Pharmacokinetics and pharmacodynamics of bacteriophage therapy: a review with a focus on multidrug-resistant Gram-negative bacterial infections.

SUMMARYDespite the early recognition of their therapeutic potential and the current escalation of multidrug-resistant (MDR) pathogens, the adoption of bacteriophages into mainstream clinical practice is hindered by unfamiliarity with their basic pharmacokinetic (PK) and pharmacodynamic (PD) properties, among others. Given the self-replicative nature of bacteriophages in the presence of host bacteria, the adsorption rate, and the clearance by the host's immunity, their PK/PD characteristics cannot be estimated by conventional approaches, and thus, the introduction of new considerations is required. Furthermore, the multitude of different bacteriophage types, preparations, and treatment schedules impedes drawing general conclusions on their in vivo PK/PD features. Additionally, the drawback of acquired bacteriophage resistance of MDR pathogens with clinical and environmental implications should be taken into consideration. Here, we provide an overview of the current state of the field of PK and PD of bacteriophage therapy with a focus on its application against MDR Gram-negative infections, highlighting the potential knowledge gaps and the challenges in translation from the bench to the bedside. After reviewing the in vitro PKs and PDs of bacteriophages against the four major MDR Gram-negative pathogens, Klebsiella pneumoniae, Acinetobacter baumannii complex, Pseudomonas aeruginosa, and Escherichia coli, specific data on in vivo PKs (tissue distribution, route of administration, and basic PK parameters in animals and humans) and PDs (survival and reduction of bacterial burden in relation to the route of administration, timing of therapy, dosing regimens, and resistance) are summarized. Currently available data merit close scrutiny, and optimization of bacteriophage therapy in the context of a better understanding of the underlying PK/PD principles is urgent to improve its therapeutic effect and to minimize the occurrence of bacteriophage resistance.

Effect of Purslane (Portulaca oleracea L.) on Intestinal Morphology, Digestion Activity and Microbiome of Chinese Pond Turtle (Mauremys reevesii) during Aeromonas hydrophila Infection.

Large-scale mortality due to Aeromonas hydrophila (A. hydrophila) infection has considerably decreased the yield of the Chinese pond turtle (Mauremys reevesii). Purslane is a naturally active substance with a wide range of pharmacological functions, but its antibacterial effect on Chinese pond turtles infected by A. hydrophila infection is still unknown. In this study, we investigated the effect of purslane on intestinal morphology, digestion activity, and microbiome of Chinese pond turtles during A. hydrophila infection. The results showed that purslane promoted epidermal neogenesis of the limbs and increased the survival and feeding rates of Chinese pond turtles during A. hydrophila infection. Histopathological observation and enzyme activity assay indicated that purslane improved the intestinal morphology and digestive enzyme (α-amylase, lipase and pepsin) activities of Chinese pond turtle during A. hydrophila infection. Microbiome analysis revealed that purslane increased the diversity of intestinal microbiota with a significant decrease in the proportion of potentially pathogenic bacteria (such as Citrobacter freundii, Eimeria praecox, and Salmonella enterica) and an increase in the abundance of probiotics (such as uncultured Lactobacillus). In conclusion, our study uncovers that purslane improves intestinal health to protect Chinese pond turtles against A. hydrophila infection.

Microbiota-Based Therapies for Clostridium difficile and Antibiotic-Resistant Enteric Infections.

Bacterial pathogens are increasingly antibiotic resistant, and development of clinically effective antibiotics is lagging. Curing infections increasingly requires antimicrobials that are broader spectrum, more toxic, and more expensive, and mortality attributable to antibiotic-resistant pathogens is rising. The commensal microbiota, comprising microbes that colonize the mammalian gastrointestinal tract, can provide high levels of resistance to infection, and the contributions of specific bacterial species to resistance are being discovered and characterized. Microbiota-mediated mechanisms of colonization resistance and pathogen clearance include bactericidal activity, nutrient depletion, immune activation, and manipulation of the gut's chemical environment. Current research is focusing on development of microbiota-based therapies to reduce intestinal colonization with antibiotic-resistant pathogens, with the goal of reducing pathogen transmission and systemic dissemination.

Clinical Epidemiology and Outcomes of Pediatric Musculoskeletal Infections.

OBJECTIVES: To understand the epidemiology of acute hematogenous osteomyelitis and septic arthritis, including clinical and demographic features, microbiology, treatment approaches, treatment-associated complications, and outcomes. STUDY DESIGN: Retrospective cohort study of 453 children with acute hematogenous osteomyelitis and/or septic arthritis from 2009 to 2015. RESULTS: Among the 453 patients, 218 (48%) had acute hematogenous osteomyelitis, 132 (29%) had septic arthritis, and 103 (23%) had concurrent acute hematogenous osteomyelitis/septic arthritis. Treatment failure/recurrent infection occurred in 41 patients (9%). Patients with concurrent acute hematogenous osteomyelitis/septic arthritis had longer hospital stays, longer duration of antibiotic therapy, and were more likely to have prolonged bacteremia and require intensive care. Staphylococcus aureus was identified in 228 (51%) patients, of which 114 (50%) were methicillin-resistant S aureus. Compared with septic arthritis, acute hematogenous osteomyelitis and concurrent acute hematogenous osteomyelitis/septic arthritis were associated with higher odds of treatment failure (OR, 8.19; 95% CI, 2.02-33.21 [P = .003]; and OR, 14.43; 95% CI, 3.39-61.37 [P < .001], respectively). The need for more than 1 surgical procedure was also associated with higher odds of treatment failure (OR, 2.98; 95% CI, 1.18-7.52; P = .021). Early change to oral antibiotic therapy was not associated with treatment failure (OR, 0.64; 95% CI, 0.24-1.74; P = .386). Most (73%) medically attended treatment complications occurred while on parenteral therapy. CONCLUSIONS: Musculoskeletal infections are challenging pediatric infections. S aureus remains the most common pathogen, with methicillin-resistant S aureus accounting for 25% of all cases. Concurrent acute hematogenous osteomyelitis/septic arthritis is associated with more severe disease and worse outcomes. Fewer treatment-related complications occurred while on oral therapy. Early transition to oral therapy was not associated with treatment failure.

Bilateral acute renal cortical necrosis after a dog bite: case report.

BACKGROUND: Capnocytophaga canimorsus is a Gram-negative capnophilic rod and part of dogs/cats' normal oral flora. It can be transmitted by bites, scratches, or even by contact of saliva with injured skin. Asplenic patients and patients with alcohol abuse are at particular risk for fulminant C. canimorsus sepsis. However, also immunocompetent patients can have a severe or even fatal infection. This is the first case of a severe C. canimorsus infection in an immunocompromised host complicated by acute renal cortical necrosis with a "reverse rim sign" in contrast-enhanced computed tomography on hospital admission. CASE PRESENTATION: We report the case of a 44-year functionally asplenic patient after an allogeneic stem cell transplantation, who presented with septic shock after a minor dog bite injury 4 days prior. Because of abdominal complaints, epigastric pain with local peritonism, and radiological gallbladder wall thickening, an abdominal focus was suspected after the initial work-up. The patient underwent emergent open cholecystectomy, but the clinical suspicion of abdominal infection was not confirmed. Septic shock was further complicated by cardiomyopathy and disseminated intravascular coagulation. As a causative pathogen, C. canimorsus could be isolated. The clinical course was complicated by permanent hemodialysis and extensive acral necrosis requiring amputation of several fingers and both thighs. CONCLUSION: We present a severe case of a C. canimorsus infection in a functionally asplenic patient after a minor dog bite. The clinical course was complicated by septic shock, disseminated intravascular coagulation, and the need for multiple amputations. In addition, the rare form of acute renal failure - bilateral acute renal cortical necrosis - was visible as "reverse rim sign" on computed tomography scan. This case is an example of the potential disastrous consequences when omitting pre-emptive antibiotic therapy in wounds inflicted by cats and dogs, particularly in asplenic patients.

Ralstonia mannitolilytica sepsis after elective cesarean delivery: a case report.

BACKGROUND: Ralstonia mannitolilytica, a newly emerging opportunistic pathogen worldwide, has been reported to be responsible for human pneumonia, septicemia and meningitis. This is the first report of a case of Ralstonia mannitolilytica sepsis after elective cesarean delivery. CASE PRESENTATION: A 25-year-old woman, gravida 1 para 0, was scheduled for an elective cesarean delivery at 39+ 1 weeks of gestation. Sudden high fever and decreased blood pressure occurred a short time after the operation. Ralstonia mannitolilytica was identified in her blood culture 5 days after the operation. Based on the presence of sepsis and septic shock, massive fluid replacement, blood transfusion, vasoactive agents, imipenem/cilastatin and cefoperazone sulbactam sodium were applied. She was discharged after intensive care without complications. CONCLUSIONS: Although the incidence of sepsis due to Ralstonia mannitolilytica is relatively low, once infection occurs in a puerpera, severe symptoms develop abruptly. Thus, prompt diagnosis and appropriate treatment are key to the cure.

Isolation and characterization of bacteriophages against virulent Aeromonas hydrophila.

BACKGROUND: Aeromonas hydrophila is an important water-borne pathogen that leads to a great economic loss in aquaculture. Along with the abuse of antibiotics, drug-resistant strains rise rapidly. In addition, the biofilms formed by this bacterium limited the antibacterial effect of antibiotics. Bacteriophages have been attracting increasing attention as a potential alternative to antibiotics against bacterial infections. RESULTS: Five phages against pathogenic A. hydrophila, named N21, W3, G65, Y71 and Y81, were isolated. Morphological analysis by transmission electron microscopy revealed that phages N21, W3 and G65 belong to the family Myoviridae, while Y71 and Y81 belong to the Podoviridae. These phages were found to have broad host spectra, short latent periods and normal burst sizes. They were sensitive to high temperature but had a wide adaptability to the pH. In addition, the phages G65 and Y81 showed considerable bacterial killing effect and potential in preventing formation of A. hydrophila biofilm; and the phages G65, W3 and N21 were able to scavenge mature biofilm effectively. Phage treatments applied to the pathogenic A. hydrophila in mice model resulted in a significantly decreased bacterial loads in tissues. CONCLUSIONS: Five A. hydrophila phages were isolated with broad host ranges, low latent periods, and wide pH and thermal tolerance. And the phages exhibited varying abilities in controlling A. hydrophila infection. This work presents promising data supporting the future use of phage therapy.

Use of bacteriophage vB_Pd_PDCC-1 as biological control agent of Photobacterium damselae subsp. damselae during hatching of longfin yellowtail (Seriola rivoliana) eggs.

AIMS: This study describes the effect of phage therapy on hatching of longfin yellowtail (Seriola rivoliana) eggs challenged with Photobacterium damselae subsp. damselae. METHODS AND RESULTS: A lytic phage (vB_Pd_PDCC-1) against P. damselae subsp. damselae was isolated and characterized. The use of phage vB_Pd_PDCC-1 increased the hatching rate of eggs, and reduced presumptive Vibrio species to non-detectable numbers, even in non-disinfected eggs. High-throughput 16S rRNA gene sequencing analysis revealed that phage vB_Pd_PDCC-1 caused significant changes in the composition and structure of the associated microbiota, allowing that members (e.g. those belonging to the family Vibrionaceae) of the class Gammaproteobacteria to be displaced by members of the class Alphaproteobacteria. CONCLUSIONS: To the best of our knowledge, this represents the first study evaluating phage therapy to control potential negative effects of P. damselae subsp. damselae during hatching of longfin yellowtail eggs. SIGNIFICANCE AND IMPACT OF THE STUDY: The Seriola genus includes several important commercial fish species due to its rapid growth and easy adaptability to confinement conditions. However, bacterial infections (especially those caused by Vibrio and Photobacterium species) are among the main limiting factors for the intensification of marine fish aquaculture, particularly during early development stages. Therefore, the use of phages, which are natural killers of bacteria, represents a promising strategy to reduce the mortality of farmed organisms caused by pathogenic bacteria.

A multifunctional platform with single-NIR-laser-triggered photothermal and NO release for synergistic therapy against multidrug-resistant Gram-negative bacteria and their biofilms.

BACKGROUND: Infectious diseases caused by multidrug-resistant (MDR) bacteria, especially MDR Gram-negative strains, have become a global public health challenge. Multifunctional nanomaterials for controlling MDR bacterial infections via eradication of planktonic bacteria and their biofilms are of great interest. RESULTS: In this study, we developed a multifunctional platform (TG-NO-B) with single NIR laser-triggered PTT and NO release for synergistic therapy against MDR Gram-negative bacteria and their biofilms. When located at the infected sites, TG-NO-B was able to selectively bind to the surfaces of Gram-negative bacterial cells and their biofilm matrix through covalent coupling between the BA groups of TG-NO-B and the bacterial LPS units, which could greatly improve the antibacterial efficiency, and reduce side damages to ambient normal tissues. Upon single NIR laser irradiation, TG-NO-B could generate hyperthermia and simultaneously release NO, which would synergistically disrupt bacterial cell membrane, further cause leakage and damage of intracellular components, and finally induce bacteria death. On one hand, the combination of NO and PTT could largely improve the antibacterial efficiency. On the other hand, the bacterial cell membrane damage could improve the permeability and sensitivity to heat, decrease the photothermal temperature and avoid damages caused by high temperature. Moreover, TG-NO-B could be effectively utilized for synergistic therapy against the in vivo infections of MDR Gram-negative bacteria and their biofilms and accelerate wound healing as well as exhibit excellent biocompatibility both in vitro and in vivo. CONCLUSIONS: Our study demonstrates that TG-NO-B can be considered as a promising alternative for treating infections caused by MDR Gram-negative bacteria and their biofilms.

Accelerate Pheno™ system in sepsis by Gram-negative pathogens: four months of hospital experience.

This study reports our experience with the Accelerate PhenoTM system (ACC) to guide management of patients with sepsis by Gram-negative pathogens. A diagnostic workflow, based on pathogen and resistance genes detection or ACC testing, was applied to 33 patients. Clinical and microbiological data were recorded, and analysis of broad-spectrum agents sparing was performed. Antimicrobial susceptibility results by ACC were available for 28 of 33 patients (84.85%). Among 434 microorganism-antimicrobial combinations, categorical agreement was 97.93%, very major errors 0.23%, major errors 1.15%, and minor errors 0.69%. Time to report (mean ± SD) of ACC results was 27.14±6.90 h from sample collection, significantly shorter (p<0.001, Δ = 19.96 h, 95% CI: 24.71-15.22) than that of the standard method (47.10±11.92 h). A switch from empiric to targeted therapy was observed in 14 of 28 patients (50.0%), duration of empiric therapy was 37.73±19.87 h, with a saving of 5.45 piperacillin/tazobactam and 5.28 carbapenems prescribed daily doses. Considering patients in which de-escalation would have been theoretically feasible, 27.69 prescribed daily doses of piperacillin/tazobactam and 19.08 of carbapenems could had been spared, compared to standard methods. In conclusion, ACC could impact positively on the management of septic patients by Gram-negative pathogens.

A subcutaneous infection mimicking necrotizing fasciitis due to Butyricimonas virosa.

INTRODUCTION: Butyricimonas virosa is a Gram-negative rod who was first identified in rat faces in 2009. Since then only six human infections have been described in literature of which five bacteremia and one bone abscess. We report a clinical case of a subcutaneous infection mimicking necrotizing fasciitis due to B. virosa. PATIENT AND METHODS: A 78-year-old man was referred to our hospital because of a wound infection at the surgical site with suspicion of necrotizing fasciitis. Treatment consisted of immediate surgical exploration with obtainment of intra-operative specimens for microbiologic examination, 15 d of negative pressure wound therapy (NPWT) and antibiotic treatment with piperacillin-tazobactam (12 d) plus vancomycin (9 d). RESULTS: Surgical exploration did not show necrotising fasciitis but a subcutaneous infection mimicking necrotising fasciitis. The results of the intra-operative specimens revealed the presence of B.virosa and Finegoldia magna. Cultures taken during the NPWT replacements became negative and the patient was able to leave the hospital after 18 d. CONCLUSIONS: Considering there was no necrotizing infection present it may have been possible to safely close the wound sooner. However, it is difficult to differentiate between an actual necrotizing fasciitis and a subcutaneous infection mimicking necrotizing fasciitis. Therefore further studies on effective assessment tools to diagnose necrotizing fasciitis, such as the (modified) laboratory risk indicator for necrotizing fasciitis (LRINEC) score and enhanced computed tomography (CT), could be helpful.

[Negative pressure wound therapy for deep sternal wound infections: microbiological characteristics and antibiotic resistance]. / Vliyanie vakuum-assistirovannoi povyazki na lechenie glubokoi infektsii grudiny: bakteriologicheskii analiz i antibiotikorezistentnost'.

OBJECTIVE: To evaluate bacterial flora in patients with deep sternal wound infection and the effect of negative pressure wound therapy on eradication of the pathogen. MATERIAL AND METHODS: There were 102 patients with deep wound infection after cardiac surgery. Mean age was 66.9±9.9 years. Diabetes mellitus was detected in 21 (20.5%) cases, chronic obstructive pulmonary disease - in 15 (14.7%). Wound debridement via daily dressings was performed in 64 patients; vacuum-assisted dressings were applied in 38 patients. Bacteriological analysis of discharge was carried out every week.Results. Mixed infection was observed in 38 (37.3%) patients. S.aureus was the most common pathogen (n=51, 50%), Gram negative bacteria were found in 36 (35.3%) patients. Negative pressure wound therapy ensured eradication of S.aureus within 3 weeks while dressings were associated with only 40% decrease of the incidence of positive analyses (p<0.05). Effectiveness of the method was not obtained for Gram negative bacteria. CONCLUSION: Negative pressure wound therapy accelerates eradication of Gram positive pathogens but does not affect eradication of Gram negative microbes.

Impact of Preemptive Granulocyte Infusions During Febrile Neutropenia in Patients Colonized with Carbapenem-Resistant Gram-Negative Bacteria Undergoing Haploidentical Transplantation.

We prospectively studied the impact of preemptive granulocyte infusions (pGIs) in 69 patients colonized with carbapenem-resistant gram-negative bacteria (CRGNB) undergoing haploidentical hematopoietic cell transplantation (HCT) compared with a previous cohort of 33 patients who received only antimicrobials directed toward CRGNB at the onset of neutropenic fever (non-pGI group). All patients developed neutropenic fever at a median of day +8 (range, -4 to +12) after transplantation. Engraftment kinetics were similar for both groups. The median number of GIs was 2 (range, 1 to 7), and the median dose of granulocytes infused was 5 × 1010 granulocytes per infusion (range, 1 to 30). The overall incidence of CRGNB bloodstream infections (BSIs) was 21.2% in non-pGI group (7/33) and 17.5% (12/69) in the pGI group (P = .8). However, the CRGNB-related mortality among those with BSI was 100% (7/7) in the non-pGI group versus 16.6% (2/12) in the pGI group (P = .001). The day 100 (4.4% versus 24.4%, P = .002) and 2-year nonrelapse mortality (7.5% versus 35.6%, P = .0001) were significantly reduced in the pGI group. The overall survival at 2 years was 75.6% in the pGI group versus 21.2% in the non-pGI group (P = .0001). Colonization and subsequent BSI with CRGNB are associated with a high incidence of mortality in patients undergoing HCT. pGI reduced early mortality associated with CRGNB in colonized patients undergoing post-transplant cyclophosphamide-based haploidentical HCT.

Complications of Hemodialysis Catheter Bloodstream Infections: Impact of Infecting Organism.

BACKGROUND: Catheter-related bloodstream infections -(CRBSI) are associated with a high burden of morbidity and mortality, but the impact of infecting organism on clinical outcomes has been poorly studied. METHODS: This retrospective analysis of a prospective vascular access database from a large academic dialysis center investigated whether the organism type affected the clinical presentation or complications of CRBSI. RESULTS: Among 339 patients with suspected CRBSI, an alternate source of infection was identified in 50 (15%). Of 289 patients with CRBSI, 249 grew a single organism and 40 were polymicrobial. Fever and/or rigors were presenting signs in ≥90% of patients with Staphylococcus aureus or Gram-negative CRBSI, but only 61% of Staphylococcus epidermidis infections (p < 0.001). Hospitalization occurred in 67% of patients with S. aureus CRBSI versus 34% of those with S. epidermidis and 40% of those with a Gram-negative bacteria (p < 0.001). Admission to the intensive care unit was required in 14, 9, and 2% (p = 0.06); metastatic infection occurred in 10, 4, and 4% (p = 0.42); and median length of stay among patients admitted to the hospital was 4, 4, and 5.5 days (p = 0.60), respectively. Death due to CRBSI occurred in only 1% of patients with CRBSI. CONCLUSION: CRBSI is confirmed in 85% of catheter-dependent hemodialysis patients in whom it is suspected. S. epidermidis CRBSI tends to present with atypical symptoms. S. aureus CRBSI is more likely to require hospitalization or intensive care admission. Metastatic infection is relatively uncommon, and death due to CRBSI is rare.

Essentials in the management of necrotizing soft-tissue infections.

AIMS: Necrotizing soft-tissue infections (NSTI) are rare but severe diseases with rapid progression. Rates of mortality and morbidity are high and early diagnosis, immediate surgical intervention and antibiotic treatment are essential to improve prognosis. Thus, our commentary emphasizes important information in the management of NSTI. METHODS: We describe the essentials in the management of necrotizing soft-tissue infections. RESULTS: Six essentials were identified: 1. Necrotizing soft-tissue infections (NSTI) are primarily diagnosed clinically; pain out of proportion, rapid progression of skin infection and systemic signs should alert clinicians. 2. Early diagnosis can be rather delayed by several factors such as absence of fever, significant cutaneous manifestations, elevation of inflammatory parameters, systemic signs, and non-specific imaging tests. 3. NSTI can occur both in the elderly or patients with underlying diseases after major trauma (usually polymicrobial Gram-negative and Gram-positive pathogens) but also in healthy patients after minor trauma (often monomicrobial; most common among Gram-positive organisms: group A Streptococcus). 4. Immediate and radical debridement (incl. re-debridement after 24 h) remains the cornerstone of surgical therapy. 5. Empirical broad-spectrum antimicrobial treatment has to be administered shortly after admission. After isolation of the causative bacteria therapy should be tailored. 6. The value of adjunctive measures (hyperbaric oxygen therapy, intravenous immunoglobulines) is uncertain and their routine use cannot be recommended. Further efforts should be undertaken to increase the awareness for and the adherence to the essentials in the management of necrotizing soft-tissue infections.

Infective endocarditis caused by Capnocytophaga canimorsus; a case report.

BACKGROUND: Capnocytophaga canimorsus is a gram-negative bacterium and an oral commensal in dogs and cats, but occasionally causes serious infections in humans. Septicemia is one of the most fulminant forms, but diagnosis of C. canimorsus infection is often difficult mainly because of its very slow growth. C. canimorsus infective endocarditis (IE) is rare and is poorly understood. Since quite a few strains produce ß-lactamase, antimicrobial susceptibility is pivotal information for adequate treatment. We herein report a case with C. canimorsus IE and the results of drug susceptibility test. CASE PRESENTATION: A 46-year-old man had a dog bite in his left hand 3 months previously. The patient was referred to our hospital for fever (body temperature > 38 °C), visual disturbance, and dyspnea. Echocardiography showed aortic valve regurgitation and vegetation on the leaflets. IE was diagnosed, and we initially administered cefazolin and gentamycin assuming frequently encountered microorganisms and the patient underwent aortic valve replacement. C. canimorsus was detected in the aortic valve lesion and blood cultures. It was also identified by 16S ribosome DNA sequencing. Ceftriaxone were started and continued because disk diffusion test revealed the isolate was negative for ß-lactamase and this case had cerebral symptoms. The patient successfully completed antibiotic treatment following surgery. CONCLUSIONS: We diagnosed C. canimorsus sepsis and IE by extended-period blood cultures and 16S ribosome DNA sequencing by polymerase chain reaction, and successfully identified its drug susceptibility.

Outcomes of Stenotrophomonas maltophilia hospital-acquired pneumonia in intensive care unit: a nationwide retrospective study.

BACKGROUND: There is little descriptive data on Stenotrophomonas maltophilia hospital-acquired pneumonia (HAP) in critically ill patients. The optimal modalities of antimicrobial therapy remain to be determined. Our objective was to describe the epidemiology and prognostic factors associated with S. maltophilia pneumonia, focusing on antimicrobial therapy. METHODS: This nationwide retrospective study included all patients admitted to 25 French mixed intensive care units between 2012 and 2017 with hospital-acquired S. maltophilia HAP during intensive care unit stay. Primary endpoint was time to in-hospital death. Secondary endpoints included microbiologic effectiveness and antimicrobial therapeutic modalities such as delay to appropriate antimicrobial treatment, mono versus combination therapy, and duration of antimicrobial therapy. RESULTS: Of the 282 patients included, 84% were intubated at S. maltophilia HAP diagnosis for duration of 11 [5-18] days. The Simplified Acute Physiology Score II was 47 [36-63], and the in-hospital mortality was 49.7%. Underlying chronic pulmonary comorbidities were present in 14.1% of cases. Empirical antimicrobial therapy was considered effective on S. maltophilia according to susceptibility patterns in only 30% of cases. Delay to appropriate antimicrobial treatment had, however, no significant impact on the primary endpoint. Survival analysis did not show any benefit from combination antimicrobial therapy (HR = 1.27, 95%CI [0.88; 1.83], p = 0.20) or prolonged antimicrobial therapy for more than 7 days (HR = 1.06, 95%CI [0.6; 1.86], p = 0.84). No differences were noted in in-hospital death irrespective of an appropriate and timely empiric antimicrobial therapy between mono- versus polymicrobial S. maltophilia HAP (p = 0.273). The duration of ventilation prior to S. maltophilia HAP diagnosis and ICU length of stay were shorter in patients with monomicrobial S. maltophilia HAP (p = 0.031 and p = 0.034 respectively). CONCLUSIONS: S. maltophilia HAP occurred in severe, long-stay intensive care patients who mainly required prolonged invasive ventilation. Empirical antimicrobial therapy was barely effective while antimicrobial treatment modalities had no significant impact on hospital survival. TRIAL REGISTRATION: clinicaltrials.gov, NCT03506191.

Difficult-to-Treat Antibiotic-Resistant Gram-Negative Pathogens in the Intensive Care Unit: Epidemiology, Outcomes, and Treatment.

Antibiotic resistance among gram-negative pathogens is a world-wide problem that poses a constant threat to patients in the intensive care unit and a therapeutic challenge for the intensivist. Furthermore, the substantial economic burden and increased mortality associated with infections due to highly resistant gram-negative pathogens exacerbate these challenges. Understanding the mechanisms, epidemiology, and risk factors for these infections is paramount to the successful control of outbreaks and for guiding therapy which often entails use of antibiotics with suboptimal efficacy and/or toxicity profiles. In this review we will discuss the global epidemiology, burden, risk factors, and treatment of highly resistant gram-negative infections as they apply to the intensive care population.

Augmented Adsorptive Blood Purification during Continuous Veno-Venous Haemodiafiltration in a Severe Septic, Acute Kidney Injury Patient: Use of oXiris®: A Single Centre Case Report.

The use of the oXiris® haemofilter during continuous veno-venous haemodiafiltration (CVVHDF) for acute kidney injury (AKI) and severe sepsis is not completely understood. Although this filter has in vitro adsorptive properties for blood-borne cytokines and other humoural mediators of sepsis, its clinical usefulness is uncertain. Given its inherent adsorptive limitation for septic mediators, we developed a CVVHDF protocol in which the oXiris haemofilter was electively changed every 12 h even though there was no clotting or adverse circuit pressures. Augmented filter membrane adsorption was conducted for 3 consecutive days. We treated a critically ill patient with severe sepsis secondary to a gram-negative bacterial infection and sepsis-associated acute kidney injury (SA- AKI) in this way. The patient required high-dose vasopressor support, required mechanical ventilation, had received 12 h of CVVHDF with conventional M100 haemofilter, was on broad spectrum antibiotics and other conventional intensive care unit (ICU) care, prior to institution of the frequent oXiris haemofilter change protocol. Following the start of elective 12 hourly oXiris filter change, the patient showed reduction in the need for vasopressor and by Day 4 of this SA- AKI frequent filter change protocol, vasopressor requirement ceased, he was extubated. He survived ICU and but not hospital stay. To this end, more clinical studies are needed.

oXiris® Use in Septic Shock: Experience of Two French Centres.

BACKGROUND: Sepsis is a dysregulated host response to an infection and can result in organ dysfunctions and death. Extracorporeal blood purification techniques aim to improve the prognosis of these patients by modulating the unbalanced immune response. This study reports our experience with the use of the oXiris® membrane for septic shock patients requiring continuous renal replacement therapy (CRRT). SUMMARY: Thirty-one patients were diagnosed with septic shock and underwent CRRT with the oXiris® membrane between 2014 and 2019. We compared the observed hospital mortality with that predicted by the Simplified Acute Physiology Score II (SAPS II). Change in the Sequential Organ Failure Assessment (SOFA) score and of the main clinical and biological parameters over time were analyzed. Hospital mortality was lower than predicted for the most severe patients (60 vs. 91% for the [74-87] SAPS II quartile and 70 vs. 98% for the [87-163] SAPS II quartile, p < 0.02). There was no significant improvement in the SOFA score from 0h to 48 h. An 88% relative decrease in norepinephrine infusion was observed (median at 0 h was 1.69 [0.52-2.45] µg/kg/min; at 48 h it was 0.20 [0.09-1.14] µg/kg/min, p = 0.002). Lactataemia and pH were significantly improved over time. Patients with intra-abdominal sepsis as well as those with Gram-negative bacilli (GNB) infections seemed to benefit the most from the therapy. Key Messages: CRRT with the oXiris® haemofilter resulted in higher observed survival than predicted by a severity score (SAPS II) for the most severe patients. Haemodynamic status and lactataemia appeared to improve, especially in intra-abdominal sepsis and GNB infections.