Antipseudomonal Antibiotics Research Articles

2172. Closing the CAP Gap: Improving the Management of Community Acquired Pneumonia (CAP)

Abstract Background In October 2019 updated community acquired pneumonia (CAP) guidelines were published, highlighting indications for empiric anti-MRSA and antipseudomonal antibiotics and use of MRSA nares screens. During a review of patients receiving vancomycin and piperacillin-tazobactam at our institution in 2020 we noted frequent use of anti-MRSA and antipseudomonal antibiotics and infrequent use of MRSA nares screens for CAP. In May 2020 we initiated a multifaceted intervention, including prospective audit and feedback, an updated pneumonia order set, and system-wide education. In this study we sought to describe gaps in the care of patients with CAP at our institution and to evaluate the impact of a multifaceted intervention on those gaps in care. Methods We performed a retrospective cohort study on a random sample of unique adult patients admitted with pneumonia from January 1, 2020 through June 30, 2021. Exclusion criteria included COVID infection within 4 weeks of admission, no antibiotics for pneumonia given during admission, immunocompromised condition, and diagnosis of hospital-acquired or ventilator-associated pneumonia. The primary objective was to describe the percentage of patients receiving appropriate anti-MRSA and antipseudomonal therapy and MRSA nares testing during the study period. The secondary objective was to compare appropriateness of these outcomes before and after the intervention. Study groups Results For the 126 patients reviewed, 68.3% received the appropriate empiric spectrum of activity for MRSA and Pseudomonas aeruginosa, improving from 60% to 80% before and after the intervention respectively. The percentage of patients screened for MRSA increased from 6 to 34%; however, the percentage of appropriate MRSA screens decreased from 71 to 54% because screens were often collected despite absence of MRSA risk factors. Results Conclusion The percentage of patients receiving appropriate anti-MRSA and antipseudomonal therapy for CAP improved after a multifaceted stewardship intervention. The percentage of patients for whom appropriate MRSA nares screens was performed worsened, mainly due to use of MRSA nares screens when not needed. Disclosures All Authors: No reported disclosures.

1839. Impact of Hypoalbuminemia on Ceftriaxone Treatment Failure in Patients With Enterobacterales Bacteremia

Abstract Background Ceftriaxone (CRO) is a third-generation cephalosporin that is commonly prescribed due to its robust Gram-negative activity and lack of renal dose adjustments. It is also highly protein bound allowing for once daily dosing. In patients with hypoalbuminemia, however, the proportion of free drug is increased thus increasing the rate at which CRO is renally eliminated. This increased clearance could lead to lower serum concentrations and increased risk of treatment failure. Methods We performed a retrospective, cohort study to assess the impact of hypoalbuminemia (serum albumin ≤ 2.5 g/dL) on treatment failure among patients with monomicrobial Enterobacterales bacteremia. Adult patients who received > 72 hours of CRO therapy for susceptible Enterobacterales bacteremia between May 1, 2016 and April 30, 2021 were eligible for inclusion. The primary outcome of treatment failure was a composite of inpatient mortality or escalation to an intravenous anti-pseudomonal antibiotic or ertapenem. Secondary outcomes included hospital length of stay, total duration of antibiotic therapy, and time to infection resolution. Baseline characteristics and outcomes were compared using R Studio (Version 4.1.0) in a 1:1 propensity-matched cohort. Results After propensity score matching, 142 patients were included in each study group. The most common organisms in our cohort were Escherichia coli (71.5%), Klebsiella pneumoniae (14.1%), and Proteus mirabilis (5.3%). The most frequently implicated source of infection was the urinary tract (71.5%). Interestingly, treatment failure was numerically higher in the hypoalbuminemia group but was not statistically significant (12.0% vs. 7.7%, p = 0.23). All secondary outcomes were similar between groups. Among the subgroup of patients admitted to the ICU at baseline, the difference in treatment failure was even greater between patients with hypoalbuminemia and those without (23.3% vs. 7.5%, P = 0.07). Conclusion Hypoalbuminemia did not appear to have a significant impact on clinical outcomes among patients with Enterobacterales bacteremia treated with CRO. However, critically ill patients may be subject to higher incidence of treatment failure in the presence of hypoalbuminemia. Disclosures All Authors: No reported disclosures.

Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis.

Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis.

Shanghai Fever: Not Only an Asian Disease.

To describe a case of Shanghai fever disease and to analyze other published reports in non-Asiatic countries, defining clinical characteristics and highlighting that this is not only an Asian disease. A computerized search without language restriction was conducted using PubMed and Scopus; all references listed were hand-searched to identify any other relevant literature. An article was considered eligible for inclusion in the systematic review if it reported cases with Shanghai fever described in non-Asiatic countries. Our case was also included in the analysis. Ten articles reporting 10 cases of Shanghai fever disease were considered. Fever, diarrhea and ecthyma gangrenosum were the most frequent symptoms observed. Blood was the most common site of isolation for Pseudomonas aeruginosa. Three patients underwent surgery due to necrotizing enteritis and intestinal perforation. Meningitis was documented in one case. None of the patients received antipseudomonal antibiotics within 24 h of admission. The outcome was good in nine cases; only one patient died due to multiple organ failure from Pseudomonas sepsis. No common primary immune deficiency was identified in these patients. Extremely young age (<1 year) was the only host factor predisposing to Shanghai fever. It is important to shed light on this disease in non-Asiatic countries and take into account that it can also affect healthy children. Pediatricians, therefore, should consider Shanghai fever among diagnoses in children with community-onset diarrhea, fever and skin lesions suggestive of ecthyma gangrenosum to start an appropriate treatment sooner and to reduce the mortality in these children.

Association Between Empirical Anti-Pseudomonal Antibiotics for Recurrent Lower Respiratory Tract Infections and Mortality: A Retrospective Cohort Study.

Whether the empirical use of anti-pseudomonal antibiotics actually improves patient outcomes is unclear. Hence, we aimed to determine whether empirical anti-pseudomonal antibiotics are better than anti-pseudomonal antibiotics in treating patients with recurrent lower respiratory tract infections (LRTIs). We extracted data from the Japanese nationwide database of the Real World Data Co., Ltd. Our target population was patients with LRTIs, defined as chronic obstructive pulmonary disease exacerbation and pneumonia. We included patients aged ≥40 years who were admitted for lower respiratory tract infections ≥2 times within 90 days. We excluded patients who had an event (death or transfer) within 24 h after admission. We ran a frailty model adjusted for the following confounding factors: number of recurrences, age, body mass index, activities of daily living, Hugh-Johns classification, altered mental status, oxygen use on admission, blood urea nitrogen, and systemic steroid use. We included 893 patients with 1362 observations of recurrent LRTIs. There were 897 (66%) observations in the non-anti-pseudomonal antibiotic group and 465 (34%) in the anti-pseudomonal group; the numbers of in-hospital deaths were 86/897 (10%) and 63/465 (14%), respectively. Our frailty model yielded an adjusted hazard ratio (HR) (anti-pseudomonal group/non-anti-pseudomonal group) of 1.49 (95% confidence interval, 1.03-2.14). The empirical use of anti-pseudomonal antibiotics was associated with a higher HR of in-hospital mortality than the use of non-anti-pseudomonal antibiotics. Physicians might need to consider limiting the prescription of anti-pseudomonal antibiotics based on background factors such as the patient's baseline function and disease severity. Further studies are needed to evaluate the causal relationship between empirical anti-pseudomonal antibiotics and mortality, and identify specific patient population who benefit from empirical anti-pseudomonal antibiotics.

Chronic tracheostomy care of ventilator-dependent and -independent children: Clinical practice patterns of pediatric respirologists in a publicly funded (Canadian) healthcare system.

To describe the current clinical practice patterns of Canadian pediatric respirologists at pediatric tertiary care institutions regarding chronic tracheostomy tube care and management of home invasive ventilation. A pediatric respirologist/pediatrician with expertise in tracheostomy tube care and home ventilation was identified at each Canadian pediatric tertiary care center to complete a 59-item survey of multiple choice and short answer questions. Domains assessed included tracheostomy tube care, caregiver competency and home monitoring, speaking valves, medical management of tracheostomy complications, decannulation, and long-term follow-up. The response rate was 100% (17/17) with all Canadian tertiary care pediatric centers represented and heterogeneity of practice was observed in all domains assessed. For example, though most centers employ Bivona™ (17/17) and Shiley™ (15/17) tracheostomy tubes, variability was observed around tube change, re-use, and cleaning practices. Most centers require two trained caregivers (14/17) and recommend 24/7 eyes on care and oxygen saturation monitoring. Discharge with an emergency tracheostomy kit was universal (17/17). Considerable heterogeneity was observed in the timing and use of speaking valves and speech-language assessment. Inhaled anti-pseudomonal antibiotics are employed by most centers (16/17) though the indication, agent, and protocol varied by center. Though decannulation practices varied considerably, the requirement of upper airway patency was universally required to proceed with decannulation (17/17) independent of ongoing ventilatory support requirements. Considerable variability in pediatric tracheostomy tube care practice exists across Canada. These results will serve as a starting point to standardize and evaluate tracheostomy tube care nationally.

Bacterial Patterns and Empiric Antibiotic Use in COPD Patients With Community-Acquired Pneumonia

IntroductionChronic obstructive pulmonary disease (COPD) is strongly associated with the development of community-acquired pneumonia (CAP). Limited data are available on risk factors for difficult to manage bacteria such as Pseudomonas aeruginosa in COPD patients with CAP. Our objective was to assess the microbiological patterns associated with risk factors that determine empiric antibiotic therapy in hospitalized COPD patients with CAP. MethodsWe performed a secondary data analysis of an international, multicenter, observational, point-prevalence study involving hospitalized COPD patients with CAP from March to June 2015. After identifying the risk factors associated with different microorganisms, we developed a scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy in this population. ResultsWe enrolled 689 hospitalized COPD patients with CAP with documented microbiological testing. The most frequent microorganisms isolated were Streptococcus pneumoniae (8%) and Gram-negative bacteria (8%), P. aeruginosa (7%) and Haemophilus influenzae (3%). We developed a scoring system incorporating the variables independently associated with P. aeruginosa that include a previous P. aeruginosa isolation or infection (OR 14.2 [95%CI 5.7–35.2]), hospitalization in the past 12 months (OR 3.7 [1.5–9.2]), and bronchiectasis (OR 3.2 [1.4–7.2]). Empiric anti-pseudomonal antibiotics were overutilized in COPD patients with CAP. The new scoring system has the potential to reduce empiric anti-pseudomonal antibiotic use from 54.1% to 6.2%. ConclusionsCOPD patients with CAP present different microbiological profiles associated with unique risk factors. Anti-pseudomonal treatment is a critical decision when selecting empiric antibiotic therapy. We developed a COPD scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy.

Bacteriophage-antibiotic combination therapy for multidrug-resistant Pseudomonas aeruginosa: In vitro synergy testing.

Here, we investigate the impact of phage-antibiotic combinations (PAC) on bacterial killing, resistance development and outer membrane vesicle (OMV) production in multidrug-resistant (MDR) P. aeruginosa. After screening 10 well-characterized MDR P. aeruginosa strains against three P. aeruginosa phages, representative strains, R10266 and R9316, were selected for synergy testing based on high phage sensitivity and substantial antibiotic resistance patterns, while phage EM was chosen based on host range. To understand the impact of phage-antibiotic combinations (PAC) against MDR P. aeruginosa, time-kill analyses, OMV quantification and phage/antibiotic resistance testing were performed. Phage and meropenem demonstrated synergistic activity against both MDR strains. Triple combination regimens, phage-meropenem-colistin and phage-ciprofloxacin-colistin, resulted in the greatest CFU reduction for strains R9316 (3.50 log10 CFU ml-1 ) and R10266 (4.50 log10 CFU ml-1 ) respectively. PAC resulted in regained and improved antibiotic susceptibility to ciprofloxacin (MIC 2 to 0.0625) and meropenem (MIC 32 to 16), respectively, in R9316. Phage resistance was prevented or reduced in the presence of several classes of antibiotics and OMV production was reduced in the presence of phage for both strains, which was associated with significantly improved bacterial eradication. These findings support the potential of phage-antibiotic synergy (PAS) to augment killing of MDR P. aeruginosa. Systematic in vitro and in vivo studies are needed to better understand phage interactions with antipseudomonal antibiotics, to define the role of OMV production in P. aeruginosa PAC therapy and to outline pharmacokinetic and pharmacodynamic parameters conducive to PAS. This study identifies novel bactericidal phage-antibiotic combinations capable of thwarting resistance development in MDR and XDR P. aeruginosa strains. Furthermore, phage-mediated OMV reduction is identified as a potential mechanism through which PAC potentiates bacterial killing.

Multidrug-Resistant and Extremely Drug-Resistant Pseudomonas aeruginosa in Clinical Samples From a Tertiary Healthcare Facility in Nigeria.

Pseudomonas aeruginosa has been globally implicated in healthcare-associated infection. The susceptibility pattern of clinical isolates of P. aeruginosa to anti-pseudomonal antibiotics is reported. Clinical samples, namely blood, urine, tracheal aspirate, cerebrospinal fluid (CSF), wound swabs, high vaginal swabs, eye, and ear exudates were obtained from patients, processed and identified using standard microbiological protocols. Antibiotic susceptibility testing was undertaken using the Kirby Bauer Disc diffusion method. Results were reported following the Clinical and Laboratory Standards Institute guidelines. Of 104 P. aeruginosa isolates identified, males (52.88%) had a higher incidence of infection than female (47.11%) patients. The highest prevalence was recorded from wound swabs [46 (44.23%)] followed by ear exudates [23 (22.12%)], urine [22 (21.15%)], while eye exudates and samples from the CSF yielded the least [1 (0.96% each)]. From the antibiogram, imipenem had the highest antibiotic activity (91.3%) followed by polymyxin B (84.6%). The isolates exhibited the highest resistance to ceftazidime (73.1%) and piperacillin-tazobactam (61.5%). The antibiotic susceptibility pattern of P. aeruginosa isolates revealed 7.69% susceptible, 26% resistant, 61% multidrug resistance (MDR), 5% extremely drug resistance (XDR), and an absence (0%) of pandrug-resistant phenotypes. The study recorded alarmingly high cases of MDR and some XDR phenotypes of P. aeruginosa in University of Port Harcourt Teaching Hospital. It will help identify existing gaps in antimicrobial resistance surveillance and assist in improving public health policies regarding antibiotic stewardship, initiatives, and interventions.

Antibiotics and outcomes of CF pulmonary exacerbations in children infected with MRSA and Pseudomonas aeruginosa

Limited data exist to inform antibiotic selection among people with cystic fibrosis (CF) with airway infection by multiple CF-related microorganisms. This study aimed to determine among children with CF co-infected with methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (Pa) if the addition of anti-MRSA antibiotics to antipseudomonal antibiotic treatment for pulmonary exacerbations (PEx) would be associated with improved clinical outcomes compared with antipseudomonal antibiotics alone. Retrospective cohort study using data from the CF Foundation Patient Registry-Pediatric Health Information System linked dataset. The odds of returning to baseline lung function and having a subsequent PEx requiring intravenous antibiotics were compared between PEx treated with anti-MRSA and antipseudomonal antibiotics and those treated with antipseudomonal antibiotics alone, adjusting for confounding by indication using inverse probability of treatment weighting. 943 children with CF co-infected with MRSA and Pa contributed 2,989 PEx for analysis. Of these, 2,331 (78%) PEx were treated with both anti-MRSA and antipseudomonal antibiotics and 658 (22%) PEx were treated with antipseudomonal antibiotics alone. Compared with PEx treated with antipseudomonal antibiotics alone, the addition of anti-MRSA antibiotics to antipseudomonal antibiotic therapy was not associated with a higher odds of returning to ≥90% or ≥100% of baseline lung function or a lower odds of future PEx requiring intravenous antibiotics. Children with CF co-infected with MRSA and Pa may not benefit from the addition of anti-MRSA antibiotics for PEx treatment. Prospective studies evaluating optimal antibiotic selection strategies for PEx treatment are needed to optimize clinical outcomes following PEx treatment.

Treatment Heterogeneity in Pseudomonas aeruginosa Pneumonia

We have previously identified substantial antibiotic treatment heterogeneity, even among organism-specific and site-specific infections with treatment guidelines. Therefore, we sought to quantify the extent of treatment heterogeneity among patients hospitalized with P. aeruginosa pneumonia in the national Veterans Affairs Healthcare System from Jan-2015 to Apr-2018. Daily antibiotic exposures were mapped from three days prior to culture collection until discharge. Heterogeneity was defined as unique patterns of antibiotic treatment (drug and duration) not shared by any other patient. Our study included 5300 patients, of whom 87.5% had unique patterns of antibiotic drug and duration. Among patients receiving any initial antibiotic/s with a change to at least one anti-pseudomonal antibiotic (n = 3530, 66.6%) heterogeneity was 97.2%, while heterogeneity was 91.5% in those changing from any initial antibiotic/s to only anti-pseudomonal antibiotics (n = 576, 10.9%). When assessing heterogeneity of anti-pseudomonal antibiotic classes, irrespective of other antibiotic/s received (n = 4542, 85.7%), 50.5% had unique patterns of antibiotic class and duration, with median time to first change of three days, and a median of two changes. Real-world evidence is needed to inform the development of treatment pathways and antibiotic stewardship initiatives based on clinical outcome data, which is currently lacking in the presence of such treatment heterogeneity.

In vitro killing of multidrug/extensively drug-resistant Pseudomonas aeruginosa by fosfomycin alone or in combination with antipseudomonal antibiotics

Pseudomonas aeruginosa is a leading cause of nosocomial infections. Given the constant rise in resistance, adequate therapy is increasingly demanding. Fosfomycin recently became an appealing treatment option of bacterial infections due to multidrug-resistant bacteria (MDR). So far, fosfomycin synergy with other antibiotics has been assessed in studies, but only a limited number focused on MDR P. aeruginosa and on the effect of these combinations on the duration of the postantibiotic effect (PAE). We investigated synergy of fosfomycin with an array of antipseudomonal antibiotics using gradient diffusion strip cross method and time-kill method, and their effect on the duration of PAE against 51 variously resistant P. aeruginosa isolates. The highest rate of synergy was observed for combination with ceftazidime (23.4%) and gentamicin (19.1%). The PAE of antibiotic combinations was superior to that of the drugs alone. Our findings indicate that fosfomycin combination therapy may be a valuable treatment alternative.

Prevalence and Predictors of Pseudomonas aeruginosa Among Hospitalized Patients With Diabetic Foot Infections.

BackgroundDiabetic foot infections (DFIs) are commonly associated with antibiotic overuse. Empiric DFI treatment often includes coverage for Pseudomonas aeruginosa (PsA), but the frequency of PsA DFIs is poorly understood. The study objectives were to quantify the prevalence of and determine predictors for PsA DFIs.MethodsThis multicenter, retrospective cohort included hospitalized patients with DFI from 2013 through 2020 who were age ≥18 years; diabetes mellitus diagnosis; and DFI based on International Classification of Diseases, Tenth Revision coding, antibiotic treatment, and DFI culture with organism growth. Osteomyelitis was excluded. Patient characteristics were described and compared; the primary outcome was presence of PsA on DFI culture. Predictors of PsA DFI were identified using multivariable logistic regression.ResultsTwo hundred ninety-two patients were included. The median age was 61 (interquartile range [IQR], 53–69) years; the majority were men (201 [69%]) and White (163 [56%]). The most commonly isolated organisms were methicillin-susceptible Staphylococcus aureus (35%) and streptococci (32%); 147 (54%) cultures were polymicrobial. Two hundred fifty-seven (88%) patients received empiric antibiotics active against PsA, but only 27 (9%) patients had PsA DFI. Immunocompromised status (adjusted odds ratio [aOR], 4.6 [95% confidence interval {CI}, 1.3–16.7]) and previous outpatient DFI antibiotic treatment failure (aOR, 4.8 [95% CI, 1.9–11.9]) were associated with PsA DFI.ConclusionsPsA DFI is uncommon, but most patients receive empiric antipseudomonal antibiotics. Empiric broad-spectrum antibiotics are warranted given the frequency of mixed infections, but patient-specific risk factors should be considered before adding antipseudomonal coverage.

Comparison of Ceftolozane/Tazobactam Infusion Regimens in a Hollow-Fiber Infection Model against Extensively Drug-Resistant Pseudomonas aeruginosa Isolates.

ABSTRACTThe aim of this study was to compare the efficacy of intermittent (1-h), extended (4-h), and continuous ceftolozane-tazobactam (C/T) infusion against three extensively drug-resistant (XDR) sequence type (ST) 175 P. aeruginosa isolates with different susceptibilities to C/T (MIC = 2 to 16 mg/L) in a 7-day hollow-fiber infection model (HFIM). C/T in continuous infusion achieved the largest reduction in total number of bacterial colonies in the overall treatment arms for both C/T-susceptible and -resistant isolates. It was also the only regimen with bactericidal activity against all three isolates. These data suggest that continuous C/T infusion should be considered a potential treatment for infections caused by XDR P. aeruginosa isolates, including nonsusceptible ones. Proper use of C/T dosing regimens may lead to better clinical management of XDR P. aeruginosa infections.IMPORTANCE Ceftolozane-tazobactam (C/T) is an antipseudomonal antibiotic with a high clinical impact in treating infection caused by extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates, but resistance is emerging. Given its time-dependent behavior, C/T continuous infusion can improve exposure and therefore the pharmacokinetic/pharmacodynamic target attainment. We compared the efficacy of intermittent, extended, and continuous C/T infusion against three XDR ST175 P. aeruginosa isolates with different C/T MICs by means of an in vitro dynamic hollow-fiber model. We demonstrated that C/T in continuous infusion achieved the largest reduction in bacterial density in the overall treatment arms for both susceptible and resistant isolates. It was also the only regimen with bactericidal activity against all three isolates. Through this study, we want to demonstrate that developing individually tailored antimicrobial treatments is becoming essential. Our results support the role of C/T level monitoring and of dose adjustments for better clinical management and outcomes.

Necrotic ulcers in an immunocompromised patient

A 68-year-old man presented to dermatology clinic with extensive ulcers for one-week duration. Patient had underlying uncontrolled Type II Diabetes Mellitus and pemphigus foliaceous. His medications were metformin 1 g twice daily, prednisolone 30 mg daily and azathioprine 50 mg daily. He denied fever, prior trauma or insect bites. On examination, there were multiple necrotic ulcers of varying sizes present on the anterior trunk and extensors of left knee (Fig. 1A & B). Some of the lesions were exudative with serous discharge. The surrounding skin was erythematous. Blood investigation revealed leucocytosis at 15,000 cells per cubic millimetre and a raised C-Reactive Protein (CRP) at 8 mg/dL. Patient was empirically started on intravenous piperacillin-tazobactam 4.5 g thrice daily to cover for bacterial skin infection. Four days later, swab from the lesion yielded Pseudomonas Aeruginosa with sensitivity towards ceftazidime. Blood culture revealed no growth. Antibiotic therapy was changed to intravenous ceftazidime 1 g thrice daily. Surgical debridement of the necrotic patches was done twice, followed by bactigrass and duoderm dressing. After 1 week of therapy, patient remained well with no new ulcers formed. Inflammatory markers such as total white cell counts and CRP have normalised too. Hence, he was discharged home. What is the diagnosis? Ecthyma gangrenosum. Ecthyma gangrenosum (EG) is a haemorrhagic and necrosing vasculitis of the small vessels, commonly associated with Pseudomonas Aeruginosa [[1]Vaiman M. et al.Ecthyma gangrenosum and ecthyma-like lesions: review article.Eur J Clin Microbiol Infect Dis. 2015; 34: 633-639https://doi.org/10.1007/s10096-014-2277-6Crossref PubMed Scopus (112) Google Scholar]. Risk factors include neutropenia, malignancies, immunosuppressive treatments and diabetes mellitus. [[1]Vaiman M. et al.Ecthyma gangrenosum and ecthyma-like lesions: review article.Eur J Clin Microbiol Infect Dis. 2015; 34: 633-639https://doi.org/10.1007/s10096-014-2277-6Crossref PubMed Scopus (112) Google Scholar, [2]Bettens S. et al.Ecthyma gangrenosum in a non-neutropaenic, elderly patient: case report and review of the literature.Acta Clin Belg. 2008; 63: 394-397https://doi.org/10.1179/acb.2008.081Crossref PubMed Scopus (18) Google Scholar] EG presents with painless erythematous macules, with or without vesicles. Within 12–24 h, the lesions become indurated with haemorrhagic blisters. Finally, deep-necrotic ulcers with a grey-black eschar formed with a surrounding erythematous halo. [[2]Bettens S. et al.Ecthyma gangrenosum in a non-neutropaenic, elderly patient: case report and review of the literature.Acta Clin Belg. 2008; 63: 394-397https://doi.org/10.1179/acb.2008.081Crossref PubMed Scopus (18) Google Scholar] Most common affected sites are perineal (57%), distal extremities (30%), facial and truncal (12%)[[2]Bettens S. et al.Ecthyma gangrenosum in a non-neutropaenic, elderly patient: case report and review of the literature.Acta Clin Belg. 2008; 63: 394-397https://doi.org/10.1179/acb.2008.081Crossref PubMed Scopus (18) Google Scholar]. Clinical assessment is sufficed to diagnose EG. Culture from tissue or swab of lesion may identify the causative pathogen. [[1]Vaiman M. et al.Ecthyma gangrenosum and ecthyma-like lesions: review article.Eur J Clin Microbiol Infect Dis. 2015; 34: 633-639https://doi.org/10.1007/s10096-014-2277-6Crossref PubMed Scopus (112) Google Scholar, [2]Bettens S. et al.Ecthyma gangrenosum in a non-neutropaenic, elderly patient: case report and review of the literature.Acta Clin Belg. 2008; 63: 394-397https://doi.org/10.1179/acb.2008.081Crossref PubMed Scopus (18) Google Scholar] Blood culture is recommended if bacteraemia is suspected. [[1]Vaiman M. et al.Ecthyma gangrenosum and ecthyma-like lesions: review article.Eur J Clin Microbiol Infect Dis. 2015; 34: 633-639https://doi.org/10.1007/s10096-014-2277-6Crossref PubMed Scopus (112) Google Scholar] Empirical treatment with anti-pseudomonal antibiotic is recommended if the diagnosis of EG is suspected. [[1]Vaiman M. et al.Ecthyma gangrenosum and ecthyma-like lesions: review article.Eur J Clin Microbiol Infect Dis. 2015; 34: 633-639https://doi.org/10.1007/s10096-014-2277-6Crossref PubMed Scopus (112) Google Scholar, [2]Bettens S. et al.Ecthyma gangrenosum in a non-neutropaenic, elderly patient: case report and review of the literature.Acta Clin Belg. 2008; 63: 394-397https://doi.org/10.1179/acb.2008.081Crossref PubMed Scopus (18) Google Scholar] Once the causative organism and its sensitivity are identified, targeted therapy of a single antimicrobial agent is administered until improvement of lesions is observed. Surgical debridement is indicated in extensive cutaneous lesions, abscess or non-responsive to medical therapy alone. [[1]Vaiman M. et al.Ecthyma gangrenosum and ecthyma-like lesions: review article.Eur J Clin Microbiol Infect Dis. 2015; 34: 633-639https://doi.org/10.1007/s10096-014-2277-6Crossref PubMed Scopus (112) Google Scholar, [2]Bettens S. et al.Ecthyma gangrenosum in a non-neutropaenic, elderly patient: case report and review of the literature.Acta Clin Belg. 2008; 63: 394-397https://doi.org/10.1179/acb.2008.081Crossref PubMed Scopus (18) Google Scholar] This case emphasizes the need to recognise EG and deliver suitable treatment early. Delay in diagnosis may result in fatal outcome as the mortality rate ranges from 38% to 77%. [[2]Bettens S. et al.Ecthyma gangrenosum in a non-neutropaenic, elderly patient: case report and review of the literature.Acta Clin Belg. 2008; 63: 394-397https://doi.org/10.1179/acb.2008.081Crossref PubMed Scopus (18) Google Scholar] Informed consent of the patient has been obtained to publish his case and images in the manuscript. The authors declare that they have no competing interests.

Hospital-level variation in the utilization of antipseudomonal antibiotics: A nationwide cross-sectional study at the VHA

Background: Avoiding unnecessary antipseudomonal coverage is 1 of the most common targets for antibiotic stewardship programs (ASPs), but little is known about the magnitude of facility-level variation in antipseudomonal agent utilization. We aimed to describe the variability in the use of antipseudomonal agents across inpatient settings within a nationwide integrated healthcare system. Method: We analyzed the data from a retrospective cohort of patients who were admitted to acute-care hospitals within the VHA system in 2019. We defined antipseudomonal agents as systemic antibiotics with activity against wild-type Pseudomonas aeruginosa, and we evaluated overall and antipseudomonal antibiotic use among 129 hospitals, according to the agents described in the NHSN Antimicrobial Usage and Resistance Module. We calculated each hospital’s overall and antipseudomonal days of therapy (DOT) per 1,000 days present and the proportion of antipseudomonal agent usage among all antibiotics based on DOT at each hospital. Hospital-level variation was assessed by comparing the proportion of total antibiotic consumption accounted for by antipseudomonal agents. Associations between antipseudomonal proportions and overall antibiotic consumption were also assessed. Results: Among 129 VHA hospitals, the median DOT per 1,000 days present for all antibiotics was 434.4 (IQR, 371.9–487.1), and the median antipseudomonal DOT per 1,000 days present was 127.7 (IQR, 99.8–159.6). The median proportion of total antibiotic consumption accounted for by antipseudomonal agents was 30.0% (range, 14.9%–40.7%; IQR, 26.4%–34.4%) (Fig. 1). We detected only a weak correlation between overall antibiotic consumption and antipseudomonal proportion (Pearson correlation coefficient, 0.396), which suggests that hospitals with higher total antibiotic consumption were not necessarily using more antipseudomonal agents. In a stratified analysis, there was more prominent hospital-level variability in surgical specialties than medical specialties (Fig. 2). Conclusions: We detected high hospital-level variability in the consumption and proportion of antipseudomonal antibiotics among an integrated healthcare system. Although it is plausible that these variabilities originated from case-mix differences among hospitals, including differing rates of P. aeruginosa infections, it may also highlight opportunities for reducing antipseudomonal antibiotic utilization, especially among surgical specialties. Further studies are needed to evaluate the contribution of modifiable patient- and facility-level factors to this variability.Funding: NoneDisclosures: None

New Drugs for the Treatment of Pseudomonas aeruginosa Infections with Limited Treatment Options: A Narrative Review.

P. aeruginosa is still one of the most threatening pathogens responsible for serious hospital-acquired infections. It is intrinsically resistant to many antimicrobial agents and additional acquired resistance further complicates the management of such infections. High rates of combined antimicrobial resistance persist in many countries, especially in the eastern and south-eastern parts of Europe. The aim of this narrative review is to provide a comprehensive assessment of the epidemiology, latest data, and clinical evidence on the current and new available drugs active against P. aeruginosa isolates with limited treatment options. The latest evidence and recommendations supporting the use of ceftolozane-tazobactam and ceftazidime-avibactam, characterized by targeted clinical activity against a significant proportion of P. aeruginosa strains with limited treatment options, are described based on a review of the latest microbiological and clinical studies. Cefiderocol, with excellent in vitro activity against P. aeruginosa isolates, good stability to all β-lactamases and against porin and efflux pumps mutations, is also examined. New carbapenem combinations are explored, reviewing the latest experimental and initial clinical evidence. One section is devoted to a review of new anti-pseudomonal antibiotics in the pipeline, such as cefepime-taniborbactam and cefepime-zidebactam. Finally, other “old” antimicrobials, mainly fosfomycin, that can be used as combination strategies, are described.

Using Structure-guided Fragment-Based Drug Discovery to Target Pseudomonas aeruginosa Infections in Cystic Fibrosis.

Cystic fibrosis (CF) is progressive genetic disease that predisposes lungs and other organs to multiple long-lasting microbial infections. Pseudomonas aeruginosa is the most prevalent and deadly pathogen among these microbes. Lung function of CF patients worsens following chronic infections with P. aeruginosa and is associated with increased mortality and morbidity. Emergence of multidrug-resistant, extensively drug-resistant and pandrug-resistant strains of P. aeruginosa due to intrinsic and adaptive antibiotic resistance mechanisms has failed the current anti-pseudomonal antibiotics. Hence new antibacterials are urgently needed to treat P. aeruginosa infections. Structure-guided fragment-based drug discovery (FBDD) is a powerful approach in the field of drug development that has succeeded in delivering six FDA approved drugs over the past 20 years targeting a variety of biological molecules. However, FBDD has not been widely used in the development of anti-pseudomonal molecules. In this review, we first give a brief overview of our structure-guided FBDD pipeline and then give a detailed account of FBDD campaigns to combat P. aeruginosa infections by developing small molecules having either bactericidal or anti-virulence properties. We conclude with a brief overview of the FBDD efforts in our lab at the University of Cambridge towards targeting P. aeruginosa infections.

Synthesis of copper oxide nanoparticles using capsular polymeric substances produced by Bacillus altitudinis and investigation of its efficacy to kill pathogenic Pseudomonas aeruginosa

Clinically relevant antibiotic-resistant bacteria are appeared to be hard or impossible to treat using conventional antibiotics. In this context, copper oxide nanoparticles (CuO NPs) with latent and flexible character showed remarkable antimicrobial activity against pathogenic Pseudomonas aeruginosa. Minimum inhibitory concentration (<1 mcg/ml) and minimum bactericidal concentration (∼3 mcg/ml) for synthesized CuO NPs were predicted, comparable to the available antipseudomonal antibiotics. Green synthesis of CuO NPs was executed using capsular polymeric substance (CPS) extracted from a marine Bacillus altitudinis SORB11.The compound CPS containing mannose, glucose and galactose was compact and agglomerated in nature with a molecular weight of 1.247 × 103 Da. Crude CPS was effectively used as a coating and stabilizing agent for the synthesis of CuO NPs. The synthesized uniform, spherical CuO NPs showed a face-centered cubic cuprous oxide with a cuprite structure that appeared in crystalline planes. This present study was demonstrated successfully synthesized CuO NPs using an eco-friendly synthesis technique and ultimately, showed a significant level of antibacterial activity against pathogenic Pseudomonas aeruginosa.

Clinical Outcomes of Antipseudomonal versus Other Antibiotics among Children with Cystic Fibrosis without Pseudomonas aeruginosa.

Rationale: Antibiotic selection for pulmonary exacerbation (PEx) management in children with cystic fibrosis is typically guided by prior respiratory culture results. Although antipseudomonal antibiotics are often used in children with chronic Pseudomonas aeruginosa (Pa) airway infection, no data exist to guide antibiotic selection in children who are culture negative for Pa for ≥1 year. Objectives: To determine among children classified as 1, 2, or 3 years' Pa negative if PEx treatment with at least one oral and/or intravenous antipseudomonal antibiotic is associated with improved clinical outcomes compared with treatment with antibiotics not effective against Pa. Methods: A retrospective cohort study was conducted using the linked Cystic Fibrosis Foundation Patient Registry-Pediatric Health Information System database. We included children 6-21 years old hospitalized between 2008 and 2018 consistently culture negative for Pa 1 year before a study PEx. Children were classified as 1 or 2 years' Pa negative if their last Pa-positive culture occurred in the 13-24 months or 25-36 months before a study PEx, respectively, with all subsequent cultures negative for Pa. Children classified as 3 years' Pa negative had no Pa-positive cultures in the 36 months before a study PEx. Inverse probability of treatment weighted linear or logistic regression models were used to compare clinical outcomes (pre- to post-PEx forced expiratory volume in 1 s, odds of returning to ≥90% of baseline lung function, and odds of having a future PEx) between antipseudomonal and non-antipseudomonal antibiotic strategies. Results: Among all children included in the linked data set, 1,290 children with 2,347 PExs were eligible for analysis. Among all study PExs, 530, 326, and 1,491 were classified as 1, 2, and 3 years' Pa negative, respectively, and antipseudomonal antibiotics were administered in 79%, 67%, and 66% of all PExs classified as 1, 2, and 3 years' Pa negative, respectively. For all Pa-negative groups, when compared with non-antipseudomonal antibiotic regimens, antipseudomonal antibiotic treatment was not associated with greater improvement in any studied clinical outcome. Conclusions: Despite their common use, including antibiotics effective against Pa may provide no additional benefit for PEx treatment among children who are Pa negative for at least 1 year prior. Prospective trials are warranted to directly test this hypothesis.