against cefepime requires a better understanding of hospital epidemiology in order to retain this drug as a therapeutic option. Aim: The aim of this study was to identify risk factors associated with healthcare associated infections (HAIs) caused by cefepime-resistant P. aeruginosa (CRPA), both in all patients with HAIs and in the subgroups of patients who died or who acquired infection with carbapenem-resistant P. aeruginosa. Methods: The academic study was designed as a combination of three nested case/ control studies within the cohort of patients with HAIs caused by P. aeruginosa regardless of localization, prospectively followed from January 2009 to December 2017 in a tertiary care hospital. The influence of risk factors on specific outcomes was estimated by adjusted odds ratios calculated from multivariate logistic regressions. Results: Our study showed that there are independent risk factors for CRPA infections: the existence of another HAI (p=0.001), hospitalization in ICU longer than one month (p=0.007), a longer stay in hospital prior to infection (p=0.004), longer use of mechanical ventilation (p=0.036), administration of antibiotics before infection (p<0.001) and previous use of fluoroquinolones (p=0.030), while traumatic injury (p=0.020), the existence of another HAI (p=0.001) and long-term use of antibiotics before HAI (p=0.034) were related to mortality. Further, independent risk factors for HAIs caused by carbapenem-resistant CRPA are the existence of another HAI (p=0.011), transfer from another facility (p=0.023), more days spent in hospital (p=0.006) and ICU (p=0.004), and administration of antibiotics before infection (p<0.001). Conclusion: Risk factors for HAIs with CRPA are primarily linked to pre-infection use of systemic antibiotics, which is a common pathway for selection of multi, extensive or pan-resistant strains of P. aeruginosa that invade tissues and cause infection.

The first experience of treatment of patients with purulent-septic diseases caused by pan-resistant strains

This article presents an assessment of the eff ectiveness of various combinations of antimicrobial therapy in the treatment of severe purulent-septic pathology. The study included 107 patients who were treated in the intensive care unit of a multidisciplinary surgical hospital. The criterion of inclusions were purulent-septic pathology and severity on the APACHE II scale of more than 25 points. Depending on the type of combination of antimicrobial therapy, all patients were divided into 4 groups. The combination of meropenem and vancomycin showed the lowest effi cacy in reducing mortality in the intensive care unit. The lowest mortality rates were observed when using a combination of prolonged meropenem infusion in combination with the administration of cefoperazone / sulbactam.

The role of a gram-positive microflora and its resistance in purulent-necrotic complications in patients, suffering syndrome of diabetic foot

Objective. To improve the results of treatment in patients, suffering diabetic foot syndrome (DFS), using conduction of the directed antibacterial therapy, taking into account the resistance of microflora revealed, and to reveal the role of a gram-positive microflora in occurrence of complications.&#x0D; Materials and methods. There were examined 1824 patients, suffering DFS for period from 2015 to 2019 yr., who suffered purulent-necrotic affections of the foot - abscess, phlegmon, purulent tendovaginitis, purulent arthritis, gangrene. All the patients suffered diabetes mellitus Type 2, average duration of which have constituted (12.3 ± 2.7) yrs. Qualitative content of microflora and sensitivity of cultures for antibiotics were revealed on automatic microbiological analizators «Vitek2» and BacT/ALERT (France).&#x0D; Results. The cause of purulent-necrotic complications was a gram-positive microflora, which in 57.1 - 66.8% patients was diagnosed in monoinfection and prevailed in a content of microbial associations. Phenomena of resistance to the main antibacterial preparations was revealed in 37.4% bacteria. The biggest resistance have had Staphylococcus aureus and Enterococcus faecalis. In 62.5% patients, owing Staphylococcus aureus, a resistance gene to Staphylococcus aureus with three genetic variations were revealed, which differed in accordance to resistance for certain groups of antibiotics. The most significant MRSA Type 3 - panresistant (in 6/2% patients).&#x0D; Conclusion. Investigations of purulent-necrotic foci in patients with the DFS witnesses, that the leading microorganism while development of complications constitutes a gram-positive microflora, which is characterized by presence of polyresistant and panresistant strains. Such a condition gives background to necessity for correcting of the antibacterial therapy administered.

Recomendaciones GEMICOMED/GEIRAS-SEIMC para el manejo de las infecciones y colonizaciones por Candida auris

Candida auris is a new species of Candida that causes nosocomial outbreaks in several countries around the world, including Spain. C.auris is resistant to fluconazole and multi- and pan-resistant strains have been described. It is highly transmissible and can survive long term in the hospital environment, causing long-lasting outbreaks that are difficult to detect in early stages, and making it difficult to control and eradicate. It is currently an emerging threat to global health.This document provides a set of guidelines, developed by a multidisciplinary team, to limit the impact and facilitate the control of C.auris infection based on the experiences gathered in the Spanish and English outbreaks. The implementation of early and strict surveillance and control measures is essential to prevent the spread of the outbreak, which can spread over time, posing a significant risk to complex, critical and immunocompromised surgical patients. Immediate notification of C.auris isolation to clinical and infection control teams, as well as to health authorities and institutions, is essential to implement infection control measures at all levels in a timely manner, to prevent internal and inter-centre transmission, and to ensure a proper surveillance and prevention to patients who are already colonized and can develop an infection.

Draft Genome Sequences of Four Metallo-Beta-Lactamase-Producing Multidrug-Resistant Klebsiella pneumoniae Clinical Isolates, Including Two Colistin-Resistant Strains, from Cairo, Egypt.

The emergence and spread of metallo-beta-lactamase-producing multidrug-resistant Klebsiella pneumoniae are a serious public health threat. Here, we report the draft genome sequences of four K. pneumoniae strains isolated from Cairo, Egypt, including two panresistant colistin-resistant strains. Genome annotation indicated a number of virulence and resistance genes agreeing with observed phenotypes.

2446. Clinical Spectrum and Outcomes of Colistin-Resistant Carbapenem-Resistant Enterobacteriaceae

BackgroundColistin is considered as one of the last resort of antibiotics against carbapenem-resistant enterobacteriaceae. During the last decade, increased use of colistin or polymyxins due to the increasing prevalence of carbapenem-resistant Gram-negative bacteria has unfortunately led to the emergence of colistin-resistant strains. There are no defined antibiotic regimens for colistin-resistant strains which makes the treatment of these organisms extremely challenging. We therefore report the clinical spectrum and outcomes of infections due to colistin-resistant carbapenem-resistant Enterobacteriaceae (Co-CRE) as well as the factors associated with acquisition of co-CRE.MethodsWe conducted a retrospective cross-sectional study from January 2013 till December 2017 on patients admitted to a tertiary care hospital in Karachi, Pakistan. Statistical analysis was done using SPSS 19.ResultsForty patients with Co-CRE were identified of which 29 (72.5%) were males. Median age was 54.5 years. The most common organism isolated was Klebsiella in 22 (55%) followed by Providencia in 5 (12.5%) patients. Most common source of infection was the lung in 12 (30%) followed by urine in 11 (27.5%) patients. Similarly, the most common cause of bacteremia was pneumonia followed by intra-abdominal infections (50% and 37.5% of bacteremia cases, respectively). Twenty-eight (70%) patients had prior cultures with multi-drug-resistant organisms and 36 (90%) had used antibiotics in the past. A quarter (10) patients had pan resistant co-CRE strains while of the remaining strains 66% were sensitive to Fosfomycin. All patients received Colistin-based regimen in combination with 2 or 3 of the following: carbapenem, Fosfomycin, Amikacin, co-triamoxazole, and tigecycline. Complete clinical cure was achieved in only 50% of patients whereas microbiological eradication was achieved in 75%. Higher PITT bacteremia score, solid-organ transplant, and acute kidney injury were associated with mortality in patients with co-CRE.ConclusionInfections with co-CRE was seen in patients with prior nosocomial exposures and led to poor outcomes, despite combination treatment guided by susceptibilities.Disclosures All authors: No reported disclosures.

615. Can We Restore the Lung Microbiome with Fecal Microbiota Transplant (FMT)?

BackgroundUnabated use of antibiotics for human diseases, in livestock and aquaculture has resulted in natural selection of multi-drug-resistant organisms (MDROs). The emergence of pan-resistant strains of Pseudomonas spp. pose a major threat to patients appropriately exposed to antibiotics (e.g., cystic fibrosis, lung transplant recipients). This organism evades antibiotics by a combination of efflux pumps, harboring multiple-resistant genes and acquiring low permeability of the outer membrane. Altering the gut microbiome could potentially modify the lung microbiome of patients colonized or infected with MDROs.MethodsA 17-year-old patient with CF developed recurrent exacerbations with an extreme drug-resistant Pseudomonas aeruginosa; due to the lack of effective antibiotics to treat her while awaiting a decision to proceed with lung transplantation, sputum cultures were collected as part of clinical care. We modeled patient-derived isolate of predominantly MDR Pseudomonas in C57Bl6/j mice, where we engrafted the isolate into humanized murine lungs and studied host cytokine responses and microbial composition of the gut and lungs to the engraftment.ResultsOur data shows that there is a dominant IL6- and IL17-mediated immune response to the engraftment, accompanied by measurable changes to the lung and gut microbiota. We also show that some of these changes can be reversed by fecal microbial transplant (FMT) of ‘normal’ microbiota into the gut and lungs.ConclusionThis murine model results suggest a potential role and effectiveness of gut FMT as a therapeutic measure for MDR bacterial infection in the lungs. Further studies are required to assess response in humans.Disclosures L. M. Abbo, Roche Diagnostics: Scientific Advisor, Consulting fee.

2100. Nitroglycerin-Citrate-Ethanol Catheter Lock Solution Is Highly Effective in Eradicating Candida auris Biofilms

BackgroundBlood stream infections due to Candida auris is a significant public health concern due to increased patient mortality, frequent misidentification, and high rates of antifungal resistance. C. auris is known to be azole resistant, however several strains have been identified with elevated MICs to all classes of antifungals. Current treatment options for a pan-resistant strain of C. auris would be extremely challenging. Previously we have shown that non-antibiotic, Nitroglycerine + Citrate + Ethanol (NiCE) lock solution was highly efficacious in eradicating various species of multi-drug-resistant Candida. In this study we compared the efficacy of NiCE with standard of care antifungals commonly used in lock solutions in eradicating C. auris biofilms.MethodsBiofilm eradication of C. auris was evaluated in 10 strains. Candida auris biofilm was grown on silicone discs for 24 hours. Discs were then washed to remove any non-adherent organisms and exposed for 2 hours to various antifungal lock solutions including NiCE, Echinocandins, Azoles, and Amphotericin B. Discs were exposed to Muller–Hinton broth as a control. Subsequently discs were sonicated for 15 minutes in 5 mL of saline and quantitatively cultured onto sabouraud dextrose agar. Plates were incubated at 37°C for 48 hours and counted for growth. All testing was conducted with 6 replicates.ResultsNiCE and Caspofungin were significantly more effective in eradicating C. auris biofilms compared with control (P = 0.002 and 0.008, respectively). However, Caspofungin failed to eradicate a few strains of C. auris biofilm while NiCE completely eradicated all 10 strains. Micafungin, Anidulafungin, Fluconazole, and Voriconazole were not significantly different than control (P > 0.05) for all strains.ConclusionNiCE catheter lock solution was capable of completely eradicating all C. auris biofilms within 2 hours indicating high potential for preventing CRBSI caused by C. auris. Caspofungin eradicated some strains of C. auris biofilm, but failed to eradicate all. Other commonly used antifungals were no different than control. Future clinical studies to verify these findings need to be conducted.Disclosures D. P. Kontoyiannis, Merck: Consultant, Research support and Speaker honorarium; Pfizer: Consultant, Research support; Astellas: Consultant, Research support and Speaker honorarium; Gilead: Speaker’s Bureau, Speaker honorarium; F2G Inc: Speaker’s Bureau, Speaker honorarium; Cidara Inc.: Speaker’s Bureau, Speaker honorarium; Jazz Pharmaceuticals: Speaker’s Bureau, Speaker honorarium. I. Raad, The University of Texas MD Anderson Cancer Center: Shareholder, Licensing agreement or royalty; The Unversity of Texas MD Anderson Cancer Center: Shareholder, Dr. Raad is a co-inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed to Novel Anti-Infective Technologies LLC, in which UTMDACC and Licensing agreement or royalty.

MCR-1 Inhibition with Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Restores Sensitivity to Polymyxin in Escherichia coli.

ABSTRACTIn late 2015, the first example of a transferrable polymyxin resistance mechanism in Gram-negative pathogens, MCR-1, was reported. Since that report, MCR-1 has been described to occur in many Gram-negative pathogens, and the mechanism of MCR-1-mediated resistance was rapidly determined: an ethanolamine is attached to lipid A phosphate groups, rendering the membrane more electropositive and repelling positively charged polymyxins. Acquisition of MCR-1 is clinically significant because polymyxins are frequently last-line antibiotics used to treat extensively resistant organisms, so acquisition of this mechanism might lead to pan-resistant strains. Therefore, the ability to inhibit MCR-1 and restore polymyxin sensitivity would be an important scientific advancement. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are antisense molecules that were designed to target mRNA, preventing translation. Peptide conjugation enhances cellular entry, but they are positively charged, so we tested our lead antibacterial PPMOs by targeting an essential Escherichia coli gene, acpP, and demonstrated that they were still effective in mcr-1-positive E. coli strains. We then designed and synthesized two PPMOs targeted to mcr-1 mRNA. Five clinical mcr-1-positive E. coli strains were resensitized to polymyxins by MCR-1 inhibition, reducing MICs 2- to 16-fold. Finally, therapeutic dosing of BALB/c mice with MCR-1 PPMO combined with colistin in a sepsis model reduced morbidity and bacterial burden in the spleen at 24 h and offered a survival advantage out to 5 days. This is the first example of a way to modulate colistin resistance with an antisense approach and may be a viable strategy to combat this globally emerging antibiotic resistance threat.

Evaluation of Machine Learning and Rules-Based Approaches for Predicting Antimicrobial Resistance Profiles in Gram-negative Bacilli from Whole Genome Sequence Data.

The time-to-result for culture-based microorganism recovery and phenotypic antimicrobial susceptibility testing necessitates initial use of empiric (frequently broad-spectrum) antimicrobial therapy. If the empiric therapy is not optimal, this can lead to adverse patient outcomes and contribute to increasing antibiotic resistance in pathogens. New, more rapid technologies are emerging to meet this need. Many of these are based on identifying resistance genes, rather than directly assaying resistance phenotypes, and thus require interpretation to translate the genotype into treatment recommendations. These interpretations, like other parts of clinical diagnostic workflows, are likely to be increasingly automated in the future. We set out to evaluate the two major approaches that could be amenable to automation pipelines: rules-based methods and machine learning methods. The rules-based algorithm makes predictions based upon current, curated knowledge of Enterobacteriaceae resistance genes. The machine-learning algorithm predicts resistance and susceptibility based on a model built from a training set of variably resistant isolates. As our test set, we used whole genome sequence data from 78 clinical Enterobacteriaceae isolates, previously identified to represent a variety of phenotypes, from fully-susceptible to pan-resistant strains for the antibiotics tested. We tested three antibiotic resistance determinant databases for their utility in identifying the complete resistome for each isolate. The predictions of the rules-based and machine learning algorithms for these isolates were compared to results of phenotype-based diagnostics. The rules based and machine-learning predictions achieved agreement with standard-of-care phenotypic diagnostics of 89.0 and 90.3%, respectively, across twelve antibiotic agents from six major antibiotic classes. Several sources of disagreement between the algorithms were identified. Novel variants of known resistance factors and incomplete genome assembly confounded the rules-based algorithm, resulting in predictions based on gene family, rather than on knowledge of the specific variant found. Low-frequency resistance caused errors in the machine-learning algorithm because those genes were not seen or seen infrequently in the test set. We also identified an example of variability in the phenotype-based results that led to disagreement with both genotype-based methods. Genotype-based antimicrobial susceptibility testing shows great promise as a diagnostic tool, and we outline specific research goals to further refine this methodology.

Bloodstream infections caused by multi-drug resistant Proteus mirabilis: Epidemiology, risk factors and impact of multi-drug resistance

ABSTRACTBackground The prevalence of antimicrobial co-resistance among ESBL-producing Enterobactereaceae is extremely high in Israel. Multidrug-resistant Proteus mirabilis strains (MDR-PM), resistant to almost all antibiotic classes have been described. The aim was to determine the risk factors for bloodstream infections caused by MDR-PM and clinical outcomes. Methods A retrospective case-control study. Adult patients with PM bacteremia during 7 years were identified retrospectively and their files reviewed for demographics, underlying diseases, Charlson Comorbidity Index, treatment and outcome. Results One hundred and eighty patients with PM-bloodstream infection (BSI) were included; 90 cases with MDR-PM and 90 controls with sensitive PM (S-PM). Compared to controls, cases more frequently were from nursing homes, had recurrent hospital admissions in the past year and received antibiotic therapy in the previous 3 months, were bedridden and suffered from peripheral vascular disease and peptic ulcer disease (p < 0.001). Two-thirds of the MDR-PM isolates were ESBL-producers vs 4.4% of S-PM isolates (p < 0.001, OR = 47.6, 95% CI = 15.9–142.6). In-hospital crude mortality rate of patients with MDR-PM BSI was 37.7% vs 23.3% in those with S-PM BSI (p = 0.0359, OR = 2, 95% CI = 1.4–3.81). Conclusions PM bacteremia in elderly and functionally-dependent patients is likely to be caused by nearly pan-resistant PM strains in the institution; 51.8% of the patients received inappropriate empiric antibiotic treatment. The crude mortality rate of patients with MDR-PM BSI was significantly higher than that of patients with S-PM BSI.

The global threat of antimicrobial resistance - The need for standardized surveillance tools to define burden and develop interventions

nti-microbial resistance (AMR) is one the biggest issues he medical community is currently facing, as evidenced y the increasing prevalence of pan-resistant strains. In ddition to treatment options, AMR also has major finanial and economical implications. It has been estimated hat up to 50% of antimicrobial use is inappropriate; each ear approximately 2 million people in the US are infected ith a resistant organism.1 Up to 23,000 yearly deaths are eportedly caused directly by such infections.1 The situation s further complicated in low-income countries by lack of ffective surveillance systems, laboratory diagnostics, and ccess to appropriate antimicrobials in the face of financial imitations. The emergence of MDR Gram-negative bacterial (GNB) esistance is particularly of concern, especially in intenive care units (ICUs) and immunocompromised patients,

Antibiotic Development and the Evolving Role of Pharmacodynamics — As Good as It Gets?

Antibiotic Development and the Evolving Role of Pharmacodynamics — As Good as It Gets?