GNB Infections Research Articles

Potent synergy and sustained bactericidal activity of polymyxins combined with Gram-positive only class of antibiotics versus four Gram-negative bacteria

BackgroundGram-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.ObjectiveTo 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.MethodsThe 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.ResultsIn 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.ConclusionsOur 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.

Ceftazidime-Avibactam as a Salvage Treatment for Severely Infected Immunosuppressed Children.

Multidrug-resistant Gram-negative bacteria (MDR-GNB) are becoming increasingly common around the world, with carbapenems frequently serving as a last resort but being threatened by the growing incidence of carbapenemase-producing bacteria. Ceftazidime-avibactam (CAZ/AVI) is a potential agent against MDR-GNB but with limited clinical experience, particularly in critically ill immunosuppressed children. This study analyzed the use of CAZ/AVI as salvage treatment in severely infected immunosuppressed children from September 2019 to July 2022. Patients with confirmed GNB infection who received CAZ/AVI were matched with patients who received other antibiotics. Twenty-five critically ill immunosuppressed children treated with CAZ/AVI were included. The majority had hematologic diseases. All patients presented with sepsis in all 30 courses. Septic shock presented in 36.7% of these courses. The primary sites of infection included bloodstream infection (20.0%), skin and skin structure infection (20.0%), intra-abdominal infection (13.3%) and hospital-acquired pneumonia (10.0%). Twelve of the 25 (48.0%) patients had positive microbiological cultures, mainly Pseudomonas aeruginosa and Klebsiella pneumoniae, including 5 carbapenem-resistant GNB-infected cases. Fifteen (50.0%) courses presented clinical improvement. For the initial course of each patient, the clinical response rate of the GNB recovered group was significantly higher than that of the group without GNB recovery (66.7% vs 23.1%, P = 0.047). The 14-day and 30-day mortality rates were 24.0% and 28.0%, respectively, which were significantly correlated with the absence of GNB recovery (P = 0.004 and 0.024, respectively) and hospital-acquired pneumonia as the primary site of infection (P = 0.001 and 0.006, respectively). There was no significant difference in major outcomes between patients who received CAZ/AVI and matched patients who received other antibiotics. CAZ/AVI could be considered a salvage strategy for immunosuppressed children with confirmed GNB infection. Caution should be taken when CAZ/AVI is applied to these patients in the absence of GNB recovery.

Outcome and Predictors of Treatment Failure in Chronic Osteomyelitis Using Bioactive Glass Granules and Putty Formulations.

The aim of this study is to evaluate the outcome of patients with cavitary chronic osteomyelitis undergoing adjuvant treatment with bioactive glass (BAG) S53P4 and identify the independent risk factors (RFs) for recurrence in 6- and 12-month patient follow-up. A retrospective, multicentre observational study conducted in tertiary specialised hospitals among patients undergoing the surgical treatment of chronic cavitary osteomyelitis using BAG-S53P4 in a granule and/or putty formulation to assess the clinical outcome and RFs for failure in 6- and 12-month patient follow-up. Of the 92 and 78 patients with 6-month and 12-month follow-ups, infection was eradicated in 85.9% and 87.2%, respectively. In the 6-month follow-up, BAG-S53P4 in the granule formulation presented a greater risk of recurrence compared to the bioactive glass putty formulation or combined granules and putty (prevalence ratio (PR) = 3.04; confidence interval 95% [CI95%]: 1.13-10.52) and neoplasia (PR = 5.26; CI95%: 1.17-15.52). In the 12-month follow-up cohort of 78 patients, smoking (PR = 4.0; 95% CI: 1.03-15.52) and nonfermenting GNB infection (PR = 3.87; CI95%: 1.09-13.73) presented a greater risk of recurrence. BAG-S53P4 is a viable option for bone-void filling and the treatment of chronic cavitary osteomyelitis. Formulations of BAG with putty or in combination with granules showed better results.

Difficult-to-treat resistant gram-negative blood stream infections – the beginning of a superbug era – a prospective observational study

IntroductionCarbapenem resistant gram-negative bacterial infections are a growing concern worldwide. However, India is already in the era of a shortage of effective antibiotics for the management of these infections. Moreover, Difficult-to-Treat Resistance (DTR) gram-negative infections, which are not much studied, further complicate the scenario. This study emphasized the incidence and outcomes of DTR infections. MethodologyThis is a single-center prospective observational study. The study included hospitalised patients aged ≥18 years with gram-negative bacterial bloodstream infections (GNBSI). Blood cultures with the growth of contaminants and/or single positive culture taken from the femoral site were excluded. Incidences of DTR infections and outcomes in the form of 30-day mortality were analysed. ResultsTwo hundred forty patients with GNBSI episodes were recorded. The Incidence of DTR GNBSI was 37.9% (91/240). Multivariate analysis found that Hospital-acquired infections, ICU admission and mechanical ventilation were independent risk factors for DTR GNBSI. The most common DTR GNB isolates were Klebsiella pneumoniae (31/49, 63.3%) and Acinetobacter baumannii (26/52, 50%). The adjusted relative risk of mortality was remarkably high in DTR GNBSI (aRR 3.9; 95% CI 1.9–7.9) as compared to CR+/DTR- GNBSI (aRR 0.3; 95% CI 0.1–1.0) and ESCR/CS GNBSI (aRR 1.1; 95% CI 0.5–2.4). ConclusionDTR GNB infections are growing concern in India and this need to be evaluated in multicentric studies. Moreover, DTR GNBSI was associated with significantly higher mortality and there is need of further empowerment of antibiotic stewardship practices.

Carbapenem-resistant gram-negative bacterial infection in intensive care unit patients: Antibiotic resistance analysis and predictive model development.

In this study, we analyzed the antibiotic resistance of carbapenem-resistant gram-negative bacteria (CR-GNB) in intensive care unit (ICU) patients and developed a predictive model. We retrospectively collected the data of patients with GNB infection admitted to the ICU of the First Affiliated Hospital of Fujian Medical University, who were then divided into a CR and a carbapenem-susceptible (CS) group for CR-GNB infection analysis. Patients admitted between December 1, 2017, and July 31, 2019, were assigned to the experimental cohort (n = 205), and their data were subjected to multivariate logistic regression analysis to identify independent risk factors for constructing the nomogram-based predictive model. Patients admitted between August 1, 2019, and September 1, 2020, were assigned to the validation cohort for validating the predictive model (n = 104). The Hosmer-Lemeshow test and receiver operating characteristic (ROC) curve analysis were used to validate the model's performance. Overall, 309 patients with GNB infection were recruited. Of them, 97 and 212 were infected with CS-GNB and CR-GNB, respectively. Carbapenem-resistant Klebsiella pneumoniae (CRKP), carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) were the most prevalent CR-GNB. The multivariate logistic regression analysis results of the experimental cohort revealed that a history of combination antibiotic treatments (OR: 3.197, 95% CI: 1.561-6.549), hospital-acquired infection (OR: 3.563, 95% CI: 1.062-11.959) and mechanical ventilation ≥ 7 days (OR: 5.096, 95% CI: 1.865-13.923) were independent risk factors for CR-GNB infection, which were then used for nomogram construction. The model demonstrated a good fit of observed data (p = 0.999), with an area under the ROC curve (AUC) of 0.753 (95% CI: 0.685-0.820) and 0.718 (95% CI: 0.619-0.816) for the experimental and validation cohort, respectively. The decision curve analysis results suggested that the model has a high practical value for clinical practice. The Hosmer-Lemeshow test indicated a good fit of the model in the validation cohort (p-value, 0.278). Overall, our proposed predictive model exhibited a good predictive value in identifying patients at high risk of developing CR-GNB infection in the ICU and could be used to guide preventive and treatment measures.

Factors associated with mortality from gram-negative bacterial infections in children with cancer

Background/objectivesGram-negative bacteria (GNB) infection in children with cancer is an undesirable consequence of high intensity treatment. Our objective was to identify the prevalence of GNB infection in children with cancer, sensitivity patterns, mortality rates and factors associated with mortality. Design/methodsWe retrospectively analysed clinical and microbiological data of all newly diagnosed paediatric (0–18 years) cancer patients in Max Super Speciality Hospital, Saket and Patparganj in New Delhi who had GNB growths in their blood cultures from March 2013 to April 2019. Bacterial sensitivity to various antimicrobial agents was determined. Outcome of interest was death from GNB infection. ResultsA total of 1170 blood cultures were obtained from 485 children (range 0–28/child, median 1/child). Of these 213 (18.2%) were positive with 108 (50.7%) gram-positive bacteria, 87 (40.8%) with GNB and 18 (8.5%) with fungal. Sensitivity to piperacillin/tazobactam, amikacin, meropenem and colistin was observed in 38.4%, 57.6%, 51.5% and 95.3% of the GNB isolates, respectively. Sensitivity to our first line combination of piperacilin/tazobactam plus amikacin was observed in 72.7% of Pseudomonas species, 71.4% Acinetobacter species, 66.7% Enterobacter cloacae, 60% Klebsiella species and 42.1% of E coli. There were 9 deaths (mortality rate 18%). There was no significant difference in mortality by age group, gender, country, hospital, cancer type and type of GNB. Factors significantly associated with mortality were low neutrophil count and resistance to first line antibiotics. ConclusionGNB Infection in children with cancer in India is characterized by high antibiotic resistance. Multidrug resistance and neutropenia are associated with increased risk of mortality.

Impact of antimicrobial stewardship program on clinical outcomes in multidrug-resistant Gram-negative bacterial infections at a tertiary care hospital from South India

Background: Increasing bacterial resistance to antimicrobial agents is resulting in high morbidity and mortality. Antimicrobial stewardship (AMS) programs aim at rationale use of antimicrobial agents in clinical settings by development and implementation of antibiotic policy. As the patterns of antimicrobial resistance vary with organism and time, there is a need for periodic surveillance. Aims and Objectives: The aim of the study was to study the impact of AMS program on appropriate use of antimicrobial agents and clinical outcomes in patients with multidrug-resistant Gram-negative bacterial (MDR GNB) infections. Materials and Methods: This is a prospective observational study that included patients diagnosed with multidrug-resistance Gram-negative bacterial infections during June to July 2019. Identification of multidrug-resistant organisms was performed as per clinical and laboratory standards institute guidelines 2016. Information on the use of empirical antibiotic and other antimicrobial agents after culture and sensitivity report were collected and assessed for appropriateness. All the patients were followed up till discharge. Results: From 170 patients, there were 211 specimens sent for culture and sensitivity and 249 pathogens were isolated. The most frequent pathogen isolated was Escherichia coli (42.6%) followed by Klebsiella spp. (22.9%). Isolates were most resistant to cefazolin (86.7%) and ceftriaxone (83.9%), and most sensitive to polymyxin B (100%) and tigecycline (97.2%). All patients were administered antimicrobial agents as per antibiotic policy of the institute and 154 (90.6%) patients have recovered from illness with a mean length of hospital stay of 19.4 ± 6.6 days. Conclusion: Adherence to antimicrobial policy helps in improved outcomes in patients with MDR GNB infections. Hence, the need to implement AMS program in all hospitals.

677. Systematic Review of the Early Use Experince of Cefiderocol in Real World Practice

Abstract Background Gram-negative bacteria (GNB) with resistance to carbapenems is a growing global public health concern. The World Health Organisation have listed three priority GNB pathogens for the development of novel antimicrobial agents; Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales. The purpose of this systematic review (SR) was to report evidence on the use of cefiderocol (FDC), a siderophore cephalosporin, for patients with GNB infections in compassionate use or expanded access settings. Methods Searches were undertaken to identify relevant evidence up to December 2021. Two independent reviewers screened the records retrieved for relevance to the SR with disagreements adjudicated by a third reviewer. Patients receiving FDC in a compassionate use, expanded access setting or those with limited treatment options for the treatment of GNB infection were eligible. Eligible case reports and case series were assessed for quality using predefined tools and data were extracted (by a single reviewer with data checking performed by a second reviewer), tabulated and summarised. Results Forty-four studies (n=150 patients) were identified reporting the use of FDC; 3 case series studies and 41 case reports. The most commonly reported pathogens were P. aeruginosa (41.3%), A. baumannii (36.0%) and A. xylosoxidans (14.3%). The diagnoses varied widely across the included patients. All patients were administered FDC at a dose between 750 mg and 2 g per day on various schedules, adjusted for renal function for between one and six weeks. Clinical cure was reported in 137 patients using author-specified definitions with 74 patients (54.0%) reporting clinical cure and 18 (13.1%) reporting failure. Microbiological eradication was reported in 78 patients of whom 56 (71.8%) reported success, while 22 (28.2%) reported failure. For mortality (n=123) 80 patients (65.0%) remained alive at the end of treatment, while 43 (35.0%) died. Adverse event (AE) data was reported for 53 patients of whom 13 (24.5%) reported AEs, while 40 (75.5%) did not. See Table 1.0. Conclusion FDC is a promising therapy for patients with GNB infections with limited treatment options. Real world practice shows a high microbiological eradication rate and a small number of AEs. Disclosures Carlo Tascini, n/a, Shionogi: Grant/Research Support Aurelien Dinh, Professor of Infectious Disease, Shionogi: Advisor/Consultant|Shionogi: Board Member Christopher M. Longshaw, PhD, Shionogi: Employee Anita C. Fitzgerald, MPH, Shionogi: Shionogi commissioned York Health Economics Consortium of which I am an associate, to conduct the systematic review we are submitting to IDWeek Hannah Wood, BA MA, Shionogi: Shionogi commissioned York Health Economics Consortium of which I am an employee, to conduct the systematic review we are submitting to IDWeek Jacoby Vivien M. Patterson, MA Cantab, MB BChir, FFPH MD, Shionogi: Shionogi commissioned York Health Economics Consortium of which I am an associate, to conduct the systematic review we are submitting to IDW Deborah Watkins, MSc, Shionogi: Shionogi commissioned York Health Economics Consortium of which I am an employee, to conduct the systematic review we are submitting to IDWeek Katy Wilson, LLM, Shionogi: Shionogi commissioned York Health Economics Consortium of which I am an employee to conduct the systematic review we are submitting to IDWeek Karan Gill, Master of Science, Shionogi: Employee.

669. Real World Use of Ceftazidime/Avibactam for the Treatment of Multidrug Resistant Gram Negative Bacilli Infections: A Real World Experience from Two Centers in Mexico

Abstract Background Ceftazidime-avibactam (C-A) is effective against many carbapenem resistant Enterobacteriaceae (CRE) and some carbapenem resistant Pseudomonas aeruginosa (CRPsa), indicated in complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI), and hospital-acquired pneumonia. To our knowledge, in Mexico, there is no data regarding the clinical efficacy (clinical cure) of its use in the treatment of cIAI, cUTI, hospital-acquired pneumonia, and the treatment of CRE and CRPsa. Methods this is a descriptive, observational, retrospective study, including infections in which ceftazidime avibactam was the definitive therapy for CRE and CRPsa, and empiric treatment of cUTI, cIAI, Hospital-acquired pneumonia. The study includes patients from 2 centers, between April 2019 and february 2020. Demographic, clinical and microbiological data were obtained. Clinical cure was defined as the absence of fever, leukocytosis, tachycardia, systolic pressure &amp;lt; 90mmHg or use of vasopressors, and lowering of C-reactive protein by at least 60% after 5 days of treatment. Results Seventy patients in which C-A was the definitive antimicrobial treatment were evaluated. UTI accounts for 24 cases (34.2%), followed by primary and secondary peritonitis (28.5%), soft tissue infection (12.8%), bacteremia (12.8%) and hospital-acquired pneumonia (11.4%). Of all infections 39.9% were secondary to CRPsa, and 60.1% were due to CRE (30.3% Klebsiella pneumoniae, 21.2% Escherichia coli and 6% for Klebsiella oxytoca, Enterobacter cloacae and Proteus mirabilis). Clinical cure was achieved in 64 patients (91.4%). Six patients died, but only one was associated to CRPsa infection. Conclusion To the best of our knowledge, this is the first study of Mexican experience with C-A. Our study brings relevant information on the treatment of carbapenem resistant GNB infections with C-A in our population. More studies, specifically RCTs are needed to prove the antibiotic efficacy in our media. Disclosures All Authors: No reported disclosures.

A nomogram for predicting the risk of mortality in patients with acute pancreatitis and Gram-negative bacilli infection.

Gram-negative bacilli (GNB) are common pathogens of infection in severe acute pancreatitis (SAP), and their occurrence increases the mortality of SAP. Early identification of SAP severity and prognosis is of great significance to SAP treatment. This study explored risk factors for mortality in patients with SAP and GNB infection and established a model for early prediction of the risk of death in GNB-infected SAP patients. Patients diagnosed with SAP from January 1, 2016, to March 31, 2022, were included, and their baseline clinical characteristics were collected. Univariate logistic regression analysis was performed to screen for death related variables, and concurrently, a Boruta analysis was performed to identify potentially important clinical features associated with mortality. The intersection of the two results was taken for further multivariate logistic regression analysis. A logistic regression model was constructed according to the independent risk factor of death and then visualized with a nomogram. The performance of the model was further validated in the training and validation cohort. A total of 151 patients with SAP developed GNB infections. Univariate logistic regression analysis identified 11 variables associated with mortality. The Boruta analysis identified 11 clinical features, and 4 out of 9 clinical variables: platelet counts (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.99-1.00; p = 0.007), hemoglobin (OR 0.96, 95% CI 0.92-1; p = 0.037), septic shock (OR 6.33, 95% CI 1.12-43.47; p = 0.044), and carbapenem resistance (OR 7.99, 95% CI 1.66-52.37; p = 0.016), shared by both analyses were further selected as independent risk factors by multivariate logistic regression analysis. A nomogram was used to visualize the model. The model demonstrated good performance in both training and validation cohorts with recognition sensitivity and specificity of 96% and 80% in the training cohort and 92.8% and 75% in the validation cohort, respectively. The nomogram can accurately predict the mortality risk of patients with SAP and GNB infection. The clinical application of this model allows early identification of the severity and prognosis for patients with SAP and GNB infection and identification of patients requiring urgent management thus allowing rationalization of treatment options and improvements in clinical outcomes.

Extended-spectrum β-lactamase-producing and carbapenem-resistant Enterobacterales bloodstream infection after solid organ transplantation: Recent trends in epidemiology and therapeutic approaches.

BackgroundInfections caused by multidrug‐resistant gram‐negative bacilli (MDR GNB), in particular extended‐spectrum β‐lactamase‐producing (ESBL‐E) and carbapenem‐resistant Enterobacterales (CRE), pose a major threat in solid organ transplantation (SOT). Outcome prediction and therapy are challenging due to the scarcity of randomized clinical trials (RCTs) or well‐designed observational studies focused on this population.MethodsNarrative review with a focus on the contributions provided by the ongoing multinational INCREMENT‐SOT consortium (ClinicalTrials identifier NCT02852902) in the fields of epidemiology and clinical management.ResultsThe 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) recently published their recommendations for the management of MDR GNB infections in SOT recipients. We revisit the SET/GESITRA‐SEIMC/REIPI document taking into consideration new evidence that emerged on the molecular epidemiology, prognostic stratification, and treatment of post‐transplant ESBL‐E and CRE infections. Results derived from the INCREMENT‐SOT consortium may support the therapeutic approach to post‐transplant bloodstream infection (BSI). The initiatives devoted to sparing the use of carbapenems in low‐risk ESBL‐E BSI or to repurposing existing non‐β‐lactam antibiotics for CRE in both non‐transplant and transplant patients are reviewed, as well as the eventual positioning in the specific SOT setting of recently approved antibiotics.ConclusionDue to the clinical complexity and relative rarity of ESBL‐E and CRE infections in SOT recipients, multinational cooperative efforts such as the INCREMENT‐SOT Project should be encouraged. In addition, RCTs focused on post‐transplant serious infection remain urgently needed.

A retrospective observational study of the treatment with polymyxin B for liver transplantation recipients infected by multidrug-resistant gram-negative bacteria.

Only a few studies about polymyxin B (PMB) against multidrug-resistant gram-negative bacteria (MDR GNB) infection were conducted in liver transplantation recipients (LTRs). The purpose of this study was to investigate the efficacy and safety of PMB in the treatment of MDR-GNB in liver transplant recipients and to determine the risk factors affecting clinical cure and 30-day all-cause mortality. Data of LTRs receiving PMB from January 2016 to February 2020 were collected. Clinical cure and 30-day all-cause mortality were the main efficacy outcomes, while the incidence of nephrotoxicity, neurotoxicity, and hyperpigmentation of PMB was the main safety outcome. Data of 42 LTRs were included. Clinical cure with PMB was observed in 27 recipients (64.3%), and the 30-day all-cause mortality rate was 31.0% (13/42). The incidence of acute kidney injury (AKI), neurotoxicity, and hyperpigmentation was 57.1% (16/28), 4.8% (2/42), and 16.7% (7/42), respectively. Logistic regression analysis showed that Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR, 1.203; 95% CI, 1.016-1.423, p= 0.032) was an independent risk factor for 30-day all-cause mortality, whereas renal replacement therapy (OR, 0.128; 95% CI, 0.019-0.860, p= 0.034) was an independent risk factor for clinical cure with PMB. This is the first study to evaluate the application of PMB in LTRs. If there were no better therapeutic options left for LTRs other than PMB, it can be used against MDR GNB infection in LTRs. We should closely observe adverse events or reactions, and adjust the dose based on the balance of efficacy and safety.

Risk factors for gram-negative infection of cardiovascular implantable electronic devices: retrospective multicenter study - CarDINe study

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Dr. Fabbricatore is supported by a research grant from the CardioPaTh PhD Program Background Gram-negative bacteria (GNB) are unfrequently isolated from patients with cardiac implantable electronic device (CIED) infection. However, data about risk factors for GNB-CIED-infection and associated clinical outcome are missing. Methods Multicenter, retrospective case-control-control study. Adult patients undergoing CIED implantation from Jan 2015 to Dec 2019 were included and classified as case (C) if diagnosed of GNB-CIED-infection; control 1 (C1) if diagnosed with Gram positive bacteria (GPB)-CIED infection; and control 2 (C2) if no CIED-infection was diagnosed during the study period. Patients were matched by center and risk period (from CIED implantation to infection diagnosis ±1 month), with a minimum follow-up period after infection diagnosis of 180 days. Results Study cohort consisted of 134 patients (33 C, 53 C1 and 42 C2) from 11 centers. Overall, 99 (73.9%) were male, median age 73 (IQR 66-81) years. Cardiac diseases leading to CIED implantation were bradi-arrythmia (48%), hearth failure (23.5), and primary prevention (20.6%). There were not differences for demographic variables and Charlson Index between C, C1 and C2. Time from implantation to infection diagnosis was similar between C and C1 [274 (39-621) vs 220 (58-866) days, p=0.581]. Shariff score was lower in C compared with C1 [1(1-2) vs 2 (1-3); p&amp;lt;0.001]. C reported more frequently than C1 a prior infection (not CIED related) (33% vs 16%, p=0.08). GN and GP causative agents of CIED-infection are depicted in Fig.1. No differences regarding CIED-infection type (pocket site, endocarditis) were observed between C and C1. Interestingly, PET-FDG was more frequently performed in C compared with C1 (41.2% vs 17%, p=0.013), with a trend toward higher yielding (83% vs. 50%, p=0.16). CIED extraction was performed in 79.4% and 92.5% (p=0.07) of C and C1, respectively. Length of stay was similar between groups [17 (7-39) vs23 (12-41) days, p=0.326]. 6-month survival was significantly lower in C compared with C1 and C2 at Kaplan Meier analysis (Fig.2). Conclusions GNB-CIED infection is associated with higher 6-month mortality than GPB- or no-CIED infections, prior GNB infection may favor subsequent GNB-CIED infection, the role of PET-FDG in diagnosing GNB-CIED infection seems to be key.

Potential Tamoxifen Repurposing to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli.

The development of new strategic therapies for multidrug-resistant bacteria, like the use of non-antimicrobial approaches and/or drugs repurposed to be used as monotherapies or in combination with clinically relevant antibiotics, has become urgent. A therapeutic alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune system modulation to improve the infection clearance. We showed that immunocompetent mice pretreated with tamoxifen at 80 mg/kg/d for three days and infected with Acinetobacter baumannii, Pseudomonas aeruginosa, or Escherichia coli in peritoneal sepsis models showed reduced release of the monocyte chemotactic protein-1 (MCP-1) and its signaling pathway interleukin-18 (IL-18), and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). This reduction of MCP-1 induced the reduction of migration of inflammatory monocytes and neutrophils from the bone marrow to the blood. Indeed, pretreatment with tamoxifen in murine peritoneal sepsis models reduced the bacterial load in tissues and blood, and increased mice survival from 0% to 60–100%. Together, these data show that tamoxifen presents therapeutic efficacy against MDR A. baumannii, P. aeruginosa, and E. coli in experimental models of infection and may be a new candidate to be repurposed as a treatment for GNB infections.

Predictive performance of critical illness scores and procalcitonin in sepsis caused by different gram-stain bacteria

OBJECTIVES:To compare the early and late predictive values of several critical illness scores (CISs) and biomarkers in sepsis-3 patients with bloodstream infections (BSIs) and to identify the prognostic value of procalcitonin (PCT) for different gram-stain bacteria infections.METHODS:Patients with at least one positive blood culture within 24h of emergency department admission and with a final diagnosis of sepsis/septic shock were enrolled. CISs were calculated based on the first parameters on the day of admission. The receiver operating characteristics curve was used to analyze the predictive value of CISs and biomarkers for early and late mortality.RESULTS:Of 834 enrolled patients with sepsis-3, death occurred in 214 patients within 28 days and in 273 patients within 60 days. Compared with biomarkers, CISs showed a significantly higher area under the curve (AUC) in the prediction of early and late mortality (p<0.01), especially for patients with GNB infection. The Sequential Organ Failure Assessment score showed a higher AUC for predicting early mortality than the Mortality in Emergency Department Sepsis score (p=0.036). Compared with GNB infections, the AUC values of the PCT for gram-positive bacteria (GPB) infections were higher for predicting early or late mortality; PCT showed higher AUC than high-sensitivity C-reactive protein and white blood cells for predicting early mortality (p<0.05).CONCLUSIONS:CISs were more advantageous in the assessment of early and late prognosis, especially for patients with GNB infections; however, for sepsis with GPB infection, PCT can be used for the prediction of early mortality.

Isolation and Molecular Characterization of Multi Drug Resistant Gram-Negative Bacteria from Clinical Samples in Tertiary Care Hospital, South India

Background and Aims Emergence of multi drug resistant MDR gram negative bacteria GNB is a serious threat and major challenge encountered by healthcare professionals. This study aimed to evaluate the distribution of antimicrobial resistance patterns in drug resistant GNB isolated at tertiary care hospital.Methods A total of 934 GNB strains were included in this study. Bacterial identification and disk diffusion testing were performed using standard microbiological techniques. Phenotypic detection of ESBL was assessed using double disk synergy test. Multiplex PCR assay was optimized to detect NDM-1 OXA-48 VIM IMP and KPC genes in carbapenem resistant GNB.Results The most common GNB identified were E. coli n46449.7 K. pneumoniae n13714.7 Acinetobacter Sp n13114 P. aeruginosa n11212 and Enterobacter Sp n313.3. Out of 934 isolates 808.6 were resistant to all tested antibiotics including carbapenems fluoroquinolones and aminoglycosides with high rate of resistant among Acinetobacter sp n454.8. On the other hand among 16818 carbapenem resistant isolates NDM-1 was most predominant in E. coli n2313.7 followed by K. pneumoniae n169.5 Acinetobacter Sp. n158.9 and P. aeruginosa n84.8. OXA-48 was most common in Acinetobacter Sp. n4124.4 followed by E. coli n74.2 and K. pneumoniae n63.6. Among 221 23.7 ESBL producing GNB E. coli n16717.9 was most common followed by K. pneumoniae n303.2 and Acinetobacter Sp n91.Conclusions The occurrence of bacterial infections caused by MDR-GNB and carbapenem resistant GNB infections is high. It is important for clinicians to evaluate and focus on the risk factors associated with the acquisition of MDR and carbapenem resistant organisms in hospital environment.

190. Osteomyelitis Following Mandibular Reconstruction with Free Fibula Flap: A Cohort Study of an Emerging and Complex Bone and Joint Infection

BackgroundFree fibular flap (FFF) mandible reconstruction is at high risk of complications due to patient comorbidities, microvascular surgery after neck irradiation and intrabuccal exposure. We aimed to describe clinical and microbiological features, management and outcome of osteomyelitis following mandibular reconstruction with FFF.MethodsPatients referred to our reference center for an osteomyelitis following FFF reconstruction of the mandible were included in a retrospective cohort. Microbiology was described based on gold-standard samples. Risk factors for treatment failure (infection persistence or relapse, need for additional surgery for septic reason, infection-related death) were assessed by logistic regression and Kaplan-Meier survival curve analysis.Results48 patients (age, 60.5 [IQR, 52.4–66.6]; 30 males; 62.5%; modified Charlson comorbidity index, 4 [3–5]) were included. Indications for FFF mandible reconstruction were mostly carcinoma (n=27; 56.3%) and osteoradionecrosis (n=12; 25.0%), with 44 (82.9%) previous neck irradiation. FFF osteomyelitis were mostly early (≤ 3 months post-surgery; n=43; 89.6%). Main symptoms were local inflammation (n=28; 59.6%), ununion or sinus tract (n=28; 59.6%), bone or device exposure (n=21; 44.7%), and were associated with radiological signs for infection in 33 (75.0%) cases. Microbiological documentation highlighted Enterobacteriaceae (n=25; 61.0%), Streptococcus spp. (n=22; 53.7%), S. aureus (n=10; 24.4%), anaerobes (n=10, 24.4%), Enterococcus spp. (n=9; 22.0%) and non-fermenting Gram negative bacilli (GNB; n=8; 19.5%). Thirty-nine (81.3%) required surgery, consisting in debridement with implant retention in 25 (64.1%) cases, associated with a 93 (64–128) day course of antibiotherapy. After a follow-up of 18 (11–31) months, 24 (50.0%) treatment failure were observed. An early ID-specialist referral was the only significant predictor of favorable outcome (OR, 0.167; p=0.005). Non-fermenting GNB infections tended to be associated with a higher risk of failure (OR, 8.4; p=0.058).Probability of treatment failure of osteomyelitis following FFF mandible reconstruction according to ID-referral (A), CRP level 2 weeks after surgery (B) and presence of non-fermenting GNB ConclusionOsteomyelitis following mandibular reconstruction with FFF represent difficult-to-treat infections. Our results advocate for a multidisciplinary management, including an early ID-specialist referral.Disclosures All Authors: No reported disclosures

Effect of Short-Term Carbapenem Restriction on Antimicrobial Susceptibility of Resistant Gram-Negative Bacilli in an ICU

Background: Carbapenem-resistant GNB infections are a serious public health problem worldwide, particularly due to the high mortality associated with them and the low number of therapeutic options. One approach to this challenge is the development of antimicrobial stewardship programs. Objective: We evaluated the impact of a carbapenem restriction program on reducing of bacterial resistance in an intensive care unit (ICU). Methods: A retrospective study conducted in 2 phases in the 80-bed ICU of an acute-care public hospital in Minas Gerais, Brazil. The preintervention phase lasted 16 months (January 2018–April 2019) and the second phase (carbapenem restriction), after the intervention, lasted 4 months (May–August 2019). The intervention was defined as carbapenem-sparing and the use of meropenem was authorized in 3 situations: (1) treatment of serious infections documented by extended-spectrum β-lactamase–producing Enterobacteriacea (ESBL); (2) therapeutic failure with the use of another antimicrobial; and (3) infectious disease recommendation. Data were obtained through consultation of electronic medical records and microbiological results, as standardized by the CLSI, for patients with a &gt;48-hour stay in the ICU and who met the criteria for healthcare-associated infection (HAI) according to the CDC NHSN definition. Results: Before the intervention, on average, 50 cultures were obtained with positive results for multidrug-resistant GNB–MER-GNB (SD, 12.2) and in the intervention phase, this number was 31 cultures (SD, 12.8; P = .010). Average carbapenem consumption decreased significantly with corresponding increase in cefepime consumption in the same period (Fig. 1). The ATB (DDD per 1,000 patient days) before the intervention for carbapenems was 110.6 (SD, 97.1) and for cefepime was 8.2 (SD, 5.9). In the intervention phase, the ATB for carbapenems was 44.7 (SD, 38.5; P = .015) and for cefepime it was 32.0 (SD, 20.3; P &lt; .001). In terms of multidrug resistance rate, before the intervention, 95 of 149 of Acinetobacter (64%) were resistant and during the intervention, 13 of 30 Acinetobacter (43%) were resistant (P = .043). Other GNB (Klebsiella, Proteus, Escherichia coli, and Pseudomonas) reduced the resistance rate, but without statistical significance. We observed a reduction in the HAI rate per MDR-GNB (Fig. 2): before the intervention, it was 22.7 (SD, 5.5) and during the intervention phase it was 16.5 (SD, 7.7; P = .07), although this change did not reach statistical significance. Nevertheless, the ICU Klebsiella infection rate did significantly decrease; it was 5.5 (SD, 1.9) before the intervention and 2.4 (SD, 1.8) after the intervention (P = .009). Conclusions: Short-term carbapenem restriction may be an effective strategy to reduce the incidence of carbapenem-resistant GNB infections in the ICU. The scarce arsenal available for the treatment of MDR-GNB and the high mortality rate justify the growing need for stewardship programs in Brazilian ICUs.Funding: NoneDisclosures: None

The role of carbapenem-resistant pathogens in cSSTI and how to manage them.

Skin and soft tissue infections (SSTIs) with a wide spectrum of disease severity ranging from uncomplicated to potentially lethal are still a leading cause of morbidity and mortality. The burden of carbapenem-resistant gram-negative bacteria (CR-GNB) in SSTIs is increasing. Luckily, the armamentarium of drugs available is recently expanding as well. The present review looks at data on the role CR-GNB in SSTIs and on the old and new drugs available for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas, and Acinetobacter. The most recent information concern the availability of new antibiotics that, even if no specific clinical trials on complicated SSTIs (cSSTIs) have been performed, may play a role in clinical practice also for the treatment of cSSTIs caused by CR-GNB. Ceftolozane-tazobactam has been found to be a good option for CR Pseudomonas infections including SSTIs. Ceftazidime-avibactam is approved for several indications, including aerobic GNB infections with limited treatment options. Meropenem-vaborbactam therapy has been associated with decreased mortality in infections caused by CRE. Eravacycline has the potential to become useful for the treatment of CR Acinetobacter for which the treatment options are limited. In the carbapenem resistance era, the physicians goal should be to stratify patients according to risk factors for CR-GNB causing SSTIs in order to minimize inappropriate initial therapies. Some recently approved drugs seem destined to become the backbone of target therapy in patients with severe infections caused by susceptible CR-GNB strains. Prompt diagnosis of cSSTIs is crucial and, when feasible, surgical debridement as source control is essential as well.

Detection and Characterization of Nosocomial Carbapenem - Resistant Gram Negative Bacilli from Assuit University Hospitals

Background: Carbapenem resistant gram negative bacilli (CRGNB) pose significant risks. They are difficult to detect, they have a role in unnoticed spread within hospitals and they are able to participate in horizontal gene transfer with other pathogens in hospitals. Objectives: This study was conducted to determine the frequency of carbapenem resistance among nosocomial GNB infections, to compare different phenotypic methods to PCR for accurate detection of CRGNB isolates, to define the risk factors for carbapenem resistance in GNB infections and to define possible treatment alternatives for CRGNB. Methodology: Three hundred fifty five specimens were collected from 134 nosocomially infected patients admitted to different hospital wards at Assuit University Hospitals. Phenotypic identification of CRGNB isolates were performed by antimicrobial susceptibility testing. Further confirmation and biotyping were done by API20E and API20NE kits. Phenotypic detection of carbapenemases was done by determination of MIC by Imipenem-E test and Meropenem-E test, CHROM agar KPC TM medium, modified Hodge test (MHT), combined disc method (CD), double disc synergy test (DDST).The isolated CRGNB were further identified genetically using the conventional polymerase reaction (PCR). Results: out of total 745 isolates, GNB represented 47.9%. Ninety seven isolates of GNB (27.17%) were resistant to carbapenems. All CRGNB isolates were tested by PCR for detection of bla genes (bla kpc, bla IMP-1, bla VIM-1 and bla oxa 48). 32.84% isolates were positive to bla KPC gene only, 17.92% were positive to bla IMP-1 gene only, 16.42% were positive to bla VIM-1 gene only, 13.43% were positive to both bla IMP-1 and bla VIM-1 genes, 7.46% were positive to bla OXA-48 gene only, 7.46% were positive to bla KPC and bla IMP-1 / bla VIM-1 and 4.47% strains were positive to bla KPC, bla IMP-1 / bla VIM-1 and bla OXA-48. Comparing the different phenotypic methods used for detection of CRGNB to PCR, E-test had 100% sensitivity and 93.33% specificity, DDST had 100% sensitivity and 96.67% specificity, CD test had 100% sensitivity and 23.33% specificity, CHROM agar KPC medium had 88.06% sensitivity and 73.33% specificity and MHT had 98.5% sensitivity and 60% specificity. In this study, both tigecycline and colistin were the most effective antimicrobial agents against carbapenem resistant GNB strains. Conclusions: resistance to carbapenems raises a significant alarm signal to put the possibility of carbapenem resistant pathogens as an important cause of worsening the patient condition especially in ICUs. DDST can be used as a convenient screening method in microbiology laboratories but genetic confirmation by PCR and analysis of carbapenemases producers is mandatory for positive isolates.