Cefiderocol for treating severe aerobic Gram-negative bacterial infections: technology evaluation to inform a novel subscription-style payment model.

Background: To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of cefiderocol in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform the National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. Methods: The health benefit of cefiderocol was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients' mortality risks and health-related quality of life. The clinical effectiveness of cefiderocol relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. Patient-level costs and health outcomes of cefiderocol under various usage scenarios compared with alternative management strategies were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population values using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for cefiderocol. Results: Among Enterobacterales isolates with the metallo-beta-lactamase resistance mechanism, the base-case network meta-analysis found that cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.32, 95% credible intervals 0.04 to 2.47), but the result was not statistically significant. The other treatments were also associated with lower susceptibility than colistin, but the results were not statistically significant. In the metallo-beta-lactamase Pseudomonas aeruginosa base-case network meta-analysis, cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.44, 95% credible intervals 0.03 to 3.94), but the result was not statistically significant. The other treatments were associated with no susceptibility. In the base case, patient-level benefit of cefiderocol was between 0.02 and 0.15 quality-adjusted life-years, depending on the site of infection, the pathogen and the usage scenario. There was a high degree of uncertainty surrounding the benefits of cefiderocol across all subgroups. There was substantial uncertainty in the number of infections that are suitable for treatment with cefiderocol, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time and rates of emergence of resistance. The population-level benefits varied substantially across the base-case scenarios, from 896 to 3559 quality-adjusted life-years over 20 years. Conclusion: This work has provided quantitative estimates of the value of cefiderocol within its areas of expected usage within the NHS. Limitations: Given existing evidence, the estimates of the value of cefiderocol are highly uncertain. Future work: Future evaluations of antimicrobials would benefit from improvements to NHS data linkages; research to support appropriate synthesis of susceptibility studies; and application of routine data and decision modelling to assess enablement value. Study registration: No registration of this study was undertaken. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Policy Research Programme (NIHR award ref: NIHR135591), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 28. See the NIHR Funding and Awards website for further award information.

This project tested new methods for estimating the value to the NHS of an antimicrobial, cefiderocol, so its manufacturer could be paid fairly even if very little drug is used in order to reduce the risk of bacteria becoming resistant to the product. Clinicians said that the greatest benefit of cefiderocol is when used for complicated urinary tract infections and pneumonia acquired within hospitals caused by two types of bacteria (called Enterobacterales and Pseudomonas aeruginosa), with a resistance mechanism called metallo-beta-lactamase. Because there were no relevant clinical trial data, we estimated how effective cefiderocol and alternative treatments were by doing a systematic literature review of studies that grew bacteria from infections in the laboratory and tested the drugs on them. We linked this to data estimating the long-term health and survival of patients. Some evidence was obtained by asking clinicians detailed questions about what they thought the effects would be based on their experience and the available evidence. We included the side effects of the alternative treatments, some of which can cause kidney damage. We estimated how many infections there would be in the UK, whether they would increase over time and how resistance to treatments may change over time. Clinicians told us that they would also use cefiderocol to treat intra-abdominal and bloodstream infections, and some infections caused by another bacteria called Stenotrophomonas. We estimated how many of these infections there would be, and assumed the same health benefits as for other types of infections. The total value to the NHS was calculated using these estimates. We also considered whether we had missed any additional elements of value. We estimated that the value to the NHS was £18­71 million over 20 years. This reflects the maximum the NHS could pay for use of cefiderocol if the health lost as a result of making these payments rather than funding other NHS services is not to exceed the health benefits of using this antimicrobial. However, these estimates are uncertain due to limitations with the evidence used to produce them and assumptions that had to be made.

Factors Affecting the Effectiveness and Safety of Polymyxin B in the Treatment of Gram-negative Bacterial Infections: A Meta-Analysis of 96 Articles.

PURPOSE: Polymyxin B, with its unique structure and mechanism of action, has emerged as a key therapeutic agent against Gram-negative bacteria. The study aims to explore potential factors to influence its effectiveness and safety. METHODS: A Model-Based Meta-Analysis (MBMA) of 96 articles was conducted, focusing on factors like dosage, bacterial species, and combined antibiotic therapy. The analysis evaluated mortality rates and incidence rate of renal dysfunction, also employing parametric survival models to assess 30-day survival rates. RESULTS: In the study involving 96 articles and 9,716 patients, polymyxin B's daily dose showed minimal effect on overall mortality, with high-dose group mortality at 33.57% (95% CI: 29.15-38.00) compared to the low-dose group at 35.44% (95% CI: 28.99-41.88), p=0.64. Mortality significantly varied by bacterial species, with Pseudomonas aeruginosa infections at 58.50% (95% CI: 55.42-63.58). Monotherapy exhibited the highest mortality at 40.25% (95% CI: 34.75-45.76), p<0.01. Renal dysfunction was more common in high-dose patients at 29.75% (95% CI: 28.52-30.98), with no significant difference across antibiotic regimens, p=0.54. The 30-day Overall Survival rate for monotherapy therapy was 63.6% (95% CI: 59.3-67.5) and 70.2% (95% CI: 64.4-76.2) for association therapy with ß-lactam drugs. CONCLUSIONS: The dosage of Polymyxin B doesn't significantly change death rates, but its effectiveness varies based on the bacterial infection. Certain bacteria like Pseudomonas aeruginosa are associated with higher mortality. Combining Polymyxin B with other antibiotics, especially ß-lactam drugs, improves survival rates. Side effects depend on the dose, with lower doses being safer. These findings emphasize the importance of customizing treatment to balance effectiveness and safety.

Acute suppurative terminal cholangitis: Clinical characteristics of a new subtype of acute cholangitis.

BACKGROUND: Acute suppurative terminal cholangitis (ASTC) is rarer than acute obstructive cholangitis and is not well studied. To explore this subtype of acute cholangitis, we described our clinical experience with ASTC. METHODS: We performed a retrospective review of patients with ASTC admitted to our center from September 2014 to August 2020. We analyzed their clinical characteristics, including etiology, clinical manifestations, imaging features, treatment and prognosis. RESULTS: A total of 32 ASTC patients were included in the analysis. The majority of the patients had a history of biliary operations, and clinical manifestations were occult and atypical. The positive rate of bacterial culture was 46.9%. All the patients had typical imaging features on computed tomography and magnetic resonance imaging. Treatment with effective antibiotics was provided as soon as diagnosis was established. After treatment, most patients had a good outcome. Elevated levels of total bilirubin, aspartate aminotransferase, procalcitonin and gamma-glutamyltransferase were the characteristics of critically ill patients and were associated with relatively poor prognosis. CONCLUSIONS: Our results demonstrated that ASTC should be recognized as a new subtype of acute cholangitis, and that earlier diagnosis and more personalized treatments are needed.

Metagenomic next-generation sequencing for the identification of infections caused by Gram-negative pathogens and the prediction of antimicrobial resistance.

OBJECTIVE: The aim of this study was to evaluate the efficacy of metagenomic next-generation sequencing (mNGS) for the identification of Gram-negative bacteria (GNB) infections and the prediction of antimicrobial resistance. METHODS: A retrospective analysis was conducted on 182 patients with diagnosis of GNB infections who underwent mNGS and conventional microbiological tests (CMTs). RESULTS: The detection rate of mNGS was 96.15%, higher than CMTs (45.05%) with a significant difference (χ 2 = 114.46, P < .01). The pathogen spectrum identified by mNGS was significantly wider than CMTs. Interestingly, the detection rate of mNGS was substantially higher than that of CMTs (70.33% vs 23.08%, P < .01) in patients with but not without antibiotic exposure. There was a significant positive correlation between mapped reads and pro-inflammatory cytokines (interleukin-6 and interleukin-8). However, mNGS failed to predict antimicrobial resistance in 5 of 12 patients compared to phenotype antimicrobial susceptibility testing results. CONCLUSIONS: Metagenomic next-generation sequencing has a higher detection rate, a wider pathogen spectrum, and is less affected by prior antibiotic exposure than CMTs in identifying Gram-negative pathogens. The mapped reads may reflect a pro-inflammatory state in GNB-infected patients. Inferring actual resistance phenotypes from metagenomic data remains a great challenge.

Network meta-analysis of antibiotic resistance patterns in gram-negative bacterial infections: a comparative study of carbapenems, fluoroquinolones, and aminoglycosides.

Introduction: Antimicrobial resistance poses a grave global threat, particularly with the emergence of multidrug-resistant gram-negative bacterial infections, which severely limit treatment options. The increasing global threat of antimicrobial resistance demands rigorous investigation, particularly concerning multidrug-resistant gram-negative bacterial infections that present limited therapeutic options. This study employed a network meta-analysis, a powerful tool for comparative effectiveness assessment of diverse antibiotics. The primary aim of this study was to comprehensively evaluate and compare resistance patterns among widely used antibiotic classes, namely carbapenems, fluoroquinolones, and aminoglycosides, for combating gram-negative pathogens. Methods: We searched PubMed, Web of Sciences, Scopus, Scholarly, Medline, Embase, and Cochrane databases up to August 27, 2023. Studies showing antibiotic resistance in clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii exposed to carbapenems, fluoroquinolones, and aminoglycosides were included. This study determined treatment-specific resistance percentages and ranked these treatments based on resistance using a random-effects network meta-analysis technique. To investigate the impact of the study and pathogen features, subgroup and meta-regression analyses were performed. Risk ratios and 95% confidence intervals (CIs) were calculated using a network meta-analysis (NMA) incorporating both direct and indirect evidence. Clinical improvement, cure, microbiological eradication, and death from any cause were the primary outcomes. Nephrotoxicity was a secondary result. Results: The analysis included 202 publications and 365,782 gram-negative isolates. The NMA included data from 20 studies and 4,835 patients. Carbapenems had the lowest resistance rates throughout the pathogen spectrum, with resistance percentages of 17.1, 22.4, and 33.5% for Enterobacteriaceae, P. aeruginosa, and A. baumannii, respectively. For the same infections, aminoglycosides showed resistance rates of 28.2, 39.1, and 50.2%, respectively. Fluoroquinolones had the highest resistance rates at 43.1, 57.3, and 65.7%, respectively. Unexpectedly, resistance to all three antibiotic classes has increased over time, with multidrug resistance being the most prevalent. Conclusion: This extensive network meta-analysis provides an overview of the patterns of resistance throughout the world and how they are changing. The most effective choice is still carbapenems, but the increasing resistance highlights the critical need for multimodal therapies to protect antibiotic effectiveness against these powerful gram-negative infections.

Comparison of the clinical efficacy and toxicity of nebulized polymyxin monotherapy and combined intravenous and nebulized polymyxin for the treatment of ventilator-associated pneumonia caused by carbapenem-resistant gram-negative bacteria: a retrospective cohort study.

Objective: To investigate the clinical efficacy and toxicity of nebulized polymyxin monotherapy and combined intravenous and nebulized polymyxin for the treatment of VAP caused by CR-GNB. Additionally, among patients treated with nebulized polymyxin monotherapy, we compared the clinical efficacy and toxicity of polymyxin B and polymyxin E. Methods: This study was a single-center, retrospective study. Included patients received aerosolized polymyxin for at least 72 h with or without intravenous polymyxin for the management of CR-GNB VAP. The primary endpoint was clinical cure at the end of polymyxin therapy. Secondary endpoints included AKI incidence, time of bacteria-negative conversion, duration of MV after inclusion, length of stay in ICU, and all-cause ICU mortality. Results: 39 patients treated with nebulized polymyxin monotherapy were assigned to the NL-polymyxin group. 39 patients treated with nebulized polymyxin combined with intravenous use of polymyxin were assigned to the IV-NL-polymyxin group. Among the NL-polymyxin group, 19 patients were treated with polymyxin B and 20 with polymyxin E. The clinical baseline characteristics before admission to the ICU and before nebulization of polymyxin were similar between the two groups. No differences were found between the two study groups in terms of microorganism distribution, VAP cure rate, time of bacteria-negative conversion, duration of MV after inclusion, length of stay in ICU and all-cause ICU mortality. Similarly, survival analysis did not differ between the two groups (χ2 = 3.539, p = 0.06). AKI incidence was higher in the IV-NL-polymyxin group. When comparing the clinical efficacy and toxicity to polymyxin B and polymyxin E, there was no difference between the two groups in terms of VAP cure rate, time of bacteria-negative conversion, duration of MV after inclusion, length of stay in ICU, SOFA score, CPIS, AKI incidence and all-cause ICU mortality. Conclusion: Our study found that nebulized polymyxin monotherapy was non-inferior to combination therapy with intravenous polymyxin in treating CR-GNB-VAP. Furthermore, we observed no differences in clinical efficacy or related toxic side effects between polymyxin B and polymyxin E during nebulized polymyxin therapy as monotherapy. However, future prospective studies with larger sample sizes are required to confirm these findings.

Clinical Impact of Oral Step-Down Therapy for Gram-Negative Bacteremia: A Retrospective Study.

Background: In recent years, there has been a growing body of evidence that supports oral step-down therapy for the treatment of gram-negative bacteremia. The purpose of this study was to compare outcomes for hospitalized patients who received intravenous-only (IV-only) therapy versus oral step-down therapy with low, moderate, and highly bioavailable antimicrobials for the treatment of gram-negative bacteremia. Methods: In this retrospective, single-center, observational study, we examined data from adult patients hospitalized with gram-negative bacteremia in a 1-year period. Data analysis was performed using information collected from electronic medical records and a clinical surveillance system. Results: A total of 199 patients were included in this study. Patients in the IV-only group had higher Charlson comorbidity index scores at baseline and higher rates of intensive care unit admission while bacteremic (P = .0096 and .0026, respectively). The primary outcome of 30-day all-cause mortality was significantly lower in the oral step-down group (P < .0001). Secondary outcomes of 30-day bacteremia recurrence, line-associated complications, and hospital length of stay were similar between groups. The total duration of antibiotic therapy was one day longer for oral step-down patients (P = .0015) and the estimated cost of antibiotic therapy was significantly lower in this group (P < .00001). Conclusion: In this retrospective study, oral step-down therapy was not associated with increased 30- day all-cause mortality. Oral step-down therapy was also more cost-effective than IV-only therapy, while both groups had similar bacteremia recurrence within 30 days.

Frecuencia de Bacilos Gram Negativos en la cavidad bucal de estudiantes de una Universidad de Asunción

Introducción: La cavidad bucal hospeda una gran cantidad de microorganismos, como los bacilos Gram negativos, y entre ellas, bacterias de gran importancia médica debido a su capacidad de producir enfermedades graves para el ser humano, especialmente en pacientes inmunodeprimidos. El objetivo de este trabajo fue determinar la presencia de Bacilos Gram Negativos y sus patrones de resistencia a antibióticos, en una población estudiantil de la ciudad de Asunción, en los años 2019 y 2020. Materiales y métodos: Se realizó un estudio observacional, descriptivo de corte transversal, donde se realizaron hisopados de la cavidad bucal a 35 alumnos de entre 18 a 24 años, de una universidad privada en la ciudad de Asunción. Se requirió consentimiento informado firmado por los participantes y fueron excluidos quienes tuvieron tratamientos antibióticos. Las muestras fueron obtenidas con un hisopo de algodón, posteriormente se colocaron en un medio de transporte para luego ser cultivadas en Agar MacConkey. El cultivo se realizó por 48 horas a 37° centígrados, luego se procedió a la identificación bacteriana. Por último, se realizó el antibiograma. Resultados: De los 35 alumnos se encontró una frecuencia de 48,57% de bacilos Gram negativos. Cepas de Klebsiella pneumoniae fueron las más frecuentes (35,29%). Se observó que las bacterias eran altamente resistentes a la Amoxicilina/Ácido Clavulánico. Conclusiones: La presencia de estos tipos de microorganismos puede ser peligrosa para la salud general de las personas, específicamente de los pacientes con algún tipo de inmunodepresión, debido a la gran la resistencia a antibióticos presentadas por algunas cepas.

Introduction: The oral cavity hosts a large number of microorganisms, such as Gram negative bacilli, and among them, bacteria of great medical importance due to their capacity to cause serious diseases for humans, especially in immunosuppressed patients. The objective of this work was to determine the presence of Gram Negative Bacilli and their patterns of resistance to antibiotics, in a student population of the city of Asunción, in the years 2019 and 2020. Materials and methods: An observational, descriptive cross-sectional study was carried out, where oral cavity swabs were made from 35 students between 18 and 24 years of age, from a private university in the city of Asunción. Informed consent signed by the participants was required and those who had antibiotic treatments were excluded. The samples were obtained with a cotton swab, later they were placed in a transport medium to later be cultured in MacConkey Agar. The culture was carried out for 48 hours at 37° Celsius, then the bacterial identification was carried out. Finally, the antibiogram was performed. Results: Of the 35 students, a frequency of 48,57% of Gram negative bacilli was found. Klebsiella pneumoniae strains were the most frequent (35.29%). The bacteria were found to be highly resistant to Amoxicillin/Clavulanic Acid. Conclusions: The presence of these types of microorganisms can be dangerous for the general health of people, specifically of patients with some type of immunosuppression, due to the great resistance to antibiotics presented by some strains.

Antibiotic appropriateness for Gram-negative bloodstream infections: impact of infectious disease consultation.

BACKGROUND: We investigated the role of infectious disease consultation (IDC) on therapeutic appropriateness in Gram-negative bloodstream infections (GNBSIs) in a setting with a high proportion of antibiotic resistance. Secondary outcomes were in-hospital mortality and the impact of rapid diagnostic tests (RDTs). METHODS: Retrospective study on hospitalised patients with GNBSIs. Therapy was deemed appropriate if it had the narrowest spectrum considering infection and patients' characteristics. Interventional-IDC (I-IDC) group included patients with IDC-advised first appropriate or last non-appropriate therapy. Time to first appropriate therapy and survival were evaluated by Kaplan-Meier curves. Factors associated with therapy appropriateness were assessed by multivariate Cox proportional-hazard models. RESULTS: 471 patients were included. High antibiotic resistance rates were detected: quinolones 45.5%, third-generation cephalosporins 37.4%, carbapenems 7.9%. I-IDC was performed in 31.6% of patients (149/471), RDTs in 70.7% (333/471). The 7-day probability of appropriate treatment was 91.9% (95% confidence interval [95%CI]: 86.4-95.8%) vs. 75.8% (95%CI: 70.9-80.4%) with and without I-IDC, respectively (p-value = 0.0495); 85.5% (95%CI: 81.3-89.1%) vs. 69.4% (95%CI: 61.3-77.2%) with and without RDTs, respectively (p-value = 0.0023). Compared to RDTs alone, the combination with I-IDC was associated with a higher proportion of appropriate therapies at day 7: 81.9% (95%CI: 76.4-86.7%) vs. 92.6% (95%CI: 86.3-96.7%). At multivariate analysis, I-IDC and RDTs were associated with time to first appropriate therapy [adjusted hazard-ratio 1.292 (95%CI: 1.014-1.647) and 1.383 (95%CI: 1.080-1.771), respectively], with no impact on mortality. CONCLUSIONS: In a setting with a high proportion of antibiotic resistance, IDC and RDTs were associated with earlier prescription of appropriate therapy in GNBSIs, without impact on mortality.

Probability of Target Attainment Analyses to Inform Ceftolozane/Tazobactam Dosing Regimens for Patients With Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia and End-Stage Renal Disease Receiving Intermittent Hemodialysis.

ASPECT-NP, a phase 3 trial of ceftolozane/tazobactam in hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), excluded patients with end-stage renal disease (ESRD). A modeling/simulation approach was undertaken to inform optimal dosing in this population, using previously developed ceftolozane and tazobactam population pharmacokinetic models informed by data from 16 clinical studies. Stochastic simulations were performed using NONMEM to support dose justification. Probability of target attainment (PTA) simulations in plasma and epithelial lining fluid were conducted using a 14-day treatment, with hemodialysis every other weekday for a high-dose (4X), middle-dose (3X), or low-dose (2X) regimen, where X was the recommended dose in patients with complicated intra-abdominal infection/complicated urinary tract infection and ESRD (500 mg/250 mg ceftolozane/tazobactam loading dose and 100 mg/50 mg ceftolozane/tazobactam maintenance dose administered by 1-hour infusion every 8 hours). PTA was determined using established pharmacokinetic/pharmacodynamic targets: ceftolozane, 30% of the interdose interval (8 hours) in which free ceftolozane concentration exceeded the minimum inhibitory concentration value of 4 µg/mL; tazobactam, 20% of the interdose interval in which free tazobactam concentration exceeded 1 µg/mL. Plasma PTA was >90% for both agents for all 3 regimens. Plasma ceftolozane exposures at the high-dose regimen exceeded those from phase 3 study experience. Epithelial lining fluid PTA was >90% for high- and middle-dose regimens but was <80% for tazobactam on dialysis days at the low-dose regimen. For patients with HABP/VABP and ESRD requiring intermittent hemodialysis, the middle-dose regimen of 1.5 g/0.75 g ceftolozane/tazobactam loading + 300 mg/150 mg maintenance every 8 hours by 1-hour infusion is recommended.

Infección urinaria de presentación atípica: caso clínico y revisión de literatura

Introducción: el síndrome de orina púrpura es una presentación clínica poco frecuente en el ámbito de urgencias, caracterizado por coloración anormal de la orina secundaria a una reacción química de algunos patógenos que producen infección de vías urinarias, siendo más frecuente en pacientes con múltiples comorbilidades y diferentes factores de riesgo. Objetivo: el objetivo de este manuscrito es presentar el caso de un paciente con síntomas atípicos de infección de vías urinarias. Presentación del caso: varón de 88 años de edad, con antecedente de diabetes mellitus no insulino-requiriente, con hiperplasia prostática benigna que ingresó al servicio de urgencias por síntomas irritativos urinarios asociados a uso de sonda vesical, con orina de coloración violeta en bolsa recolectora. El urocultivo reportó la presencia de Proteus vulgaris multisensible, por lo que se decidió dar manejo con cefepima de 1 gr cada ocho horas, con lo cual se obtuvo una adecuada evolución clínica. Discusión y conclusión: el síndrome de la bolsa de orina púrpura es una presentación clínica atípica, pero muy llamativa de la infección urinaria. Esta se genera como resultado de la conversión del triptófano en la dieta en indoxil sulfato que, una vez se elimina por la orina, se transforma en índigo (color violeta) e indirrubina (color rojo), dando este aspecto clínico.

Background: Purple urine syndrome is a rare clinical presentation in the emergency room, characterized by abnormal colouration of the urine secondary to a chemical reaction of some pathogens that cause urinary tract infection, being more frequent in patients with multiple comorbidities and different risk factor's. Purpose: The objective of the article is present the case of a patient with atypical symptoms of urinary tract infection. Clinical case: An 88-year-old male, with a history of non-insulin diabetes mellitus, benign prostatic hyperplasia, who was admitted to the emergency room due to irritative urinary symptoms associated with the use of a urinary catheter, with purple urine in a collection bag. Urine culture reported the presence of multisensitive Proteus vulgaris, for which it was decided to give treatment with Cefepime 1 g every 8 hours, with which it was obtained with adequate clinical evolution. Conclusions: Purple urine bag syndrome is an atypical but very striking clinical presentation of urinary tract infection. This is generated as a result of the conversion of tryptophan in the diet into indoxyl sulfate, which, once it is eliminated in the urine, transforms into indigo (purple color) and indirubin (red color), giving this clinical appearance.

Systematic review on efficacy of preventive measures for surgical site infection by multiple-drug resistant gram-negative bacilli.

BACKGROUND: There are no specific recommendations for prevention of surgical site infection (SSI) caused by multidrug resistant Gram-negative bacilli (MDR-GNB). Our objective was to systematically review the literature evaluating the efficacy and safety of measures specifically designed to prevent MDR-GNB SSI. METHODS: We searched MEDLINE, EMBASE, CINAHL and LILACS databases up to February 18, 2020. Randomized trials and observational cohort studies evaluating the efficacy of preventive measures against MDR-GNB SSI in adult surgical patients were eligible. We evaluated methodological quality of studies and general quality of evidence using Newcastle-Ottawa scale, Cochrane ROBINS-I and GRADE method. Random-effects meta-analyses were performed using Review Manager V.5.3 software. RESULTS: A total of 10,663 titles by searching databases were identified. Two retrospective observational studies, comparing surgical antibiotic prophylaxis (SAP) with or without aminoglycoside in renal transplantation recipients, and one non-randomized prospective study, evaluating ertapenem vs. cephalosporin plus metronidazole for SAP in extended spectrum beta-lactamase producing Enterobacteriales carriers undergoing colon surgery, were included. Risk of bias was high in all studies. Meta-analysis was performed for the renal transplantation studies, with 854 patients included. Combined relative risk (RR) for MDR GNB SSI was 0.57 (95%CI: 0.25-1.34), favoring SAP with aminoglycoside (GRADE: moderate). CONCLUSIONS: There are no sufficient data supporting specific measures against MDR-GNB SSI. Prospective, randomized studies are necessary to assess the efficacy and safety of SAP with aminoglycoside for MDR-GNB SSI prevention among renal transplantation recipients and other populations. PROSPERO 2018 CRD42018100845.

[Current status of antimicrobial resistance in pediatric population in a Mexican hospital]. / Estado actual de resistencia antimicrobiana en población pediátrica en un hospital de México.

Background: Today bacterial resistance is a global problem, it is estimated that in 2050 it could reach 10 million deaths per year. Bacterial resistance can be caused by different mechanisms, in the case of beta-lactams they include the production of flow pumps, the modification or reduction of porin production, alteration of penicillin-binding proteins and production of an enzyme capable of inactivating the antibiotic. Objective: To describe the main bacterial agents reported in the Hospital para el Niño de Toluca and their sensitivity pattern. Material and methods: This is an observational, descriptive, retrospective cohort study, evaluated from January 1, 2018 to December 31, 2020, in hospitalized patients under 18 years of age, with confirmed infections from blood culture specimens, urine culture, fluid cerebrospinal and secretions. Results: 599 patients with positive cultures were reported. The five most frequently isolated agents were Staphylococci aureus, Escherichia coli, Klebsiella sp, Candida sp and Enterococci sp, Pseudomonas third in frequency in 2019 and fifth in 2020. The main isolated gram positive coconut was S. epidermidis with 52.3% in 2020 , while the BGN report an increase in positive ESBL organisms by 21.5% for 2020. Conclusions: S aureus, E coli, Klebsiella, Candida, and pseudomonas remain the main causative agents of infection. The GNBs showed an increase in frequency up to 21.5%, showing high resistance in fourth grade cephalosporins, gentamicin, ciprofloxacin and meropenem.

Introducción: hoy en día, la resistencia bacteriana es un problema mundial, se estima que en 2050 podría llegar a 10 millones de muertes por año. La resistencia bacteriana puede ser causada por diferentes mecanismos, en el caso de los betalactámicos incluyen la producción de bombas de flujo, la modificación o reducción de producción de porinas, alteración de las proteínas de unión a penicilina y producción de una enzima capaz de inactivar el antibiótico. Objetivo: describir los principales agentes bacterianos reportados en el Hospital para el Niño de Toluca y su patrón de sensibilidad. Material y métodos: se trata de un estudio observacional, descriptivo de cohorte retrospectivo, evaluado del 01 de enero 2018 al 31 de diciembre del 2020, en pacientes menores de 18 años hospitalizados, con infecciones confirmadas a partir de especímenes de hemocultivo, urocultivo, líquido cefalorraquídeo y secreciones. Resultados: se reportaron 599 pacientes con cultivos positivos. Los cinco agentes aislados con mayor frecuencia fueron Estafilococos aureus, Escherichia coli, Klebsiella sp, Candida sp y Enterococcus sp, pseudomonas tercer lugar en frecuencia en 2019 y quinto en 2020. El principal coco gram positivo aislado fue S. epidermidis con 52.3% en 2020, mientras que los BGN reportan un alza de los organismos BLEE positivos en 21.5% para 2020. Conclusiones: se mantienen como principales agentes causantes de infección S aureus, E coli, Klebsiella, Candida, enterococos y pseudomonas. Los BGN mostraron un incremento de frecuencia hasta 21.5%, mostrando resistencia alta en cefalosporinas de cuarta, gentamicina, ciprofloxacino y meropenem.

Effectiveness and Nephrotoxicity of Intravenous Polymyxin B in Carbapenem-Resistant Gram-Negative Bacterial Infections Among Chinese Children.

Background: No clinical study on the use of polymyxin B in Chinese children has been reported, thus making it difficult for pediatric clinicians to rationally select these drugs. Methods: A retrospective analysis of children treated with polymyxin B during hospitalization in a hospital from June 2019 to June 2021 was conducted to analyze its effectiveness and the incidence of acute kidney injury (AKI) during treatment with polymyxin B. Results: A total of 55 children were included in this study, and the results showed that the intravenous polymyxin B-based regimen had an effective rate of 52.7% in the treatment of Carbapenem-resistant Gram-negative bacterial (CR-GNB) infection in children. The results of the subgroup analysis showed that the course of treatment was longer in the favorable clinical response group than in the unfavorable outcome group (p = 0.027) and that electrolyte disturbances in children during the course of treatment could lead to unfavorable clinical outcomes (p = 0.042). The risk of incidence of AKI during treatment was 27.3%, and the all-cause mortality rate in the children on their discharge from the hospital was 7.3%. Conclusion: Polymyxin B can be used as a salvage therapy for CR-GNB infection in children when no other susceptible antibiotics are available, and the monitoring of kidney function should be strengthened.

Evaluation of Biological Activities of Quinone-4-oxoquinoline Derivatives against Pathogens of Clinical Importance.

BACKGROUND: Microbial resistance has become a worldwide public health problem and may lead to morbidity and mortality in affected patients. OBJECTIVES: Therefore, this work aimed to evaluate the antibacterial activity of quinone-4- oxoquinoline derivatives. METHODS: These derivatives were evaluated against Gram-positive and Gram-negative bacteria by their antibacterial activity, anti-biofilm, and hemolytic activities and in silico assays. RESULTS: The quinone-4-oxoquinoline derivatives presented broad-spectrum antibacterial activities and, in some cases, were more active than commercially available reference drugs. These compounds also inhibited bacterial adhesion, and the assays revealed seven non-hemolytic derivatives. The derivatives seem to cause damage to the bacterial cell membrane, and those containing the carboxyl group at the C-3 position of the 4-quinolonic nucleus were more active than those containing a carboxyethyl group. CONCLUSION: The isoquinoline-5,8-dione nucleus also favored antimicrobial activity. The study showed that the target of the derivatives must be a non-conventional hydrophobic allosteric binding pocket on the DNA gyrase enzyme.

A bundle of infection control measures reduces postoperative sternal wound infection due to Staphylococcus aureus but not Gram-negative bacteria: a retrospective analysis of 6903 patient episodes.

BACKGROUND: Prevention of cardiac surgical site infection has largely focused on reducing infection due to Staphylococcus aureus, although other bacteria also play an important role in this complication. AIM: To assess the impact of an evolving infection control programme on the incidence of sternal wound infection (SWI), and the changing incidence of non-staphylococcal infections. METHODS: A retrospective cohort study of all patients who underwent primary sternotomy at a single UK centre between September 2010 and May 2018 was undertaken. Data were collated from the 2 years preceding the stepwise introduction of a broad-ranging infection control programme, including S. aureus decolonization. FINDINGS: In total, 6903 primary sternotomies were performed, of which 2.6% (N=178) were complicated by SWI. Gram-negative bacteria (GNB) and S. aureus were most commonly identified as causative pathogens (45.5% and 30.3%, respectively). Following programme introduction, there was a reduction in the rate of SWI from 3.9 to 1.8 cases/100 patients/month. This was mainly due to a sustained reduction in cases of S. aureus infection, with no discernible impact on GNB. Multi-variable logistic regression analysis identified coronary artery bypass grafting, procedural urgency, and procedures performed in the third quarter of the calendar year (July to September) as independent risk factors for postoperative infection. CONCLUSION: A multi-faceted infection control programme was successful at reducing the rate of SWI, primarily due to a reduction in S. aureus infections. GNB also play an important role in SWI, and traditional preventative measures fail to address these. Future intervention and impact assessments should consider GNB infections when measuring effectiveness.

Temporal Changes in Extended Spectrum ß-Lactamase Producing Organisms in Acute Care Surgery.

BACKGROUND: Extended-spectrum ß-lactamase (ESBL) producing organisms are resistant to a wide range of broad-spectrum antibiotics, and their emergence is a significant driving force of antibiotic resistance. Most South-Asian countries have become hotspots for antibiotic resistance, so specifics of ESBL data are critical to tackling antibiotic resistance. We present the temporal changes in ESBL-producing organisms cultured in our tertiary care referral centre. METHODS: Over a year, a historical cohort analysis was carried out at our tertiary care referral centre in Southeast Asia. Samples from patients presenting with acute surgical conditions were sent for culture and sensitivity. The phenotype of all specimens was checked using the combination disc method. Antimicrobial susceptibilities to various antibiotics were also checked as per CLSI (Clinical and Laboratory Standard Institute) guidelines. RESULTS: Specimens from 170 patients were analysed. The mean age was 44.73±19.89 years, and there was a female predominance of 62%. The most common organisms were Escherichia coli (70%), Klebsiella pneumoniae (18%), and Pseudomonas aeruginosa (16%). The percentage of ESBL-producing organisms was 54.7%, which is significantly higher than in previous reports. Widespread resistance was found against commonly used antibiotics, including co-amoxiclav (81.9%), ceftriaxone (75%), ciprofloxacin (47%), and levofloxacin (35.7%). Sensitivities to combination antibiotics like piperacillin-tazobactam (79.2% sensitive), cefoperazone-sulbactam (84.3% sensitive), and imipenem-cilastatin (91.1% sensitive) were also noted to be falling. CONCLUSION: The incidence of ESBL-producing organisms continues to increase at an alarming rate, which mandates strict antibiotic stewardship and amendments to local guidelines.

Systematic review on efficacy of preventive measures for surgical site infection by multiple-drug resistant gram-negative bacilli

ABSTRACT Background: There are no specific recommendations for prevention of surgical site infection (SSI) caused by multidrug resistant Gram-negative bacilli (MDR-GNB). Our objective was to systematically review the literature evaluating the efficacy and safety of measures specifically designed to prevent MDR-GNB SSI. Methods: We searched MEDLINE, EMBASE, CINAHL and LILACS databases up to February 18, 2020. Randomized trials and observational cohort studies evaluating the efficacy of preventive measures against MDR-GNB SSI in adult surgical patients were eligible. We evaluated methodological quality of studies and general quality of evidence using Newcastle-Ottawa scale, Cochrane ROBINS-I and GRADE method. Random-effects meta-analyses were performed using Review Manager V.5.3 software. Results: A total of 10,663 titles by searching databases were identified. Two retrospective observational studies, comparing surgical antibiotic prophylaxis (SAP) with or without aminoglycoside in renal transplantation recipients, and one non-randomized prospective study, evaluating ertapenem vs. cephalosporin plus metronidazole for SAP in extended spectrum beta-lactamase producing Enterobacteriales carriers undergoing colon surgery, were included. Risk of bias was high in all studies. Meta-analysis was performed for the renal transplantation studies, with 854 patients included. Combined relative risk (RR) for MDR GNB SSI was 0.57 (95%CI: 0.25-1.34), favoring SAP with aminoglycoside (GRADE: moderate). Conclusions: There are no sufficient data supporting specific measures against MDR-GNB SSI. Prospective, randomized studies are necessary to assess the efficacy and safety of SAP with aminoglycoside for MDR-GNB SSI prevention among renal transplantation recipients and other populations. PROSPERO 2018 CRD42018100845.

Plesiomonas shigelloides Septic Shock Following Ingestion of Dojo Nabe (Loach Hotpot).

Plesiomonas shigelloides is a gram-negative bacillus that commonly causes self-limited diarrhea in humans. We present the case of P shigelloides bacteremia in a 49-year-old man with alcoholic cirrhosis who developed septic shock a day after eating Dojo nabe (loach hotpot), a Japanese traditional dish.

Factores pronósticos de mortalidad por agente infeccioso en un hospital de alta complejidad de Cartagena-Colombia / Prognostic factors for mortality caused by an infectious agent in a high complexity hospital in Cartagena-Colombia

Introducción: La identificación de los principales factores clínico-epidemiológicos que determinan causas de mortalidad en pacientes hospitalizados es una necesidad apremiante, principalmente cuando los esfuerzos realizados en la actualidad no permiten asumir acciones fundamentadas en la identificación de las causas de dicho evento. Objetivo: Establecer cuáles son los factores pronósticos de mortalidad por agente infeccioso en un hospital de alta complejidad de la ciudad de Cartagena- Colombia. Material y Métodos: Se realizó un estudio de casos y controles retrospectivo, con muestra proyectada de 86 casos y 258 controles, en una relación 1:3, que cumplieron con los criterios de elegibilidad respectivos y en los que realizaron análisis bivariados y posteriormente un análisis multivariado que incluyó métodos de regresión logística binaria. Resultados: El riesgo de mortalidad en el análisis multivariado está determinado por variables como sexo masculino (ORa 1,695 IC 95 por ciento: 1,005-2,856); Cáncer (ORa 2,389 IC 95 por ciento 1,230-4,642); inmunosupresión (ORa 3,211 IC 95 por ciento 1,004-10,26); Ventilación mecánica (ORa 2,541 IC 95 por ciento 1,128-5,722); Estancia en la UCI (ORa 2,331 IC 95 por ciento1,227-4,425) e Infección por bacterias productoras de carbapenemasas (ORa 4,778 IC95 por ciento 1,313-17,38). Conclusiones: En pacientes masculinos con cáncer o cualquier otra forma de inmunosupresión, en los que se requiera el uso del ventilador mecánico o estancia en la unidad de cuidado intensivo y que además desarrollen infecciones por bacterias productoras de carbapenemasas existe mayor riesgo de muerte por agente infeccioso(AU)

Introduction: The identification of the main epidemiological clinical factors that determine the causes of mortality in hospitalized patients is a pressing need, mainly when the efforts made at present do not allow us to take actions based on the identification of the causes of the aforementioned event. Objective: To identify the prognostic factors for mortality caused by infectious agents in a high complexity hospital in the city of Cartagena, Colombia. Material and Methods: A retrospective case-control study was conducted in 86 cases and 258 control samples that met the eligibility criteria, at the 1: 3 ratio. Bivariate analyses and a subsequent multivariate analysis that included binary logistic regression methods were also performed. Results: In the multivariate analysis, the risk of mortality is determined by variables such as male sex (ORa 1,695 95 percent CI: 1.005-2.856); cancer (ORa 2,389 95 percent CI 1,230-4,642); immunosuppression (ORa 3.211 95 percent CI 1.004-10.26); mechanical ventilation (ORa 2.541 95 percent CI 1.128-5.722); stay in the ICU (ORa 2,331 95 percent CI 1,227-4,425) and infection caused by carbapenemase-producing bacteria (ORa 4,778 95 percent CI 1,313-17.38). Conclusions: Male patients with cancer or any other form of immunosuppression who require the use of a mechanical ventilator or admission to the intensive care unit who also develop infections caused by carbapenemase-producing bacteria, are at greater risk of death from an infectious agent(AU)