Antipseudomonal Antibiotics Research Articles

A Three-year Longitudinal Assessment of Pseudomonas aeruginosa Antibiotic Susceptibility in Children With Cystic Fibrosis in the Era of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy

fibrosis is a genetic disease characterized by chronic lung infection, often with Pseudomonas aeruginosa, requiring repeated antibiotic treatment for pulmonary exacerbations. In the era of cystic fibrosis transmembrane conductance regulator modulator therapy, we assessed susceptibility to antipseudomonal antibiotics in modulator-eligible and modulator-ineligible children over 3 years and found that P. aeruginosa isolates largely remained susceptible to standard parenteral but not oral antimicrobial agents.

Prophages are Infrequently Associated With Antibiotic Resistance in Pseudomonas aeruginosa Clinical Isolates.

Antimicrobial resistance (AMR) is a significant obstacle to the treatment of bacterial infections, including in the context of Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF). Lysogenic bacteriophages can integrate their genome into the bacterial chromosome and are known to promote genetic transfer between bacterial strains. However, the contribution of lysogenic phages to the incidence of AMR is poorly understood. Here, in a set of 184 clinical isolates of Pseudomonas aeruginosa collected from 83 patients with CF, we evaluate the links between prophages and both genomic and phenotypic AMR associated with five anti-pseudomonal antibiotics: tobramycin, colistin, ciprofloxacin, meropenem, aztreonam, and tazobactam. We find that P. aeruginosa isolates contain on average XX +/- XX predicted prophages. There was no significant association between the number of prophages per isolate and the mean inhibitory concentration (MIC) for any of these antibiotics. We then investigate the relationship between particular prophages and AMR. We identify only a single lysogenic phage that is associated with phenotypic resistance to an antibiotic, tobramycin. Consistent with this association, we identify AMR genes associated with resistance to tobramycin in these strains and find that they are proximal to but not encoded by prophages within the bacterial genome. These findings suggest that prophages are infrequently associated with the AMR genes in clinical isolates of P. aeruginosa.

Inhaled Medications for Maintenance Therapy in Pediatric Noncystic Fibrosis Bronchiectasis.

This review focuses on evaluating literature for the use of inhaled mucolytics (hypertonic saline, mannitol, and dornase alfa), inhaled antibiotics (tobramycin, aztreonam, colistin, and amikacin), and inhaled corticosteroids in pediatric noncystic fibrosis bronchiectasis. A literature search via PubMed was conducted using the search terms "non-cystic fibrosis bronchiectasis," "primary ciliary dyskinesia," and "bronchiectasis" in combination with each inhaled agent of interest. Studies were included if they were specific to patients with a clinical diagnosis of noncystic fibrosis bronchiectasis published from 1998 to July 2024. Several inhaled medications can be considered as maintenance therapies for pediatric patients with noncystic fibrosis bronchiectasis. Hypertonic saline could be considered for its potential airway clearance benefits and low risk of causing harm. Inhaled antipseudomonal antibiotics should be considered in patients who are colonized with Pseudomonas aeruginosa. Inhaled corticosteroid therapy should be reserved for patients with concomitant asthma. Dornase alfa has shown worse outcomes in adults with noncystic fibrosis bronchiectasis and should be used with caution. Risks and benefits should be carefully considered when evaluating these therapies for use in noncystic fibrosis bronchiectasis, and patient-specific treatment regimens should be developed. Chronic management of pediatric noncystic fibrosis bronchiectasis remains challenging due to paucity of applicable literature. Risks and benefits of different agents are discussed in this article with recommendations for application to clinical practice based on studies performed in both adult and pediatric patients with noncystic fibrosis bronchiectasis. Several inhaled medications could be considered as maintenance therapies for pediatric patients with noncystic fibrosis bronchiectasis, with more robust evidence to support use of inhaled antipseudomonal antibiotics and hypertonic saline compared with other available agents. Further investigation is needed to identify a clear place in therapy for inhaled therapies in pediatric noncystic fibrosis bronchiectasis.

Clinical profiles of community-acquired Pseudomonas aeruginosa infections in children

Objectives: To investigate clinical characteristics, outcomes and antimicrobial resistance of community-acquired Pseudomonas aeruginosa (CAPA) infections in Chinese pediatric patients. Methods: This retrospective study was conducted at 6 tertiary hospitals in China during January 2016 to December 2018. The clinical and microbiological data of CAPA infected hospitalized children in Hainan and in other regions were collected and compared, and the antimicrobial resistance patterns, clinical characteristics and antibiotic therapy were analyzed. Between different groups were compared using the Chi-square test and Mann-Whitney U test. Results: Among 91 patients, 63 cases were males, 28 cases were females, and 74 cases were from Hainan province, 17 cases were from other regians. The age of consultation was 22.5 (5.4, 44.0) months. Twenty-four cases (26%) had underlying diseases. Fever (79 cases (87%)) and cough (64 cases (70%)) were common initial symptoms. Other concomitant symptoms included wheezing 8 cases (9%), diarrhea 3 cases (3%) and vomiting 4 cases (4%). Twenty-eight cases (31%) had organ infections, including pneumonia 22 cases (24%), skin infection 5 cases (5%), meningitis, intra-abdominal infection and upper urinary tract infection each 1 case (1%). The resistance rate of CAPA isolates to cefepime (4% (4/90)), amikacin (1% (1/90)), ciprofloxacin (2% (2/90)) and levofloxacin (1% (1/89)) was low, and to ceftazidime, piperacillin, piperacillin-azobactam, carbapenem was 12% (11/90), 3/16, 18% (10/56) and 6% (5/90), respectively. Antimicrobial combination therapy accounted for 52% (47/91) of empirical therapy and 59% (52/88) of definite therapy. Two cases (2%) were hopeless discharged, and 3 cases (3%) died during hospitalization. The worse prognosis of CAPA infection is significantly different among children in other regions and in Hainan (4/17 vs. 1% (1/74), χ²=9.74, P<0.05). Conclusions: The invasive CAPA-infection has regional difference in incidence and prognosis in China. Clinical symptoms and signs are non-specific. CAPA strains isolated from pediatric patients display low level of resistance to most of the common antipseudomonal antibiotics. The proportion of poor prognostic outcome is lower in Hainan than in other regions.

Antibiotic practice and stewardship in the management of neutropenic fever: a survey of US institutions.

To describe neutropenic fever management practices among healthcare institutions. Survey. Members of the Society for Healthcare Epidemiology of America Research Network (SRN) representing healthcare institutions within the United States. An electronic survey was distributed to SRN representatives, with questions pertaining to demographics, antimicrobial prophylaxis, supportive care, and neutropenic fever management. The survey was distributed from fall 2022 through spring 2023. 40 complete responses were recorded (54.8% response rate), with respondent institutions accounting for approximately 15.7% of 2021 US hematologic malignancy hospitalizations and 14.9% of 2020 US bone marrow transplantations. Most entities have institutional guidelines for neutropenic fever management (35, 87.5%) and prophylaxis (31, 77.5%), and first-line treatment included IV antipseudomonal antibiotics (35, 87.5% cephalosporin; 5, 12.5% penicillin; 0, 0% carbapenem).We observed significant heterogeneity in treatment course decisions, with roughly half (18, 45.0%) of respondents continuing antibiotics until neutrophil recovery, while the remainder having criteria for de-escalation prior to neutrophil recovery. Respondents were more willing to de-escalate prior to neutrophil recovery in patients with identified clinical (27, 67.5% with pneumonia) or microbiological (30, 75.0% with bacteremia) sources after dedicated treatment courses. We found substantial variation in the practice of de-escalation of empiric antibiotics relative to neutrophil recovery, highlighting a need for more robust evidence for and adoption of this practice. No respondents use carbapenems as first-line therapy, comparing favorably to prior survey studies conducted in other countries.

Methyl gallate attenuates virulence and decreases antibiotic resistance in extensively drug-resistant Pseudomonasaeruginosa

Pseudomonas aeruginosa infections have become a serious threat to public health due to the increasing emergence of extensively antibiotic-resistant strains and high mortality rates. Therefore, the search for new therapeutic alternatives has become crucial. In this study, the antivirulence and antibacterial activity of methyl gallate was evaluated against six clinical isolates of extensively antibiotic-resistant P. aeruginosa. Methyl gallate exhibited minimal inhibitory concentrations of 256–384 μg/mL; moreover, the use of subinhibitory concentrations of the compound inhibited biofilm formation, swimming, swarming, proteolytic activity, and pyocyanin production. Methyl gallate plus antipseudomonal antibiotics showed a synergistic effect by reduced the MICs of ceftazidime, gentamicin and meropenem. Furthermore, the potential therapeutic effect of methyl gallate was demonstrated in an infection model. This study evidenced the antivirulence and antimicrobial activity of methyl gallate as a therapeutic alternative against P. aeruginosa.

Sequential development of diffuse panbronchiolitis and myasthenia gravis after thymectomy for thymic neoplasm: a case report

BackgroundMyasthenia gravis (MG) is the most common paraneoplastic disorder associated with thymic neoplasms. MG can develop after thymectomy, and this condition is referred to post-thymectomy myasthenia gravis (PTMG). Diffuse panbronchiolitis (DPB), is a rare form of bronchiolitis and is largely restricted to East Asia, has been reported in association with thymic neoplasms. Only three cases of combined MG and DPB have been reported in the literature.Case presentationA 45-year-old Taiwanese woman presented to our hospital with productive cough, rhinorrhea, anosmia, ear fullness, shortness of breath, and weight loss. She had a history of thymoma, and she underwent thymectomy with adjuvant radiotherapy 7 years ago. Chest computed tomography scan revealed diffuse bronchitis and bronchiolitis. DPB was confirmed after video-assisted thoracoscopic surgery lung biopsy, and repeated sputum cultures grew Pseudomonas aeruginosa. She has been on long-term oral azithromycin therapy thereafter. Intravenous antipseudomonal antibiotics, inhaled amikacin, as well as oral levofloxacin were administered. Three months after DPB diagnosis, she developed ptosis, muscle weakness, and hypercapnia requiring the use of noninvasive positive pressure ventilation. MG was diagnosed based on the acetylcholine receptor antibody and repetitive stimulation test results. Her muscle weakness gradually improved after pyridostigmine and corticosteroid therapies. Oral corticosteroids could be tapered off ten months after the diagnosis of MG. She is currently maintained on azithromycin, pyridostigmine, and inhaled amikacin therapies, with intravenous antibiotics administered occasionally during hospitalizations for respiratory infections.ConclusionsTo our knowledge, this might be the first case report of sequential development of DPB followed by PTMG. The coexistence of these two disorders poses a therapeutic challenge for balancing infection control for DPB and immunosuppressant therapies for MG.

Staphylococcus aureus Is the Predominant Pathogen in Hospitalised Patients with Diabetes-Related Foot Infections: An Australian Perspective.

Diabetes prevalence continues to increase worldwide, which has led to a rising incidence of diabetes-related foot infections (DFIs). There is significant local variation in the microbiology of DFIs, and Pseudomonas spp. is suggested to be more prevalent in subtropical climates. The aim of this study was to investigate the local microbiological findings in patients admitted to the hospital with DFIs. This retrospective study analysed data from all adult patients diagnosed with diabetes and admitted to the hospital for the treatment of a DFI between 1 January 2021 and 31 December 2022. Both superficial wound swabs and tissue cultures were included. The Infectious Diseases Society of America classification system was used to categorise the severity of the DFI. Patient characteristics and demographics were analysed using descriptive statistics. One hundred fifty-one episodes of care were included. Most of the DFIs were classified as moderate infections 101/151 (67%). The most commonly isolated microorganism was Staphylococcus aureus (33%) followed by normal skin flora (11%) and β-haemolytic streptococci (7%). P. aeruginosa was isolated more commonly in those with chronic DFIs (10%) compared to those with acute DFIs (2%). Despite the frequent identification of S. aureus, 83% of patients received an antipseudomonal antibiotic. The introduction of multidisciplinary DFI rounds should be considered.

In Vitro Antibiofilm Activity of Fosfomycin Alone and in Combination with Other Antibiotics against Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa.

Due to its rapid resistance development and ability to form biofilms, treatment of Pseudomonas aeruginosa infections is becoming more complicated by the day. Drug combinations may help reduce both resistance and biofilm formation. Using the microtiter plate assay, we investigated the in vitro inhibition of biofilm formation and the disruption of preformed biofilms in multidrug-resistant and extensively drug-resistant clinical isolates of P. aeruginosa in the presence of peak plasma levels of eight antipseudomonal antibiotics alone and in combination with fosfomycin: ceftazidime, piperacillin/tazobactam, cefepime, imipenem, gentamicin, amikacin, ciprofloxacin and colistin. Combination therapy was significantly superior to monotherapy in its inhibition of biofilm formation. The highest inhibition rates were observed for combinations with colistin, cefepime and ceftazidime. Our results support fosfomycin combination therapy as an enhanced prophylactic option. Moreover, combinations with β-lactam antibiotics and colistin demonstrated a more potent inhibition effect on biofilm formation than protein synthesis inhibitors.

Medical Causes of Hospitalisation among Patients with Bronchiectasis: A Nationwide Study in Japan.

Although the international guidelines for managing bronchiectasis are centred on preventing the exacerbation of bronchiectasis, the medical causes of admissions to hospital among patients with bronchiectasis have not been fully investigated. This study targeted patients with bronchiectasis who were admitted to hospitals between April 2018 and March 2020 using the national inpatient database in Japan. The causes of hospitalisation and types of antibiotics used for hospitalised patients were recorded. In total, 21,300 hospitalisations of 16,723 patients with bronchiectasis were analysed. The most common cause was respiratory diseases in 15,145 (71.1%) admissions, including bacterial pneumonia and the exacerbation of bronchiectasis in 6238 (41.2%) and 3151 (20.8%), respectively. Antipseudomonal antibiotics were used in approximately 60% of patients with bacterial pneumonia who were administered antibiotic treatments and in approximately 50% of patients with the exacerbation of bronchiectasis. Bacterial pneumonia was the most frequent cause of hospitalisation, followed by the exacerbation of bronchiectasis, among patients with bronchiectasis. Physicians need to focus on the prevention of bacterial pneumonia in addition to the exacerbation of bronchiectasis in patients with bronchiectasis.

Systemic antibiotics for Pseudomonas aeruginosa infection in outpatients with non-hospitalised exacerbations of pre-existing lung diseases: a randomised clinical trial

BackgroundThe effect of dual systemic antibiotic therapy against Pseudomonas aeruginosa in patients with pre-existing lung disease is unknown. To assess whether dual systemic antibiotics against P. aeruginosa in outpatients with COPD, non-cystic fibrosis (non-CF) bronchiectasis, or asthma can improve outcomes.MethodsMulticenter, randomised, open-label trial conducted at seven respiratory outpatient clinics in Denmark. Outpatients with COPD, non-CF bronchiectasis, or asthma with a current P. aeruginosa-positive lower respiratory tract culture (clinical routine samples obtained based on symptoms of exacerbation not requiring hospitalisation), regardless of prior P. aeruginosa-status, no current need for hospitalisation, and at least two moderate or one hospitalisation-requiring exacerbation within the last year were eligible. Patients were assigned 1:1 to 14 days of dual systemic anti-pseudomonal antibiotics or no antibiotic treatment. Primary outcome was time to prednisolone or antibiotic-requiring exacerbation or death from day 20 to day 365.ResultsThe trial was stopped prematurely based in lack of recruitment during the COVID-19 pandemic, this decision was endorsed by the Data and Safety Monitoring Board. Forty-nine outpatients were included in the study. There was a reduction in risk of the primary outcome in the antibiotic group compared to the control group (HR 0.51 (95%CI 0.27–0.96), p = 0.037). The incidence of admissions with exacerbation within one year was 1.1 (95%CI 0.6–1.7) in the dual antibiotic group vs. 2.9 (95%CI 1.3–4.5) in the control group, p = 0.037.ConclusionsUse of dual systemic antibiotics for 14 days against P. aeruginosa in outpatients with chronic lung diseases and no judged need for hospitalisation, improved clinical outcomes markedly. The main limitation was the premature closure of the trial.Trial RegistrationClinicalTrials.gov, NCT03262142, registration date 2017–08-25.

Reply to Lau et al Re: "Antipseudomonal Antibiotics in Diabetic Foot Infections: A Practical Perspective From a Community Hospital".

Reply to Lau et al Re: "Antipseudomonal Antibiotics in Diabetic Foot Infections: A Practical Perspective From a Community Hospital".

Investigating Sulforaphane's anti-virulence and anti-quorum sensing properties against Pseudomonas aeruginosa.

P. aeruginosa, a significant bacterium, can cause severe illness and resistance to antibiotics. Quorum sensing (QS) systems regulate virulence factors production. Targeting QS could reduce bacteria pathogenicity and prevent antibiotic resistance. Cruciferous vegetables contain sulforaphane, known for its anti-inflammatory, antioxidant, anticancer, and antimicrobial properties. We aimed to examine the inhibitory influences of sulforaphane, at a sub-inhibitory concentration (¼ minimum inhibitory concentration, MIC), on virulence and QS in P. aeruginosa. The sulforaphane's anti-virulence actions at sub-inhibitory concentrations were explored in vitro and in vivo. A sub-MIC concentration of sulforaphane was combined with anti-pseudomonal drugs, and the results of this combination were assessed. The virtual affinity of sulforaphane for the receptors of QS was studied, and its effect on the expression of QS genes was quantified. Sulforaphane significantly decreased the biofilm formation, motility, ability to withstand oxidative stress, and the synthesis of virulence extracellular enzymes such as proteases, hemolysins, and elastase, as well as other virulence factors like pyocyanin. In addition, sulforaphane lessened the severity of P. aeruginosa infection in mice. Sulforaphane reduced the antipseudomonal antibiotics' MICs when used together, resulting in synergistic effects. The observed anti-virulence impacts were attributed to the ability of sulforaphane to inhibit QS via suppressing the QS genes' expression. Sulforaphane shows promise as a potent anti-virulence and anti-QS agent that can be used alongside conventional antimicrobials to manage severe infections effectively. Furthermore, this study paves the way for further investigation of sulforaphane and similar structures as pharmacophores for anti-QS candidates.

Association between Empirical Anti-Pseudomonal Antibiotics and Progression to Thoracic Surgery and Death in Empyema: Database Research.

Evidence on the optimal antibiotic strategy for empyema is lacking. Our database study aimed to evaluate the effectiveness of empirical anti-pseudomonal antibiotics in patients with empyema. We utilised a Japanese real-world data database, focusing on patients aged ≥40 diagnosed with empyema, who underwent thoracostomy and received intravenous antibiotics either upon admission or the following day. Patients administered intravenous vasopressors were excluded. We compared thoracic surgery and death within 90 days after admission between patients treated with empirical anti-pseudomonal and non-anti-pseudomonal antibiotics. Cause-specific hazard ratios for thoracic surgery and death were estimated using Cox proportional hazards models, with adjustment for clinically important confounders. Subgroup analyses entailed the same procedures for patients exhibiting at least one risk factor for multidrug-resistant organisms. Between March 2014 and March 2023, 855 patients with empyema meeting the inclusion criteria were enrolled. Among them, 271 (31.7%) patients received anti-pseudomonal antibiotics. The Cox proportional hazards models indicated that compared to empirical non-anti-pseudomonal antibiotics, empirical anti-pseudomonal antibiotics were associated with higher HRs for thoracic surgery and death within 90 days, respectively. Thus, regardless of the risks of multidrug-resistant organisms, empirical anti-pseudomonal antibiotics did not extend the time to thoracic surgery or death within 90 days.

Risk of Pseudomonas aeruginosa antimicrobial resistance using time series analysis of antibiotic usage

AbstractBackgroundAntimicrobial resistance is emerging as one of the most potentially disastrous threats of the 21st century. Pseudomonas aeruginosa (P. aeruginosa) is a leading resistant pathogen and is clinically significant due to its limited available treatment using antibiotics. Rising resistance of P. aeruginosa is of increasing concern and it is currently listed as one of the top three critically resistant pathogens by the World Health Organization. It is currently known that resistance in P. aeruginosa is significantly linked with the consumption of all antibiotics, making usage surveillance of particular concern.AimThe aim of the current study was to model current and future antibiotic usage using available prescription data for antipseudomonal antibiotics.MethodA time‐series analysis was performed on Pharmaceutical Benefits Scheme/Repatriation Pharmaceutical Benefits Scheme data from January 2000–June 2020 using Facebook Prophet time‐series methods in Python 3.9.14 to analyse and forecast trends to 2025. Ethical approval was not required for this research article as it used publicly available data and did not involve human subjects.ResultsThe usage of antipseudomonal antibiotics decreased by 14.3% from 2014 to 2020 (95% confidence interval [CI] −30.4% to 2.3%) and is projected to further decrease by 11.7% by 2025 (95% CI −30.6% to 7.3%).ConclusionThe current study showed a decline in the use of certain antipseudomonal antibiotics in Australia since 2015 and projects that their use will continue to decline. This is likely due to an increased judicious use of these antibiotics.

Evaluation of Recurrence Rates of Pseudomonas Pneumonia in Mechanically Ventilated ICU Patients Receiving ≤7 Versus &gt;7 Days of Antibiotic Therapy

Background Pseudomonas aeruginosa (PA) is commonly implicated in ventilator-associated pneumonia (VAP). Consensus guidelines for VAP recommend a 7-day course of appropriate antibiotics. However, recent studies have shown higher recurrence rates of PA pneumonia with shorter courses of antibiotics. This study was designed to compare PA pneumonia recurrence rates in patients who received appropriate antibiotics for ≤7 days vs &gt;7 days. Methods A retrospective, single-center, observational cohort study of adults diagnosed with PA-VAP between January 2017 and May 2022 was conducted. Patients were divided into a &gt;7-day cohort or a ≤7-day cohort based on duration of appropriate antibiotics. The primary outcome was the recurrence rate of PA pneumonia. Results A total of 106 patients were included, 59 in the &gt;7-day cohort and 47 in the ≤7-day cohort. The median (interquartile range) duration of appropriate antipseudomonal therapy was 12 days (8–18 days) in the &gt;7-day cohort and 7 days (6–7 days) in the ≤7-day cohort. Pseudomonas aeruginosa recurrence was observed in 15 (25.4%) patients in the &gt;7-day cohort and 20 (42.6%) patients in the ≤7-day cohort (P = 0.059). Over 33% of patients in the &gt;7-day cohort had persistently positive PA cultures after at least 7 days of appropriate antibiotic therapy. Conclusion Extending duration of antipseudomonal antibiotics beyond 7 days did not significantly reduce the recurrence of PA pneumonia. However, the lower rate of recurrence in the &gt;7-day group and high rate of persistent positive cultures may be clinically significant, suggesting a role for extended treatment. Further prospective studies are needed to determine the optimal duration of therapy for PA-VAP.

Risk and Time-to-Onset of Acute Kidney Injury With Vancomycin Plus Piperacillin-tazobactam Combination: Analysis Using JADER.

Pharmacovigilance data and clinical studies have indicated a risk of acute kidney injury (AKI) associated with concomitant administration of vancomycin and piperacillin-tazobactam. However, no pharmacovigilance studies have evaluated time-to-onset and outcomes of AKI related to this combination. Therefore, this study used a pharmacovigilance database to investigate the incidence, time-to-onset, and outcomes of AKI in patients treated with intravenous vancomycin plus piperacillin-tazobactam or other antipseudomonal antibiotics. From data in the Japanese Adverse Drug Event Report (JADER) database, we calculated the reporting odds ratios (RORs) and 95% confidence intervals (CIs), time-to-onset, and outcomes of AKI following intravenous administration of vancomycin plus piperacillin-tazobactam or other antipseudomonal antibiotics and with other vancomycin regimens, including monotherapy. The JADER database contained 4,471 reports of intravenous vancomycin treatment, including 517 reports of AKI. The adjusted RORs (95%CIs) of AKI in cases with co-administration of intravenous vancomycin and piperacillin-tazobactam was 2.58 (2.06-3.24). The median time-to-onset for AKI in vancomycin plus piperacillin-tazobactam was 6.0 (interquartile range=3.0-10.3). Weibull shape parameter analysis showed that the pattern of onset of AKI in vancomycin plus piperacillin-tazobactam represented a wear out failure, predicting an increasing hazard with time. For the outcome of AKI, there was no significant difference between all vancomycin regimen and the piperacillin-tazobactam combination groups. Concomitant use of intravenous vancomycin and piperacillin-tazobactam may increase the incidence of AKI but may not affect the outcome. This combination does not necessarily have to be avoided, but long-term use is not advisable.

Mutations in genes lpxL1, bamA, and pmrB impair the susceptibility of cystic fibrosis strains of Pseudomonas aeruginosa to murepavadin.

Murepavadin is a peptidomimetic exhibiting specific inhibitory activity against Pseudomonas species. In the present study, its in vitro activity was assessed on 230 cystic fibrosis (CF) strains of Pseudomonas aeruginosa isolated from 12 French hospitals, in comparison with 12 other antipseudomonal antibiotics. Although murepavadin is still in preclinical stage of development, 9.1% (n = 21) of strains had a minimum inhibitory concentration (MIC) >4 mg/L, a level at least 128-fold higher than the modal MIC value of the whole collection (≤0.06 mg/L). Whole-genome sequencing of these 21 strains along with more susceptible isogenic counterparts coexisting in the same patients revealed diverse mutations in genes involved in the synthesis (lpxL1 and lpxL2) or transport of lipopolysaccharides (bamA, lptD, and msbA), or encoding histidine kinases of two-component systems (pmrB and cbrA). Allelic replacement experiments with wild-type reference strain PAO1 confirmed that alteration of genes lpxL1, bamA, and/or pmrB can decrease the murepavadin susceptibility from 8- to 32-fold. Furthermore, we found that specific amino acid substitutions in histidine kinase PmrB (G188D, Q105P, and D45E) reduce the susceptibility of P. aeruginosa to murepavadin, colistin, and tobramycin, three antibiotics used or intended to be used (murepavadin) in aerosols to treat colonized CF patients. Whether colistin or tobramycin may select mutants resistant to murepavadin or the opposite needs to be addressed by clinical studies.

Stability Studies of Antipseudomonal Beta Lactam Agents for Outpatient Therapy.

Outpatient parenteral antimicrobial therapy (OPAT) is a useful treatment strategy against Pseudomonas aeruginosa and other multidrug-resistant bacteria. However, it is hindered by the lack of stability data for the administration of antibiotics under OPAT conditions. Our objective was to investigate the stability of nine antipseudomonal and broad-spectrum beta lactam antibiotics (aztreonam, cefepime, cefiderocol, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, meropenem/vaborbactam, and piperacillin/tazobactam) to allow the spread of OPAT programs. All the antibiotics were diluted in 500 mL 0.9% sodium chloride and stored at 4, 25, 32, and 37 °C for 72 h in two different devices (infusion bags and elastomeric pumps). The solutions were considered stable if the color, clearness, and pH remained unchanged and if the percentage of intact drug was ≥90%. All the antimicrobials remained stable 72 h under refrigerated conditions and at least 30 h at 25 °C. At 32 °C, all the antibiotics except for meropenem and meropenem/vaborbactam remained stable for 24 h or more. At 37 °C, only aztreonam, piperacillin/tazobactam, cefepime, cefiderocol, and ceftolozane/tazobactam were stable for at least 24 h. The stability results were the same in the two devices tested. All the antibiotics studied are actual alternatives for the treatment of antipseudomonal or multidrug-resistant infections in OPAT programs, although the temperature of the devices is crucial to ensure antibiotic stability.

Use of Antipseudomonal Antibiotics is Not Associated With Lower Rates of Postoperative Drainage Procedures or More Favorable Culture Profiles in Children With Complicated Appendicitis: Results From a Multicenter Regional Research Consortium.

To compare rates of postoperative drainage and culture profiles in children with complicated appendicitis treated with the 2 most common antibiotic regimens with and without antipseudomonal activity [piperacillin-tazobactam (PT) and ceftriaxone with metronidazole (CM)]. Variation in the use of antipseudomonal antibiotics has been driven by a paucity of multicenter data reporting clinically relevant, culture-based outcomes. A retrospective cohort study of patients with complicated appendicitis (7/2015-6/2020) using NSQIP-Pediatric data from 15 hospitals participating in a regional research consortium. Operative report details, antibiotic utilization, and culture data were obtained through supplemental chart review. Rates of 30-day postoperative drainage and organism-specific culture positivity were compared between groups using mixed-effects regression to adjust for clustering after propensity matching on measures of disease severity. In all, 1002 children met the criteria for matching (58.9% received CM and 41.1% received PT). In the matched sample of 778 patients, children treated with PT had similar rates of drainage overall [PT: 11.8%, CM: 12.1%; odds ratio (OR): 1.44 (OR: 0.71-2.94)] and higher rates of drainage associated with the growth of any organism [PT: 7.7%, CM: 4.6%; OR: 2.41 (95% CI: 1.08-5.39)] and Escherichia coli [PT: 4.6%, CM: 1.8%; OR: 3.42 (95% CI: 1.07-10.92)] compared to treatment with CM. Rates were similar between groups for drainage associated with multiple organisms [PT: 2.6%, CM: 1.5%; OR: 3.81 (95% CI: 0.96-15.08)] and Pseudomonas [PT: 1.0%, CM: 1.3%; OR: 3.42 (95% CI: 0.55-21.28)]. The use of antipseudomonal antibiotics is not associated with lower rates of postoperative drainage procedures or more favorable culture profiles in children with complicated appendicitis.