Multidrug-resistant Pseudomonas Aeruginosa Infections Research Articles

The Guardian of Vision: Intelligent Bacteriophage-Based Eyedrops for Clinical Multidrug-Resistant Ocular Surface Infections.

Clinical multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is the leading cause of refractory bacterial keratitis (BK). However, the reported BK treatment methods lack biosecurity and bioavailability, which usually causes irreversible visual impairment and even blindness. Herein, for BK caused by clinically isolated MDR-PA infection, armed phages are modularized with the type I photosensitizer (PS) ACR-DMT, and an intelligent phage eyedrop is developed for combined phagotherapy and photodynamic therapy (PDT). These eyedrops maximize the advantages of bacteriophages and ACR-DMT, enabling more robust and specific targeting killing of MDR-PA under low oxygen-dependence, penetrating and disrupting biofilms, and efficiently preventing biofilm reformation. Altering the biofilm and immune microenvironments alleviates inflammation noninvasively, promotes corneal healing without scar formation, protects ocular tissues, restores visual function, and prevents long-term discomfort and pain. This strategy exhibits strong scalability, enables at-home treatment of ocular surface infections with great patient compliance and a favorable prognosis, and has significant potential for clinical application.

The impact of multi-drug resistant Pseudomonas aeruginosa infections on acute pancreatitis patients

IntroductionAcute pancreatitis (AP) accounts for a high proportion of digestive diseases worldwide and has a high risk of infection. Pseudomonas aeruginosa, a common pathogen of hospital infections, has been observed to increase the resistance rate to several antibiotics, causing difficulties in treatments. Our study aims to investigate the impact of the multi-drug resistant Pseudomonas aeruginosa (MDR-PA) infections on AP patients.MethodsAt two Chinese tertiary referral centers for AP patients infected with MDR-PA, a retrospective case-control study with a 1:2 case-control ratio was performed. Comparisons were preformed between with/without MDR-PA infections and different drug-resistance of MDR-PA infections patients, respectively. Independent risk factors of overall mortality were assessed via univariate and multivariate binary logistic regression analyses, and the distribution and antibiotic resistant rates of strains were described.ResultsMortality in AP patients with MDR-PA infections was significantly higher than in those without MDR-PA infections (7 (30.4%) vs. 4 (8.7%), P = 0.048). The rate of prophylactic use of carbapenem for 3 days (0 vs. 50%, P = 0.019) and the incidence rate of multiple organ failure (MOF) (0 vs. 57.1%, P = 0.018) were remarkably higher in the carbapenem-resistant Pseudomonas aeruginosa group compared with the carbapenem-sensitive Pseudomonas aeruginosa group. In the multivariate analysis, the severe categories of AP (OR = 13.624, 95% CIs = 1.567–118.491, P = 0.018) and MDR-PA infections (OR = 4.788, 95% CIs = 1.107–20.709, P = 0.036) were independent risk factors for mortality. The resistance rates of MDR-PA strains were low for amikacin (7.4%), tobramycin (3.7%), and gentamicin (18.5%). The resistance rates of MDR-PA strains to imipenem and meropenem were up to, 51.9% and 55.6%, respectively.ConclusionIn AP patients, severe categories of AP and MDR-PA infections were both independent risk factors for mortality. Inappropriate use of carbapenem antibiotics and MOF were related to carbapenem-resistant Pseudomonas aeruginosa infections. Amikacin, tobramycin, and gentamicin are recommended for the treatment of AP patients with MDR-PA infections.

Selective Photothermal Therapy Based on Lipopolysaccharide Aptamer Functionalized MoS2 Nanosheet-Coated Gold Nanorods for Multidrug-Resistant Pseudomonas aeruginosa Infection.

Chronic wounds infected by multidrug-resistant gram-negative bacteria have evolved resistance to traditional antibiotic therapy, posing a threat to global public health in recent years. Herein, a selective therapeutic nanorod (MoS2 -AuNRs-apt) based on molybdenum disulfide (MoS2 ) nanosheets coated gold nanorods (AuNRs) targeting lipopolysaccharide (LPS) is presented. AuNRs have excellent photothermal conversion efficiency in 808nm laser-guided photothermal therapy (PTT), and the MoS2 nanosheets coating significantly enhances the biocompatibility of AuNRs. Furthermore, the conjugation of the nanorods with aptamer permits active targeting of LPS on the surface of gram-negative bacteria and a specific anti-inflammatory ability in the multidrug-resistant Pseudomonas aeruginosa (MRPA)-infected wound murine model. It is concluded that the antimicrobial effect of these nanorods is considerably more significant than non-targeted PTT. Moreover, they can precisely overcome MRPA bacteria by physical damage and effectively reduce excess M1 inflammatory macrophages to accelerate the healing of infected wounds. Overall, this molecular therapeutic strategy displays great potential as a prospective antimicrobial treatment for MRPA infections.

415. Epidemiological Evaluation of Antibiotic Resistance and Subsequent Effect on Healthcare Resource Utilization among Subjects with Pseudomonas aeruginosa Infections in Italy

Abstract Background The aims of the study were to 1) evaluate the prevalence of multidrug resistant (MDR) /Extensively drug resistant (XDR) strains among hospitalized adults with Pseudomonas aeruginosa (PA) infections, and 2) examine whether antimicrobial resistance in PA infections is associated with worsening functional status and higher health care resource utilization (HCRU). Methods This multicenter prospective study was conducted in 9 large Italian teaching hospitals between June 2018-February 2020. We included patients aged ≥18 years with a diagnosis of nosocomial pneumonia (NP), complicated urinary tract infections (cUTI) or complicated intra-abdominal infections (cIAI) due to PA as confirmed by local evaluation of microbiological results. MDR PA was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories. XDR PA was defined as acquired non-susceptibility to at least one agent in all but two or fewer antimicrobial categories. HCRU metrics evaluated included hospital length of stay (LOS) and intensive care unit (ICU) LOS. Results A total of 95 patients with a nosocomial infection due to PA were enrolled. The main baseline characteristics of overall patients were reported in Table 1. Almost one-third of patients (28.4%) reported either MDR or XDR PA infection, with more patients experiencing MDR (Table 1). Health care resource use stratified by patients with and without MDR/XDR status are reported in Table 2. Overall, in our study population, median hospital LOS and ICU LOS were 42.0 (IQR=39.0) and 15.5 (IQR=37.0) days, respectively. There was a statistically significant longer median hospital LOS for patients with MDR/XDR infections compared to non MDR/XDR PA infections (53.0 vs. 36.5 days, p=0.04). ICU LOS also trended towards being longer for patients with MDR/XDR infections compared to those with non-MDR/XDR infections (25.5 vs. 13.5 days, p=0.10). Conclusion MDR/XDR isolates were prevalent among patients with nosocomial infections due to PA, particularly in those with cIAI. Overall, the present study may suggest a positive correlation between having MDR-XDR PA nosocomial infections (NP, cUTI, and cIAI) and increased HCRU that require further attention from a disease management perspective. Disclosures Matteo Bassetti, PhD, Angelini: Advisor/Consultant|Astellas: Grant/Research Support|Bayer: Advisor/Consultant|Bayer: Honoraria|BioMe ́ rieux: Advisor/Consultant|BioMe ́ rieux: Honoraria|Cidara: Advisor/Consultant|Cidara: Honoraria|Cipla: Advisor/Consultant|Cipla: Honoraria|Gilead: Advisor/Consultant|Gilead: Honoraria|Menarini: Advisor/Consultant|Menarini: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Nabriva: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Board Member|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|Tetraphase: Advisor/Consultant Francesco Menichetti, n/a, Aneglini: Advisor/Consultant|Aneglini: Board Member|Aneglini: Grant/Research Support|Aneglini: Honoraria|Astellas: Advisor/Consultant|Astellas: Honoraria|Becton: Advisor/Consultant|Becton: Honoraria|bioMérieux: Advisor/Consultant|bioMérieux: Honoraria|Biotest: Advisor/Consultant|Biotest: Board Member|Biotest: Honoraria|Bristol-Myers Squibb: Advisor/Consultant|Bristol-Myers Squibb: Honoraria|Correvio: Advisor/Consultant|Correvio: Speaker honoraria|Dickinson: Advisor/Consultant|Dickinson: Honoraria|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Honoraria|MSD: Advisor/Consultant|MSD: Speaker honoraria|Nordic pharma: Board Member|Nordic pharma: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria Nicola Petrosillo, n/a, Becton & Dickinson,: Honoraria|MSD: Honoraria|ohnson & Johnson: Honoraria|Pfizer: Honoraria|Shionogi: Honoraria.

Qiguiyin Decoction Improves Multidrug-Resistant Pseudomonas aeruginosa Infection in Rats by Regulating Inflammatory Cytokines and the TLR4/MyD88/NF-κB Signaling Pathway.

Pseudomonas aeruginosa (PA), a Gram-negative bacterium, has a high detection rate in hospital-acquired infections. Recently, the frequent appearance of multidrug-resistant (MDR) PA strain with high morbidity and mortality rates has aggravated the difficulty in treating infectious diseases. Due to its multiple resistance mechanisms, the commonly used antibiotics have gradually become less effective. Qiguiyin decoction (QGYD) is a clinically experienced prescription of Chinese herbal medicine, and its combined application with antibiotics has been confirmed to be effective in the clinical treatment of MDR PA infection, which could be a promising strategy for the treatment of drug-resistant bacterial infections. However, the mechanism of QGYD restoring antibiotics susceptibility to MDR PA remains unclear. In the present study, we investigated the effects of QGYD and levofloxacin (LEV) singly or in combination on MDR PA-induced pneumonia rat models. Further analysis was carried out in the serum differential expression profiles of inflammatory cytokines by cytokine antibody array. Besides, the lung TLR4/MyD88/NF-κB signaling pathway was detected by RT-qPCR. Our results showed that based on the treatment of MDR PA-infected rat model with LEV, the combination of QGYD improved the general state and immune organ index. Furthermore, it moderately increased the expressions of proinflammatory cytokines including IL-1β, IL-6, and TNF-α in the early stage of infection and decreased their release rapidly in the later stage, while regulated the same phase change of anti-inflammatory cytokine IL-10. In addition, the adhesion molecule ICAM-1 was significantly downregulated after QGYD combined with LEV treatment. Moreover, the mRNA expressions of TLR4, MyD88, NF-κB, and ICAM-1 were significantly downregulated. These results indicated that the mechanism of QGYD restoring LEV susceptibility to MDR PA was related to its regulation of inflammatory cytokines and the TLR4/MyD88/NF-κB signaling pathway, which provides theoretical support for the clinical application of QGYD combined with LEV therapy to MDR PA infection.

Multidrug-Resistant Pseudomonas aeruginosa Triggers Differential Inflammatory Response in Patients With Endophthalmitis.

PurposeInfections with multidrug-resistant Pseudomonas aeruginosa (MDR-PA) lead to poor clinical outcomes in endophthalmitis patients, and its interactions with the host immune system remain largely unknown. The current study aimed to determine the association of MDR-PA infection with the cytokine expression profile in patients with endophthalmitis.MethodsVitreous of 12 patients with culture-proven MDR-PA along with 12 samples from antibiotic-susceptible P. aeruginosa (S-PA) and 20 non-infectious controls were included in the study. Expression patterns of IL-6, IL-10, IL-1α, IL-1β, IFN-γ, TNF-α, IL-8, and GM-CSF in the vitreous were analyzed by multiplex immunoassay and correlated with the clinical severity. We also assessed the phosphorylation level of different immune pathway molecules.ResultsIn the MDR-PA group, significantly (P < 0.05) increased expression of IL-6, IL-8, IL-10, IL-1β, and TNF-α was observed in comparison with the S-PA group. The increased inflammatory mediators in MDR-PA correlated with the disease severity. Additionally, the increased expression of inflammatory mediators was positively correlated to the activation levels of Akt, STAT3, JNK, p70 S6 kinase, and NF-кB (P < 0.05) in the MDR-PA group.ConclusionsThe current study shows the differential host immune response and phosphorylation levels of signaling molecules in MDR-PA endophthalmitis, thereby linking antibiotic resistance with distinct immune regulation.Translational RelevanceThis study provides evidence for the use of inflammatory mediator levels of IL-6, IL-8, IL-10, IL-1β, and TNF-α as potential diagnostic biomarkers of MDR endophthalmitis warranting prompt administration of immune modulators to avoid irreversible damage to the retina and vision loss.

Evaluating the clinical effectiveness of new beta-lactam/beta-lactamase inhibitor combination antibiotics: A systematic literature review and meta-analysis.

Ceftazidime/avibactam (C/A), ceftolozane/tazobactam (C/T), imipenem/relebactam (I/R), and meropenem/vaborbactam (M/V) combine either a cephalosporin (C/T and C/A) or a carbapenem antibiotic (M/V and I/R) with a β-lactamase inhibitor. They are used to treat carbapenem-resistant Enterobacterales (CRE) and/or multidrug-resistant Pseudomonas aeruginosa (MDRPA). We compared the pooled clinical success of these medications to older therapies. PubMed and EMBASE were searched from January 1, 2012, through September 2, 2020, for C/A, C/T, I/R, and M/V studies. The main outcome was clinical success, which was assessed using random-effects models. Stratified analyses were conducted for study drug, sample size, quality, infection source, study design, and multidrug-resistant gram-negative organism (MDRGNO) population. Microbiological success and 28- and 30-day mortality were assessed as secondary outcomes. Heterogeneity was determined using I2 values. Overall, 25 articles met the inclusion criteria; 8 observational studies and 17 randomized control trials. We detected no difference in clinical success comparing new combination antibiotics with standard therapies for all included organisms (pooled OR, 1.21; 95% CI, 0.96-1.51). We detected a moderate level of heterogeneity among the included studies I2 = 56%. Studies that focused on patients with CRE or MDRPA infections demonstrated a strong association between treatment with new combination antibiotics and clinical success (pooled OR, 2.20; 95% CI, 1.60-3.57). C/T, C/A, I/R, and M/V are not inferior to standard therapies for treating various complicated infections, but they may have greater clinical success for treating MDRPA and CRE infections. More studies that evaluate the use of these antibiotics for drug-resistant infections are needed to determine their effectiveness.

Meta-analysis of Outcomes Using Ceftolozane-Tazobactam and Ceftazidime-Avibactam for Multidrug-Resistant Organism Infections

Background: Ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (C/A) are new β-lactam/β-lactamase combination antibiotics that were approved by the FDA in 2014 and 2015, respectively, to treat complicated intra-abdominal and urinary tract infections. They are commonly used to treat multidrug-resistant Pseudomonas aeruginosa (MDRPA) and carbapenem-resistant Enterobacteriaceae (CRE) infections at any site. Both medications are also often used as salvage therapy when empiric therapy has failed or when the infectious organism tests resistant to all other available antibiotics. The purpose of this review is to present the clinical experience and reported clinical success rates of C/T and C/A. Methods: PubMed, EMBASE, and Google Scholar were searched from January 1, 2013, through October 1, 2019, for publications detailing clinical experience with C/T and C/A in patients with CRE and MDRPA infections. Included study designs were extended cases series and clinical observational studies. Information on infection type, bacterial agent, salvage therapy uses, clinical success, and resistance development during treatment were abstracted. Meta-regression analysis was used to determine the pooled effectiveness of C/T and C/A among included studies. Results: The literature search returned 1,645 publications. After exclusion criteria were applied, 16 publications representing 769 patients were retained. The study population was mostly male (pooled average, 62%). The major comorbidities represented in the pooled population were solid organ transplantation (20.0%), kidney disease (19.5%), cardiovascular disease (15.3%), and diabetes (15.3%). Pneumonia was the predominant infection type (41.4%) and MDRPA was the pathogen most frequently evaluated (57.7%). The pooled clinical success rate was 70.2% (95% CI, 64.5%–75.3%). Also, 10 studies explicitly evaluated C/A or C/T as salvage therapy. The pooled clinical success rate for salvage therapy studies was 75.2% (95% CI, 69.7%–80.0%). Development of resistance to C/T or C/A during or after treatment was reported for 2.0% of the population. Conclusion: Overall, these medications have a high clinical success rate in patients with severe and complicated infections and limited treatment options. Pooled clinical success rates were high (70.2%) and the medications were particularly effective as salvage therapy. Resistance rates were low, although this could have been biased by the small percentage of studies that reported on this outcome. More longitudinal studies comparing the effectiveness of C/T and C/A against other antibiotic regimens are needed.Funding: NoneDisclosures: None

2254. Multicenter Evaluation of Ceftazidime–Avibactam for Multidrug-Resistant Pseudomonas aeruginosa Infections

BackgroundCeftazidime–avibactam (CZA) is a novel cephalosporin/β-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae (CRE) and multidrug-resistant (MDR) Pseudomonas aeruginosa (PA). Real-world experience with CZA for CRE infections is accumulating but data on its use for MDR PA infections remains limited.MethodsRetrospective, multicenter cohort study describing the clinical characteristics and outcomes of patients treated with CZA (≥ 72 hours) for MDR PA infections between 2015 and 2018.ResultsFifty-one patients were included. The median (IQR) age was 61 (43, 71) years. Most patients had MDR risk factors including recent hospitalization (74.5%), recent antimicrobial exposure (84.3%), and/or previous infection or colonization with an MDR pathogen (58.8%). The median Charlson Comorbidity score was 4 (2, 6) and the median APACHE II score was 20 (12, 29). Infections were predominantly (68.6%) hospital-acquired and 52.9% of patients were in the ICU at infection onset. The common sources were respiratory tract (60.8%), osteoarticular (11.8%) and skin and soft tissue (11.8%). Two patients had positive blood cultures. PA antibiotic susceptibilities were as follows: ceftazidime 52.6% (n = 51), CZA 92.0% (n = 25), ciprofloxacin 10% (n = 30), meropenem 19.6% (n = 46), piperacillin–tazobactam 30.4% (n = 4) and tobramycin 72.9% (n = 48). Most (60.8%) infections were polymicrobial including 15 (29.4) CRE co-infections. CZA was started 97 (50, 170) hours after culture collection and continued for 9 (7, 14) days. Only 8 patients (15.7%) received active antibiotic therapy before CZA. Combination CZA therapy was used 35.3%, most often an aminoglycoside (8/18, 44.4%). Clinical cure or improvement was achieved in 40 patients (78.4%), and 42 (82.4%) were discharged alive. Among patients with repeat cultures (n = 11), CZA resistance development was not detected. Three patients (5.9%) experienced infection recurrence within 30 days of completing therapy.ConclusionThe use of CZA was associated with high rates of favorable outcomes in complex patients with MDR PA infections. Future studies evaluating long-term outcomes and comparative studies are needed to more precisely define the role of CZA for MDR PA infections.Disclosures All authors: No reported disclosures.

2382. Ceftolozane/Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections in Immunocompromised Patients: A Multi-Center Study

BackgroundCeftolozane/tazobactam (TOL-TAZ) is a novel cephalosporin antibiotic combined with a known β-lactamase inhibitor. It has activity against some extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and multidrug-resistant Pseudomonas aeruginosa (MDRPA). To date, little experience has been published on outcomes with TOL-TAZ for MDRPA infections in immunocompromised patients.MethodsThis was a retrospective study of adult patients (≥18 years) with an immunocompromising condition (solid-organ transplant; hematologic malignancy; solid tumors; metastatic cancer) at 20 academic medical centers who had microbiologically confirmed MDRPA isolated in culture and received TOL-TAZ for at least 24 hours. 30-day survival, in-hospital mortality, and the rates of microbiologic and clinical cure were assessed.ResultsCharacteristic Result (N = 65)Immunocompromising condition:Solid-organ transplantSolid tumorLeukemiaLymphoma/multiple myelomaMetastatic cancer n(%)35 (53.8)20 (30.7)4 (6.1)3 (4.6)3 (4.6)Male, n(%)38 (58.4)Age (median, IQR)64 (20–87)Charlson Comorbidity Index (median, IQR)6 (1–12)APACHE II score (median, IQR)20 (4–41)ICU, n(%)37(56.9)Hospital day index infection diagnosed (median, IQR)17 (0–265)Hospital day TOL-TAZ started (median, IQR)19 (0–284)3grs q8hrs, n(%)1.5grs q8hrs, n(%)23 (35.3)23 (35.3)Concomitant IV antibiotics, n(%)Aminoglycoside, n/N(%)Fluoroquinolone, n/N(%)Polymyxin, n/N(%)Β-lactam, n/N(%)15 (23.0)7/15 (46.7)4/15 (26.7)3/15 (20)1/15 (6.6)TOL-TAZ susceptible isolates, n/N (%)35/37 (94.6) Outcomes by primary infection Primary infectionn (%)30-day survival n/N(%)Microbiologic cure n/N(%)Clinical cure n/N(%)Pneumonia33 (50.7)30/33 (90.9)24/33 (72.7)28/33 (84.8)Wound/Bone/Joint12 (18.4)8/12 (66.6)7/12 (58.3)7/12 (58.3)UTI9 (13.8)7/9 (77.7)7/9 (77.7)8/9 (88.8)Intra-abdominal7 (10.7)7/7 (100)7/7 (100)4/7 (57.1)Bloodstream4 (6.1)4/4 (100)4/4 (100)4/4 (100) Overall outcomes, n(%)30-day survival56 (86.1)In-hospital mortality17 (26.1)Microbiologic cure49 (75.3)Clinical cure51(78.4)ConclusionIn this study of 65 critically-ill immunocompromised patients, the 30-day survival was 86.1%; clinical cure was78.4% and microbiologic cure 75.3%. TOL-TAZ is a viable option for immunocompromised patients with MDRPA infections.Disclosures J. Gallagher, Achaogen: Consultant, Consulting fee. Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee and Research grant. Allergan: Consultant and Speaker’s Bureau, Consulting fee. Astellas: Consultant and Speaker’s Bureau, Consulting fee. Cempra: Consultant, Consulting fee. Cidara: Consultant, Consulting fee. CutisPharma: Consultant, Consulting fee. Paratek: Consultant, Consulting fee. Shionogi: Consultant, Consulting fee. Tetraphase: Consultant, Consulting fee. Theravance: Consultant, Consulting fee. The Medicines Company: Consultant, Consulting fee. Melinta: Speaker’s Bureau, Consulting fee.

Activity of Ceftolozane-Tazobactam against Carbapenem-Resistant, Non-Carbapenemase-Producing Pseudomonas aeruginosa and Associated Resistance Mechanisms.

Although carbapenems are effective for treating serious multidrug-resistant Pseudomonas aeruginosa infections, carbapenem-resistant P. aeruginosa (CRPA) is now being reported worldwide. Ceftolozane-tazobactam (C/T) demonstrates activity against many multidrug-resistant isolates. We evaluated the activity of C/T and compared its activity to that of ceftazidime-avibactam (C/A) using a well-characterized collection of non-carbapenemase-producing CRPA isolates. Forty-two non-carbapenemase-producing CRPA isolates from a previous study (J. Y. Lee and K. S. Ko, Int J Antimicrob Agents 40:168-172, 2012, https://doi.org/10.1016/j.ijantimicag.2012.04.004) were included. All had been previously shown to be negative for blaIMP, blaVIM, blaSPM, blaGIM, blaSIM, and blaKPC by PCR. In the prior study, expression of oprD, ampC, and several efflux pump genes had been defined by quantitative reverse transcription-PCR. Here, antimicrobial susceptibility was determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Time-kill curve assays were performed using three C/T- and C/A-susceptible CRPA isolates. Among 42 non-carbapenemase-producing CRPA isolates, overall susceptibility to C/T was 95.2%, compared to 71.4%, 42.9%, 23.8%, 21.4%, and 2.4% for C/A, ceftazidime, piperacillin-tazobactam, cefepime, and meropenem, respectively. The C/T resistance rate was significantly lower than that of C/A among isolates showing decreased oprD and increased mexB expression (5.1% versus 25.6%, P = 0.025, and 4.3% versus 34.8%, P = 0.022, respectively). In time-kill curve studies, C/T was less bactericidal than C/A against an isolate with decreased oprD and increased ampC expression. C/T was active against 95.2% of non-carbapenemase-producing CRPA clinical isolates. No apparent correlation of C/T MIC values with specific mutation-driven resistance mechanisms was noted.

Control of Multidrug-Resistant Pseudomonas aeruginosa in Allogeneic Hematopoietic Stem Cell Transplant Recipients by a Novel Bundle Including Remodeling of Sanitary and Water Supply Systems.

Infections by multidrug-resistant Pseudomonas aeruginosa (MDRPa) are an important cause of morbidity and mortality in patients after allogeneic hematopoietic stem cell transplantation (HSCT). Humid environments can serve as a reservoir and source of infection by this pathogen. To minimize the risk of infection from these reservoirs, we performed extensive remodeling of sanitation and water installations as the focus of our hygiene bundle. During the reconstruction of our transplantation unit (April 2011-April 2014) we implemented several technical modifications to reduce environmental contamination by and subsequent spreading of MDRPa, including a newly designed shower drain, disinfecting siphons underneath the sinks, and rimless toilets. During a 3-year study period (2012-2014), we tracked the number of patients affected by MDRPa (colonized and/or infected) and the outcome of infected patients, and monitored the environmental occurrence of this pathogen. We further performed whole-genome sequencing of nosocomial MDRPa strains to evaluate genotypic relationships between isolates. Whereas 31 (9.2%; 18 colonized, 13 infected) patients were affected in 2012 and 2013, the number decreased to 3 in 2014 (17%; 3 colonized, 0 infected). Lethality by MDRPa similarly decreased from 3.6% to 0%. Environmental detection of MDRPa decreased in toilets from 18.9% in 2012-2013 to 6.1% in the following year and from 8.1% to 3.0%, respectively, in shower outlets. Whole-genome sequencing showed close relationships between environmental and patient-derived isolates. Hospital construction measures aimed at controlling environmental contamination by and spread of MDRPa are effective at minimizing the risk of highly lethal MDRPa infections.

Salvage Therapy with Ceftolozane-Tazobactam for Multidrug-Resistant Pseudomonas aeruginosa Infections.

Infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRPA) present a major problem for therapeutic management. We report here our experience with 12 patients with a severe MDRPA infection (6 of which were pneumonia) who received salvage therapy with ceftolozane-tazobactam after inappropriate empirical treatment and/or suboptimal targeted treatment. Although 10 of the 12 patients (83.3%) experienced septic shock, only 3 patients (25%) died during the follow-up period. Microbiological cure in 7 patients (58.3%) was observed.

Infections in intensive care unit adult patients harboring multidrug-resistant Pseudomonas aeruginosa: implications for prevention and therapy.

The purpose of this paper was to report the burden and characteristics of infection by multidrug-resistant Pseudomonas aeruginosa (MDR-PA) in clinical samples from intensive care unit (ICU) adults, and to identify predictors. This was a retrospective observational study at four medical-surgical ICUs. The case cohort comprised adults with documented isolation of an MDR-PA strain from a clinical specimen during ICU stay. Multivariate analysis was performed to identify predictors for MDR-PA infection. During the study period, 5667 patients were admitted to the ICU and P. aeruginosa was isolated in 504 (8.8%). MDR-PA was identified in 142 clinical samples from 104 patients (20.6%); 62 (43.6%) of these samples appeared to be true infections. One hundred and eighteen (83.1%) isolates were susceptible only to amikacin and colistin, and 13 (9.2%) were susceptible only to colistin. Overall, the MIC50 to meropenem was 16 μg/mL and the MIC90 was >32 μg/mL, with 60.4% of respiratory samples being MIC >32 μg/mL to meropenem. Independent predictors for MDR-PA infection were fever/hypothermia [odds ratio (OR) 9.09], recent antipseudomonal cephalosporin therapy (OR 6.31), vasopressors at infection onset (OR 4.40), and PIRO (predisposition, infection, response, and organ dysfunction) score >2 (OR 2.06). This study provides novel information that may be of use for the clinical management of patients harboring MDR-PA and for the control of the spread of this organism.

Activity of Liposomal-Oleic Acid on Drug Resistant Strains of Pseudomonas aeruginosa Isolated from Clinical Specimens

Pseudomonas aeruginosa has rapidly developed resistance to multiple drugs throughout its antibiotic history and thus it is essential to develop novel antimicrobial strategies to minimize their resistance pattern. This study evaluated the antimicrobial activity of oleic acid (OA) in a liposomal formulation as a bactericidal drug against Multidrug Resistant Pseudomonas aeruginosa (MDRPa). Hence, we report the synthesis, characterization and the antimicrobial activity of liposomal oleic acids (LipoOA) against MDRPa. P. aeruginosa, isolated from pus on wound site and sputum from pulmonary infections were tested for its resistance against antibiotics by standard Kirby Bauer's disc diffusion method. Oleic acid (OA) in a liposomal formulation (LipoOA) was prepared by an extrusion method. Scanning electron microscopy (SEM) was utilized to monitor the surface morphology of LipoOA. The hydrodynamic size (diameter, nm), surface zeta potential (mV) of LipoOA and bare liposomes were measured using the Malvern Zetasizer. The encapsulation efficiency of OA in the synthesized LipoOA was determined using an LC-MS system. LipoOA were prepared to assess their antimicrobial activity against MDRPa. Encapsulation efficiency of OA in LipoOA was 33.7%. Strains were 100% resistance to cefepime and amikacin and 97.14% to to bramycin, ciprofloxacin and imipenem. Highly significant difference in LipoOA was observed for the clinical strain PS13 which exhibited an MIC of 1024 mg/L for amikacin and 512mg/L for cefepime by reducing the value to 67.4mg/L. In this study, therapeutic potential of liposomal oleic acids (LipoOA) against MDRPa was demonstrated. The synthesized LipoOA with diameter86.1 ± 0.5 nm fuses with bacterial membranes and subsequently releases the entrapped OA. Overall, this study highlights the promising possibility of using LipoOA as a new therapeutic option to the current antimicrobial strategies against MDRPa infections.

Enhancement of Antibiotic Efficacy against Multi-drug Resistant Pseudomonas Aeruginosa Infections via Combination with Curcumin and 1-(1-Naphthylmethyl)-Piperazine

Objective: The aim of this study was to determine if the plant phenolic curcumin (CUR) and the arylpiperazine 1-(1-naphthylmethyl)-piperazine (NMP) could restore antibiotic efficacy versus MDR P. aeruginosa infection. Methods: The MICs of piperacillin, meropenem and levofloxacin in the presence or absence of CUR or NMP against a MDR strain that over-expresses the MexAB-OprM efflux-pump and the isogenic parent strain were compared. The efficacy of the same combination treatments was also tested in a Galleria mellonella in vivo infection model and larval survival and bacterial burden compared. Results: In vitro, CUR restored the activity of piperacillin, meropenem and levofloxacin versus the MDR strain of P. aeruginosa only weakly. There was no evidence in vitro of a similar effect with NMP. In vivo, treatment of G. mellonella larvae infected with the MDR strain with a combination of NMP or CUR plus levofloxacin, and piperacillin plus CUR, resulted in enhanced therapeutic benefit compared to the monotherapies. When compared with monotherapies, the enhanced efficacy of the combination treatments correlated with reduced bacterial burden.Conclusion: CUR and NMP restored the efficacy of antibiotic therapy in vivo versus MDR P. aeruginosa infection.

Multidrug-resistant Pseudomonas aeruginosa infections pose growing threat to health care–associated infection control in the hospitals of Southern China: A case-control surveillance study

Multidrug-resistant Pseudomonas aeruginosa (MDRPA) is one of the most common agents among health care-associated infections. There is a lack of data on the clinical features of MDRPA from Southern China. A case-control surveillance study of P aeruginosa was conducted based on surveillance from July 2008-December 2012, in 5 hospitals of Guangzhou, China. Data were analyzed by univariate analysis and multivariate logistic regression using Stata 13 (StataCorp, College Station, TX). Of the 348 P aeruginosa strains, the prevalence of MDRPA was 54%, and it has increased over time. Isolates of P aeruginosa showed increased resistance to most antimicrobials during this time period. Independent risk factors were tracheal intubation insertion (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.16-4.23; P = .02) and use of carbapenem (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.75-6.47; P < .01). The distribution of MDRPA infections was uneven among the 5 hospitals (P = .01). Being infected with MDRPA strains resulted in longer duration of hospitalization (39 vs 24 days) and higher mortality (49% vs 20%). The infections of MDRPA were severe issues. More stringent measures should be applied for those with independent predictors of MDRPA infections because they may induce adverse clinical outcomes.

Clinical outcomes of multidrug resistant pseudomonas aeruginosa infection and the relationship with type III secretion system in patients with diabetic foot.

The objective was to analyze the clinical outcomes of multidrug resistant Pseudomonas aeruginosa (MDRPA) infection and determine the relationship between type III secretion system (TTSS) and MDRPA in diabetic foot (DF) patients. A total of 117 patients infected with P aeruginosa were recruited and grouped into MDRPA and non-MDRPA group according to antimicrobial susceptibility testing. TTSS genes were detected by polymerase chain reaction (PCR). Potential risk factors for MDRPA infection were examined using univariate and multivariate analyses. Clinical outcomes were compared on the basis of MDRPA or TTSS virulence gene. Previous antibiotic therapy, previous hospitalization and osteomyelitis were associated with MDRPA infection. MDRPA group had a higher amputation/toe rate (32.6% vs 16.2%) and lower healing rate (20.9% vs 41.9%) than non-MDRPA group (P = .032). A significantly higher proportion of exoU was present in MDRPA group (75.0% vs 25.0%, P < .05) than non-MDRPA group. Patients infected with exoU isolates had a lower healing rate and higher amputation/toe rate (25.0% vs 65.2%, 33.3% vs 8.7%, P < .05) than infected with exoS isolates. The exoU gene was predominance among MDRPA strains. The poor clinical outcomes of MDRPA infection in patients with DF were attributable to exoU gene.

OprMas a new target for reversion of multidrug resistance inPseudomonas aeruginosaby antisense phosphorothioate oligodeoxynucleotides

Multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is one of the leading Gram-negative organisms associated with nosocomial infections. The increasing frequency of MDR-PA has represented a huge challenge in conventional antibacterial therapy. The loss of effectiveness of commonly used antibiotics calls for the immediate need to develop an alternative strategy for combating MDR-PA infections. The multiantibiotic resistance of MDR-PA is largely attributable to the production of multidrug efflux pumps, MexAB-OprM. OprM forms the antibiotic-ejecting duct and plays a crucial role in exporting incoming chemotherapeutic agents across the membranes. Disruption of the OprM expression may inhibit the function of multidrug efflux pumps and lead to restoration of MDR-PA susceptibility to antibiotics. In this study, we developed a novel anion liposome for encapsulating and delivering specific anti-oprM phosphorothioate oligodeoxynucleotide (PS-ODN617) and polycation polyethylenimine (PEI) complexes. The additions of the encapsulated anti-oprM PS-ODN617/PEI to MDR-PA isolates caused a significant reduction of oprM expression and inhibition of MDR-PA growth in the presence of piperacillin in a concentration-dependent manner. The encapsulated PS-ODN617 treatment also reduced minimal inhibitory concentrations of five most commonly used antibiotics to the sensitive margin values on MDR-PA clinical isolates, respectively. The results of present study firstly indicate that PS-ODN targeted to oprM can significantly restore the susceptibility of MDR-PA to existing antibiotics, which appears to be a novel strategy for treating MDR-PA infections.

Epidemics of Drug-Resistant Bacterial Infections Observed in Infectious Disease Surveillance in Japan, 2001-2005

BACKGROUNDDrug-resistant bacteria have been increasing together with advancement of antimicrobial chemotherapy in recent years. In Japan, the target diseases in the National Epidemiological Surveillance of Infectious Diseases (NESID) include some drug-resistant bacterial infections.METHODSWe used the data in the NESID in Japan, 2001-2005. Target diseases were methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP) and multi-drug-resistant Pseudomonas aeruginosa (MDRPA) infections. The numbers of patients reported by sentinel hospitals (about 500) on a monthly basis were observed.RESULTSThe numbers of patients per month per sentinel hospital of 2001-2005 were 3.37-3.98 in MRSA, 0.96-1.19 in PRSP, and 0.11-0.13 in MDRPA infections. The sex ratios (male / female) of patients were 1.69-1.82, 1.34-1.43, and 1.71-2.52, respectively. More than 50% of all patients were adults aged 70 years or older in MRSA and MDRPA infections, but more than 60% were children under 10 years in PRSP infections. The number of patients per sentinel hospital in MRSA infections showed little variation between months, but evidenced a large variation in PRSP and MDRPA infections. The annual trend in the number of patients per sentinel hospital was increasing significantly for the 5-year period in MRSA and PRSP infections, but not in MDRPA infections.CONCLUSIONSWe revealed sex-age distributions of the patients reported to NESID in Japan, 2001-2005. An increasing incidence of MRSA and PRSP infections and monthly variation in PRSP and MDRPA infections were observed for the 5-year period. Extended observation would be necessary to confirm these trends and variations.