RESUMO
INTRODUCTION: Pseudomonas aeruginosa isolates producing metallo-ß-lactamase have caused nosocomial outbreaks, severe infections, and ineffective carbapenem therapy worldwide since 1991. Due to their prevalence, hospital infection control techniques are difficult. This study aimed to find out the prevalence of metallo-ß-lactamase among P. aeruginosa isolates from two tertiary care hospitals in Kathmandu. METHODS: A descriptive cross-sectional study was conducted at the Department of Microbiology and Department of Pathology of two tertiary care centres in Kathmandu from 7 December 2021 to 6 April 2023, after receiving ethical approval from the Ethical Review Board. Isolated strains were identified and tested for antibiotic susceptibility by modified Kirby-Bauer Methods. Metallo-ß-lactamase presence was confirmed using an imipenem-imipenem/ ethylenediaminetetraacetic acid disc. A convenience sampling method was used. The point estimate was calculated at 95% Confidence Interval. RESULTS: Among 255, Pseudomanas aeruginosa isolates, the distribution of metallo-ß-lactamase-producing Pseudomanas aeruginosa was 103 (40.39%) (34.32-46.69 at 95% Confidence Interval). Multidrug resistance categories included multidrug resistance 74 (71.80%), extensively drug resistance 32 (31.10%), P. aeruginosa difficult-to-treat 16 (15.53%) and carbapenem-resistant P. aeruginosa was determined to be 82 (79.60%). CONCLUSIONS: The study found a high prevalence of metallo-ß-lactamase-producing Pseudomanas aeruginosa isolates, requiring early identification, infection control measures, and an all-inclusive antimicrobial therapy protocol to reduce their spread in medical settings.
Assuntos
Antibacterianos , Infecções por Pseudomonas , Pseudomonas aeruginosa , Centros de Atenção Terciária , beta-Lactamases , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/efeitos dos fármacos , Nepal/epidemiologia , beta-Lactamases/metabolismo , Estudos Transversais , Humanos , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Infecção Hospitalar/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla , PrevalênciaRESUMO
Chronic non-healing wounds pose significant challenges due to an elevated inflammatory response caused in part by bacterial contamination (Physiol Rev. 2019;99:665). These wounds lead to billions being spent in the health care system worldwide (N Engl J Med. 2017;376:2367, Int J Pharm. 2014;463:119). We studied the in-vitro and in-vivo antimicrobial effects of a multimodal wound matrix (MWM) against two common wound pathogens, Methicillin-Resistant Staphylococcus aureus (MRSA USA300) and Pseudomonas aeruginosa ATCC 27312 (PA27312) (Int Wound J. 2019;16:634). The in-vitro study conducted was a zone of inhibition test with the two microbes at 104 Log CFU/mL inoculated on Tryptic soy agar with 5% sheep blood (TSAII) plates. Treatments used were MWM, Mupirocin (Positive control for MRSA), Silver Sulfadiazine (Positive Control for PA), Petrolatum and Sterile Saline (both serving as Negative Controls). Treatments were allowed to diffuse into the agar for 3 h and then were incubated for 24 h at 37°C. The in-vivo study utilized a deep dermal porcine wound model (22 × 22 × 3 mm) created on six animals. Three animals were inoculated with MRSA USA300 and the other three with PA27312 with each allowing a 72-h biofilm formation. After 72 h, baseline wounds were assessed for bacterial concentration and all remaining wounds were treated with either MWM alone, Silver Treatment or Untreated Control. Wounds were assessed on days 4, 8 and 12 after treatment application for microbiological analysis. In-vitro, MWM exhibited significant inhibition of MRSA USA300 and PA27312 growth when compared to negative controls (p ≤ 0.05). Likewise, in-vivo, the MWM-treated wounds exhibited a significant (p ≤ 0.05) bacterial reduction compared to all other treatment groups, especially on days 8 and 12 for both pathogens. MWM demonstrated promise in addressing colonized wounds with biofilms. Additional studies on MWM's benefits and comparisons with existing treatments are warranted to optimize wound care strategies (Adv Wound Care. 2021;10:281).
Assuntos
Modelos Animais de Doenças , Staphylococcus aureus Resistente à Meticilina , Pseudomonas aeruginosa , Infecção dos Ferimentos , Animais , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Suínos , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia , Cicatrização/efeitos dos fármacos , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Testes de Sensibilidade Microbiana , BandagensRESUMO
Pseudomonas aeruginosa is a frequent cause of antimicrobial-resistant hospital-acquired pneumonia, especially in critically ill patients. Inflammation triggered by P. aeruginosa infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Emerging data have shed light on the pro-resolving actions of angiotensin-(1-7) [Ang-(1-7)] signaling through the G protein-coupled receptor Mas (MasR) during infections. Herein, we investigated the role of the Ang-(1-7)/Mas axis in pneumonia caused by P. aeruginosa by using genetic and pharmacological approach and found that Mas receptor-deficient animals developed a more severe form of pneumonia showing higher neutrophilic infiltration into the airways, bacterial load, cytokines, and chemokines production and more severe pulmonary damage. Conversely, treatment of pseudomonas-infected mice with Ang-(1-7) was able to decrease neutrophilic infiltration in airways and lungs, local and systemic levels of pro-inflammatory cytokines and chemokines, and increase the efferocytosis rates, mitigating lung damage/dysfunction caused by infection. Notably, the therapeutic association of Ang-(1-7) with antibiotics improved the survival rates of mice subjected to lethal inoculum of P. aeruginosa, extending the therapeutic window for imipenem. Mechanistically, Ang-(1-7) increased phagocytosis of bacteria by neutrophils and macrophages to accelerate pathogen clearance. Altogether, harnessing the Ang-(1-7) pathway during infection is a potential strategy for the development of host-directed therapies to promote mechanisms of resistance and resilience to pneumonia.
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Angiotensina I , Antibacterianos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos , Proto-Oncogene Mas , Infecções por Pseudomonas , Pseudomonas aeruginosa , Receptores Acoplados a Proteínas G , Animais , Angiotensina I/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Camundongos , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/microbiologia , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Pneumonia Bacteriana/metabolismo , Citocinas/metabolismo , Camundongos Knockout , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Pneumonia/microbiologia , Masculino , Pulmão/microbiologia , Pulmão/metabolismo , Pulmão/patologia , Transdução de Sinais/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacosRESUMO
Introduction: Managing burn injuries is a challenge in healthcare. Due to the alarming increase in antibiotic resistance, new prophylactic and therapeutic strategies are being sought. This study aimed to evaluate the potential of live Lactic Acid Bacteria for managing burn infections, using Galleria mellonella larvae as an alternative preclinical animal model and comparing the outcomes with a common antibiotic. Methods: The antimicrobial activity of LAB isolated from human breast milk was assessed in vitro against Pseudomonas aeruginosa ATCC 27853. Additionally, the immunomodulatory effects of LAB were evaluated in vivo using the G. mellonella burn wound infection model. Results and discussion: In vitro results demonstrated the antimicrobial activity of Lactic Acid Bacteria against P. aeruginosa. In vivo results show that their prophylactic treatment improves, statistically significant, larval survival and modulates the expression of immunity-related genes, Gallerimycin and Relish/NF-κB, strain-dependently. These findings lay the foundation and suggest a promising alternative for burn wound prevention and management, reducing the risk of antibiotic resistance, enhancing immune modulation, and validating the potential G. mellonella as a skin burn wound model.
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Queimaduras , Modelos Animais de Doenças , Lactobacillales , Larva , Leite Humano , Pseudomonas aeruginosa , Animais , Queimaduras/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Humanos , Larva/microbiologia , Leite Humano/microbiologia , Feminino , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/imunologia , Mariposas/microbiologia , Infecção dos Ferimentos/microbiologia , Infecção dos Ferimentos/tratamento farmacológico , Antibacterianos/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
Sodium houttuyfonate (SH), derived from the widely utilized natural herb Houttuynia cordata, exhibits an effective therapeutic effect on various diseases, including bacterial and fungal infections, especially the respiratory tract infection. Therefore, the anti-microbial mechanisms of SH may be different from the single-target action mechanism of conventional antibiotics, and further research is needed to clarify this. Firstly, we discovered that SH can effectively intervene in mouse lung infections by reducing bacterial load and acute inflammation response related to pneumonia caused by Pseudomonas aeruginosa. Interestingly, our results confirmed that SH has surface activity and can directly induce changes in the cell wall the shedding of surface lipopolysaccharide (LPS). Additionally, we found that SH-induced shedding of LPS can induce M1 polarization of macrophages in the early stage, leading to the production of corresponding polarization effector molecules. Subsequently, we discovered that SH-induced M1 polarization cells can effectively phagocytose and kill bacterial cells. The protein expression results indicated that SH can enhance the expression of M1 polarization pathway of TLR4/MyD88/NF-κB during the initial phase of macrophage and pathogen interaction. In summary, our results imply that SH could directly induce the shedding of P. aeruginosa LPS in a surfactant-like manner. Afterwards, the SH induced abscisic LPS can initiate the TLR4/MyD88/NF-κB immune pathway to trigger the M1 polarization of macrophages, which might intervene the P. aeruginosa-caused acute lung infection at early stage. Based on these findings, we attempted to coin the term "immune feedback eradication mechanism against pathogen of natural product" to describe this potent antimicrobial mechanism of SH.
Assuntos
Lipopolissacarídeos , Macrófagos , Pseudomonas aeruginosa , Sulfitos , Animais , Lipopolissacarídeos/farmacologia , Camundongos , Pseudomonas aeruginosa/efeitos dos fármacos , Sulfitos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Receptor 4 Toll-Like/metabolismo , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Alcanos/farmacologia , Células RAW 264.7 , Camundongos Endogâmicos C57BL , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Fagocitose/efeitos dos fármacos , Antibacterianos/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Carbapenem-resistant Pseudomonas aeruginosa is a common multidrug-resistant bacterium encountered in clinical practice. This pathogen causes pneumonia, which is difficult to treat owing to the limited choice of antimicrobial drugs, resulting in a relatively high mortality rate. Carrimycin is a new macrolide antibiotic with broad-spectrum antibacterial and potential immunomodulatory effects. Herein, we report a case of severe pneumonia caused by carbapenem-resistant Pseudomonas aeruginosa that presented with septic shock and Acute Respiratory Distress Syndrome (ARDS). Initially, we used piperacillin-tazobactam and ceftazidime-avibactam but without satisfactory results. Finally, we administered carrimycin in combination with piperacillin-tazobactam; the patient's condition improved, and he was successfully weaned off the ventilator. Therefore, the combined use of carrimycin should be considered for patients infected with carbapenem-resistant Pseudomonas aeruginosa who do not respond to conventional anti-infection treatments.
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Antibacterianos , Carbapenêmicos , Infecções por Pseudomonas , Pseudomonas aeruginosa , Humanos , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Masculino , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pessoa de Meia-Idade , Testes de Sensibilidade Microbiana , IdosoRESUMO
Microorganisms are the most common cause of food spoilage. Pseudomonas aeruginosa is a common foodborne pathogen that causes food spoilage and poses a serious threat to food safety. As a crucial target in antitoxicity strategies, the quorum sensing (QS) system shows promising potential for further development. The garlic extract diallyl disulfide exhibits inhibitory activity against the QS system of P. aeruginosa, with disulfide bonds serving as the active component. However, the biological activity of other symmetric disulfides has not been investigated in this capacity. The study synthesized 39 disulfide bond-containing analogs and evaluated their activity as quorum sensing inhibitors (QSIs). The results showed that p-hydroxyphenyl substitution can replace the allyl groups while maintaining strong biological activity. The virulence factors production was reduced by compound 2i, with the strongest inhibitory effect being observed on elastase production. Synergistic inhibition was observed in the presence of antibiotics like ciprofloxacin and tobramycin. 2i successfully inhibited P. aeruginosa infection in the Galleria mellonella larvae model. Primary mechanism studies using transcriptome, surface plasmon resonance and molecular docking suggested that 2i inhibits the QS system by targeting the LasR protein. Thus, compound 2i could be used in developing QSIs for the control of P. aeruginosa infections.
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Antibacterianos , Dissulfetos , Alho , Extratos Vegetais , Pseudomonas aeruginosa , Percepção de Quorum , Percepção de Quorum/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Alho/química , Dissulfetos/química , Dissulfetos/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antibacterianos/farmacologia , Antibacterianos/química , Animais , Mariposas/efeitos dos fármacos , Mariposas/microbiologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologiaRESUMO
Pseudomonas aeruginosa infections are difficult to treat due to rapid development of antibiotic drug resistance. The synergistic combination of already-in-use drugs is an alternative to developing new antibiotics to combat antibiotic-resistant bacteria. Here we demonstrate that bismuth-based drugs (bismuth subsalicylate, colloidal bismuth subcitrate) in combination with different classes of antibiotics (tetracyclines, macrolides, quinolones, rifamycins and so on) can eliminate multidrug-resistant P. aeruginosa and do not induce development of antibiotic resistance. Bismuth disrupts iron homeostasis by binding to P. aeruginosa siderophores. Inside cells, bismuth inhibits the electron transport chain, dissipates the proton motive force and impairs efflux pump activity by disrupting iron-sulfur cluster-containing enzymes, including respiration complexes. As a result, bismuth facilitates antibiotic accumulation inside bacteria, enhancing their efficacy. The combination therapy shows potent antibacterial efficacy and low toxicity in an ex vivo bacteraemia model and increases the survival rate of mice in in vivo mouse lung-infection models. Our findings highlight the potential of bismuth-based drugs to be repurposed to combat P. aeruginosa infections in combination with clinically used antibiotics.
Assuntos
Antibacterianos , Bismuto , Sinergismo Farmacológico , Homeostase , Ferro , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas , Pseudomonas aeruginosa , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Antibacterianos/farmacologia , Ferro/metabolismo , Animais , Bismuto/farmacologia , Homeostase/efeitos dos fármacos , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Camundongos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Humanos , Modelos Animais de Doenças , FemininoRESUMO
PURPOSE: This study aimed to present real-life data on the use, effectiveness, and safety of administering Ceftolozane/Tazobactam (C/T) through elastomeric pumps (EP) in the outpatient setting. METHODS: This case series study was conducted from January 2022 to July 2023 in a large University Hospital in Rome, Italy. Patients receiving continuous infusion of C/T via EP were included up to a follow-up period of 90 days after the end of antibiotic therapy. The primary endpoint was the infection's clinical cure rate. Secondary endpoints were adverse events attributable to continuous home infusion of Ceftolozane/Tazobactam via elastomeric pumps. RESULTS: Seven patients received C/T continuously infused via EP and were included in the final analysis. Three patients suffered from prosthetic joint infection (n = 3/7; 43%), two patients from osteomyelitis (n = 2/7; 29%), one patient from otomastoiditis (n = 1/7; 15%) and one from pneumonia (n = 1/7; 15%). All infection were sustained by P. aeruginosa. Five strains had MDR-type susceptibility profiles (n = 5/7; 71%) and two of these were DTR (n = 2/7; 29%). The infection cure rate reached 86% (n = 6/7). Two patients reported a complication related to the vascular catheter for drug infusion (n = 2/7; 29%). CONCLUSIONS: Continuous infusion of Ceftolozane/Tazobactam by elastomeric pumps has been shown to be safe and effective in practice representing a viable option of intravenous treatment in outpatient setting for infection sustained by P. aeruginosa especially for multidrug-resistant strains.
Assuntos
Antibacterianos , Cefalosporinas , Tazobactam , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Tazobactam/administração & dosagem , Tazobactam/uso terapêutico , Tazobactam/efeitos adversos , Cefalosporinas/administração & dosagem , Cefalosporinas/uso terapêutico , Cefalosporinas/efeitos adversos , Bombas de Infusão , Infecções por Pseudomonas/tratamento farmacológico , Elastômeros , Resultado do Tratamento , Adulto , Idoso de 80 Anos ou mais , Infusões Intravenosas , Itália , Pseudomonas aeruginosa/efeitos dos fármacos , Infecções Relacionadas à Prótese/tratamento farmacológicoRESUMO
RATIONALE: Infections due to multidrug-resistant (MDR) Pseudomonas aeruginosa are strongly associated with poor outcomes, including prolonged hospitalization and an increased risk of mortality. Antimicrobial options for the treatment of severe infections due to MDR P aeruginosa are quite limited, and treatment remains challenging. PATIENT CONCERNS: A 65-year-old woman presented to our orthopedic clinic with a 3-month history of progressive pain and stiffness in her left knee. Her primary care provider administered a hyaluronic acid injection, which unfortunately resulted in worsening symptoms. Subsequent treatment included a 1-month course of intravenous gentamicin and ceftriaxone, which failed to alleviate her symptoms. DIAGNOSIS: MDR P aeruginosa septic arthritis of the knee. The culture isolate was tested for susceptibility to multiple antibiotics. Magnetic resonance imaging evaluations were conducted, showing notable erosive and osteolytic changes around the joint surfaces that had progressed significantly. INTERVENTIONS: The patient underwent arthroscopic irrigation and synovectomy. The treatment regimen included a combination of intravenous colistin and piperacillin/tazobactam administered over a 6-week period. Total knee arthroplasty was performed 6 months later without additional antibiotic treatment. OUTCOMES: Patient's knee condition remained continuously stable without abnormal findings of inflammation. The patient's knee range of motion increased 0 to 125 degrees, her pain almost disappeared, and she was able to maintain activities of daily life. LESSONS: This case underscores the challenges of managing infections with MDR organisms in complex clinical scenarios, emphasizing the need for timely intervention and appropriate antibiotic therapy.
Assuntos
Antibacterianos , Artrite Infecciosa , Farmacorresistência Bacteriana Múltipla , Infecções por Pseudomonas , Pseudomonas aeruginosa , Humanos , Feminino , Idoso , Artrite Infecciosa/microbiologia , Artrite Infecciosa/tratamento farmacológico , Artrite Infecciosa/diagnóstico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/isolamento & purificação , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Articulação do Joelho/microbiologiaRESUMO
INTRODUCTION: Multi-drug-resistant (MDR) Pseudomonas aeruginosa is a dangerous pathogen causing nosocomial infection, particularly in low- and middle-income countries like Brazil. This retrospective study at a Brazilian university hospital examined the relationship between antimicrobial use and MDR-P. aeruginosa. METHODOLOGY: Data was collected from 358 patients with non-repetitive P. aeruginosa infections from 2009 to 2019. Antibiotic use was measured in grams and expressed as defined daily dose (DDD) per 1000 patient-days for meropenem, imipenem, polymyxin, and tigecycline. RESULTS: Extensively drug-resistant (XDR) P. aeruginosa occurred in 36.1%, and MDR in 32.6% of cases. Risk factors for XDR infection were hospitalization prior to infection (OR = 0.9901), intensive care unit (ICU) admission (OR = 0.4766), previous antibiotic use (OR = 1.4417), and use of cefepime (OR = 0.3883). Over the ten-year period, utilization of the monitored antibiotics increased, and there was a positive correlation between the rise in MDR-P. aeruginosa and the consumption of ceftriaxone, imipenem, meropenem, and polymyxin B. The 30-day mortality rate was 40.0% for all patients and 41.0% for those infected with XDR-P. aeruginosa. CONCLUSIONS: This study highlights the negative impact of the indiscriminate use of antimicrobials, which has led to a significant increase in multidrug-resistant P. aeruginosa strains in hospitals.
Assuntos
Antibacterianos , Farmacorresistência Bacteriana Múltipla , Infecções por Pseudomonas , Pseudomonas aeruginosa , Humanos , Pseudomonas aeruginosa/efeitos dos fármacos , Estudos Retrospectivos , Brasil/epidemiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Masculino , Feminino , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Pessoa de Meia-Idade , Adulto , Idoso , Infecção Hospitalar/microbiologia , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/epidemiologia , Hospitais Universitários , Fatores de Risco , Meropeném/uso terapêutico , Unidades de Terapia Intensiva/estatística & dados numéricosRESUMO
BACKGROUND: The 2016 IDSA guideline recommends a treatment duration of at least 7 days for hospital-acquired (HAP)/ventilator-associated pneumonia (VAP). The limited literature has demonstrated higher rates of recurrence for non-glucose fermenting gram-negative bacilli with short course therapy, raising the concern of optimal treatment duration for these pathogens. Therefore, we aimed to compare the outcomes for patients receiving shorter therapy treatment (≤ 8 days) versus longer regimen (> 8 days) for the treatment of multidrug resistant (MDR) Pseudomonas pneumonia. METHODS: A single-center, retrospective cohort study was conducted to evaluate adult patients receiving an antimicrobial regimen with activity against MDR Pseudomonas aeruginosa in respiratory culture between 2017 and 2020 for a minimum of 6 consecutive days. Exclusion criteria were inmates, those with polymicrobial pneumonia, community-acquired pneumonia, and infections requiring prolonged antibiotic therapy. RESULTS: Of 427 patients with MDR P. aeruginosa respiratory isolates, 85 patients were included. Baseline characteristics were similar among groups with a median age of 65.5 years and median APACHE 2 score of 20. Roughly 75% had ventilator-associated pneumonia. Compared to those who received ≤ 8 days of therapy, no difference was seen for clinical success in patients treated for more than 8 days (80% vs. 65.5%, p = 0.16). The number of 30-day and 90-day in-hospital mortality, 30-days relapse, and other secondary outcomes did not significantly differ among the treatment groups. CONCLUSIONS: Prolonging treatment duration beyond 8 days did not improve patient outcomes for MDR P. aeruginosa HAP/VAP.
Assuntos
Antibacterianos , Farmacorresistência Bacteriana Múltipla , Infecções por Pseudomonas , Pseudomonas aeruginosa , Humanos , Masculino , Feminino , Pseudomonas aeruginosa/efeitos dos fármacos , Estudos Retrospectivos , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Idoso , Pessoa de Meia-Idade , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/mortalidade , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/microbiologia , Pneumonia Associada à Ventilação Mecânica/mortalidade , Resultado do Tratamento , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/mortalidade , Duração da TerapiaRESUMO
The biofilm formation of Pseudomonas aeruginosa involves multiple complex regulatory pathways; thus, blocking a single pathway is unlikely to achieve the desired antibiofilm efficacy. Herein, a series of hybrids of 3-hydroxypyridin-4(1H)-ones and long-chain 4-aminoquinolines were synthesized as biofilm inhibitors against P. aeruginosa based on a multipathway antibiofilm strategy. Comprehensive structure-activity relationship studies identified compound 30b as the most valuable antagonist, which significantly inhibited P. aeruginosa biofilm formation (IC50 = 5.8 µM) and various virulence phenotypes. Mechanistic studies revealed that 30b not only targets the three quorum sensing systems but also strongly induces iron deficiency signals in P. aeruginosa. Furthermore, 30b demonstrated a favorable in vitro and in vivo safety profile. Moreover, 30b specifically enhanced the antibacterial activity of tobramycin and polymyxin B in in vitro and in vivo combination therapy. Overall, these results highlight the potential of 30b as a novel anti-infective candidate for treating P. aeruginosa infections.
Assuntos
Antibacterianos , Biofilmes , Testes de Sensibilidade Microbiana , Polimixina B , Infecções por Pseudomonas , Pseudomonas aeruginosa , Tobramicina , Pseudomonas aeruginosa/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Relação Estrutura-Atividade , Tobramicina/farmacologia , Tobramicina/química , Animais , Polimixina B/farmacologia , Polimixina B/química , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Camundongos , Sinergismo Farmacológico , Percepção de Quorum/efeitos dos fármacos , Piridonas/farmacologia , Piridonas/química , Piridonas/síntese química , Humanos , AminoquinolinasRESUMO
Pseudomonas aeruginosa is an opportunistic pathogen that causes severe infections in compromised hosts. P. aeruginosa infections are difficult to treat because of the inherent ability of the bacteria to develop antibiotic resistance, secrete a variety of virulence factors, and form biofilms. The secreted aminopeptidase (PaAP) is an emerging virulence factor, key in providing essential low molecular weight nutrients and a cardinal modulator of biofilm development. PaAP is therefore a new potential target for therapy of P. aeruginosa infections. The present review summarizes the current knowledge of PaAP, with special emphasis on its biochemical and enzymatic properties, activation mechanism, biological roles, regulation, and structure. Recently developed specific inhibitors and their potential as adjuncts in the treatment of P. aeruginosa infections are also described.
Assuntos
Aminopeptidases , Pseudomonas aeruginosa , Fatores de Virulência , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/patogenicidade , Pseudomonas aeruginosa/metabolismo , Aminopeptidases/metabolismo , Humanos , Fatores de Virulência/metabolismo , Proteínas de Bactérias/metabolismo , Biofilmes/crescimento & desenvolvimento , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , AnimaisRESUMO
Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) is widely used in clinical microbiology laboratories for bacterial identification but its use for detection of antimicrobial resistance (AMR) remains limited. Here, we used MALDI-TOF MS with artificial intelligence (AI) approaches to successfully predict AMR in Pseudomonas aeruginosa, a priority pathogen with complex AMR mechanisms. The highest performance was achieved for modern ß-lactam/ß-lactamase inhibitor drugs, namely, ceftazidime/avibactam and ceftolozane/tazobactam. For these drugs, the model demonstrated area under the receiver operating characteristic curve (AUROC) of 0.869 and 0.856, specificity of 0.925 and 0.897, and sensitivity of 0.731 and 0.714, respectively. As part of this work, we developed dynamic binning, a feature engineering technique that effectively reduces the high-dimensional feature set and has wide-ranging applicability to MALDI-TOF MS data. Compared to conventional feature engineering approaches, the dynamic binning method yielded highest performance in 7 of 10 antimicrobials. Moreover, we showcased the efficacy of transfer learning in enhancing the AUROC performance for 8 of 11 antimicrobials. By assessing the contribution of features to the model's prediction, we identified proteins that may contribute to AMR mechanisms. Our findings demonstrate the potential of combining AI with MALDI-TOF MS as a rapid AMR diagnostic tool for Pseudomonas aeruginosa.IMPORTANCEPseudomonas aeruginosa is a key bacterial pathogen that causes significant global morbidity and mortality. Antimicrobial resistance (AMR) emerges rapidly in P. aeruginosa and is driven by complex mechanisms. Drug-resistant P. aeruginosa is a major challenge in clinical settings due to limited treatment options. Early detection of AMR can guide antibiotic choices, improve patient outcomes, and avoid unnecessary antibiotic use. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) is widely used for rapid species identification in clinical microbiology. In this study, we repurposed mass spectra generated by MALDI-TOF and used them as inputs for artificial intelligence approaches to successfully predict AMR in P. aeruginosa for multiple key antibiotic classes. This work represents an important advance toward using MALDI-TOF as a rapid AMR diagnostic for P. aeruginosa in clinical settings.
Assuntos
Antibacterianos , Inteligência Artificial , Pseudomonas aeruginosa , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Tazobactam , Pseudomonas aeruginosa/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Antibacterianos/farmacologia , Humanos , Tazobactam/farmacologia , Tazobactam/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Testes de Sensibilidade Microbiana/métodos , Farmacorresistência Bacteriana , Combinação de Medicamentos , Ceftazidima/farmacologia , Compostos Azabicíclicos/farmacologia , CefalosporinasRESUMO
BACKGROUND: Antimicrobial-resistant (AMR) bacterial infection is a significant global threat to the healthcare systems. Pseudomonas aeruginosa, the leading infectious agent in the healthcare setting is now one of the major threats due to AMR. A comprehensive understanding of the magnitude of AMR, particularly highly public health important pathogens such as P. aeruginosa, is necessary for the management of infections based on local information. OBJECTIVE: This systematic review and meta-analysis aimed to determine the country-wide AMR of P. aeruginosa. METHODS: Systematic searches were performed to retrieve articles from PubMed, Scopus, Web of Science, ScienceDirect electronic databases, Google Scholar search engine, and repository registrars from 2015 to 31st December 2023. Twenty-three studies that provided important data on AMR in P. aeruginosa were systematically reviewed and analyzed to determine the country-wide magnitude of P. aeruginosa AMR profile from healthcare-associated infections. AMR of P. aeruginosa to 10 different antibiotics were extracted separately into Microsoft Excel and analyzed using STATA 17.0. Cohen's kappa was computed to determine the agreement between reviewers, the Inverse of variance (I2) was used to evaluate heterogeneity across studies, and Egger's test to identify publication bias. A random effect model was used to determine the pooled resistance to each antibiotic. Subgroup analysis was performed by infection type and year of publication. RESULTS: This systematic review and meta-analysis revealed that the pooled prevalence of P. aeruginosa in clinical specimens associated with HAI was 4.38%(95%CI: 3.00-5.76). The pooled prevalence of AMR in P. aeruginosa for different antibiotics varies, ranging from 20.9% (95%CI: 6.2-35.8) for amikacin to 98.72% (95%CI: 96.39-101.4) for ceftriaxone. The pooled resistance was higher for ceftriaxone (98.72%), Trimethoprim-sulfamethoxazole (75.41), and amoxicillin-clavulanic acid (91.2). In contrast relatively lower AMR were observed for amikacin (20.9%) and meropenem (28.64%). The pooled multi-drug resistance (MDR) in P. aeruginosa was 80.5% (95%CI: 66.25-93.84). Upon subgroup analysis by infection types and year of publication, P. aeruginosa isolated from healthcare-associated infections exhibited higher resistance to ceftazidime (94.72%) compared to isolates from mixed types of healthcare-associated infections (70.84%) and surgical site infections (57.84%). Antimicrobial resistance in gentamicin was higher during the periods of 2018-2020 (73.96%), while comparatively lower during 2021-2023 (42.69%) and 2015-2017 (29.82%). CONCLUSIONS: Significantly high AMR and MDR were observed from this systematic review and meta-analysis. AMR obtained from this systematic review and meta-analysis urges the need for improved infection control, antimicrobial stewardship practices, and strengthened surveillance systems to control the spread of AMR and ensure effective treatment of P. aeruginosa infections. PROTOCOL REGISTRATION: This systematic review and meta-analysis was registered on PROSPERO (Registration ID: CRD42024518145).
Assuntos
Antibacterianos , Infecção Hospitalar , Infecções por Pseudomonas , Pseudomonas aeruginosa , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Humanos , Infecção Hospitalar/microbiologia , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/tratamento farmacológico , Etiópia/epidemiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/epidemiologia , Farmacorresistência Bacteriana , Testes de Sensibilidade MicrobianaRESUMO
The bacterium Pseudomonas aeruginosa is an exceptionally resilient opportunistic pathogen, presenting formidable challenges for treatment due to its proclivity for developing drug resistance. To address this predicament, we have devised a self-assembled supramolecular antibiotic known as dHTSN1@pHPplus, which can circumvent the drug resistance mechanism of Pseudomonas aeruginosa and effectively combat Pseudomonas aeruginosa infection by impeding the secretion of key virulence factors through the inhibition of the type III secretion system while simultaneously mobilizing immune cells to eradicate Pseudomonas aeruginosa. Furthermore, dHTSN1@pHPplus was ingeniously engineered with infection-targeting capabilities, enabling it to selectively concentrate precisely at the site of infection. As anticipated, the administration of dHTSN1@pHPplus exhibited a remarkable therapeutic efficacy in combating dual resistance to Meropenem and imipenem in a mouse model of P. aeruginosa lung infection. The results obtained from metagenomic detection further confirmed these findings, demonstrating a significant reduction in the proportion of Pseudomonas aeruginosa compared to untreated mice with Pseudomonas aeruginosa-infected lungs. Additionally, no notable acute toxicity was observed in the acute toxicity experiments. The present study concludes that the remarkable efficacy of dHTSN1@pHPplus in treating drug-resistant P. aeruginosa infection confirms its immense potential as a groundbreaking antibiotic agent for combating drug-resistant P. aeruginosa.
Assuntos
Antibacterianos , Infecções por Pseudomonas , Pseudomonas aeruginosa , Fatores de Virulência , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Camundongos , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Imunidade Adaptativa/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Humanos , Farmacorresistência Bacteriana/efeitos dos fármacos , Camundongos Endogâmicos BALB C , FemininoRESUMO
Introduction: Biofilm-associated infections persist as a therapeutic challenge in contemporary medicine. The efficacy of antibiotic therapies is ineffective in numerous instances, necessitating a heightened focus on exploring novel anti-biofilm medical strategies. Among these, iminosugars emerge as a distinctive class of compounds displaying promising biofilm inhibition properties. Methods: This study employs an in vivo wound infection mouse model to evaluate the effectiveness of PDIA in treating biofilm-associated skin wound infections caused by Staphylococcus aureus and Pseudomonas aeruginosa. Dermic wounds in mice were infected with biofilm-forming strains, specifically S. aureus 48 and P. aeruginosa 5, which were isolated from patients with diabetic foot, and are well-known for their strong biofilm formation. The subsequent analysis included clinical, microbiological, and histopathological parameters. Furthermore, an exploration into the susceptibility of the infectious strains to hydrogen peroxide was conducted, acknowledging its potential presence during induced inflammation in mouse dermal wounds within an in vivo model. Results: The findings revealed the efficacy of PDIA iminosugar against the S. aureus strain, evidenced by a reduction in bacterial numbers within the wound and the inflammatory focus. Discussion: This study suggests that PDIA iminosugar emerges as an active and potentially effective antibiofilm agent, positioning it as a viable treatment option for staphylococcal infections.
Assuntos
Antibacterianos , Biofilmes , Modelos Animais de Doenças , Infecções por Pseudomonas , Pseudomonas aeruginosa , Infecções Estafilocócicas , Staphylococcus aureus , Animais , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Camundongos , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecção dos Ferimentos/microbiologia , Infecção dos Ferimentos/tratamento farmacológico , Humanos , FemininoRESUMO
Pseudomonas aeruginosa (P. aeruginosa) pneumonia can have serious physiological consequences, particularly when P. aeruginosa biofilms are formed. Although inhaled therapy is preferred, inhaled drugs tend to get trapped by pulmonary mucus, which hinders efficient antibiotic permeability through mucus and biofilms. In this study, we prepare poly[2-(pentamethyleneimino)ethyl methacrylate]-block-poly[2-(N-oxide-pentamethyleneimino)ethyl methacrylate] (PPEMA-b-PPOEMA) micelles loaded with azithromycin (AZM) using reversible addition-fragmentation chain transfer (RAFT) polymerization to achieve effective treatment of P. aeruginosa pneumonia. The zwitterionic structure on the surface of the micelle facilitates the successful traversal of the mucus and optimal concentration within the biofilm. Furthermore, the protonation of piperidine in the polymer enables the micelles to exhibit a positive charge in the acidic environment of a bacterial infection, enhancing AZM's interaction with the bacterium. Both in vivo and in vitro experiments demonstrate that this transmucosal zwitterionic polymer, in combination with a charge reversal strategy, effectively promotes the enrichment of micelles at the site of bacterial infection, thereby increasing the number of antibiotics reaching the bacterial interior and demonstrating remarkable antibacterial synergy. Overall, this work offers a promising approach for trans-airway drug delivery in the treatment of pneumonia.
Assuntos
Antibacterianos , Micelas , Pseudomonas aeruginosa , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Mucinas/química , Mucinas/metabolismo , Camundongos , Administração por Inalação , Azitromicina/química , Azitromicina/farmacologia , Azitromicina/administração & dosagem , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Biofilmes/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Pneumonia/tratamento farmacológico , Doença Crônica , Portadores de Fármacos/químicaRESUMO
INTRODUCTION: Although rare, Malignant otitis externa is responsible for a high morbidity and could sometimes be fatal. The management of this condition is still challenging. AIM: To analyse the clinical, microbiological and radiological profile of malignant otitis externa, and the management of this condition. METHODS: A descriptive, cross-sectional study was conducted at ENT Department of Kairouan's hospital including 38 patients hospitalised and treated for malignant otitis externa from January 2013 to August 2021. RESULTS: The mean age of patients was 67.7 ± 12.9 years (35-98). All patients presented with continuous otalgia that resists to usual analgesics. Otorrhea was noticed in 76.3% of cases, facial palsy in 2 cases (5.3%) and dysphonia in one case (2.6%). Pseudomonas Aeruginosa was the main responsible pathogen (42%). Concomitant bacterial and fungal infection was noticed in 6.4% of the cases. First-line intravenous antibiotherapy used was mainly based on an association of Cephalosporins and Fluoroquinolones. Complete remission was noticed in 30 patients (79%). However, 8 cases of recurrences (21%) and 2 cases of deaths (5.2%) were noticed in our series. The mean follow-up was 4.6±6.3 (1-26 months). CONCLUSIONS: Pseudomonas Aeruginosa remains the main responsible pathogen for malignant otitis externa. Nevertheless, fungal infections are rising because of the overuse of antibiotics. Antibiotherapy should be adapted to culture results and resistance profile of pathogens in hospital. Practionners should be aware of the possibility of concomitant fungal infection, especially in the case of unfavorable evolution.