Target attainment of intravenous lefamulin for treatment of acute bacterial skin and skin structure infections.

OBJECTIVES: Lefamulin is a pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). Its spectrum of activity, good penetration into soft tissues and low rates of cross-resistance also make lefamulin a potentially valuable option for treatment of acute bacterial skin and skin structure infections (ABSSSIs). A Phase 2 trial of lefamulin for ABSSSI indicated similar efficacy of 100 and 150 mg q12h IV dosing regimens. In the present study, the potential of lefamulin for this indication was further evaluated from a translational pharmacokinetic/pharmacodynamic perspective. METHODS: PTA was determined for various dosages using Monte Carlo simulations of a population pharmacokinetic model of lefamulin in ABSSSI patients and preclinical exposure targets associated with bacteriostasis and a 1-log reduction in bacterial count. Overall target attainment against MSSA and MRSA was calculated using lefamulin MIC distributions. RESULTS: Overall attainment of the bacteriostasis target was 94% against MSSA and 84% against MRSA for the IV dosage approved for CABP (150 mg q12h). Using the same target, for the 100 mg q12h regimen, overall target attainment dropped to 68% against MSSA and 50% against MRSA. Using the 1-log reduction target, overall target attainment for both regimens was <40%. CONCLUSIONS: Lefamulin at the currently approved IV dosage covers most Staphylococcus aureus isolates when targeting drug exposure associated with bacteriostasis, suggesting potential of lefamulin for the treatment of ABSSSIs. Lefamulin may not be appropriate in ABSSSI when rapid bactericidal activity is warranted.

Zinc deficiency enhances sensitivity to influenza A associated bacterial pneumonia in mice.

Although zinc deficiency (secondary to malnutrition) has long been considered an important contributor to morbidity and mortality of infectious disease (e.g. diarrhea disorders), epidemiologic data (including randomized controlled trials with supplemental zinc) for such a role in lower respiratory tract infection are somewhat ambiguous. In the current study, we provide the first preclinical evidence demonstrating that although diet-induced acute zinc deficiency (Zn-D: ~50% decrease) did not worsen infection induced by either influenza A (H1N1) or methicillin-resistant staph aureus (MRSA), Zn-D mice were sensitive to the injurious effects of superinfection of H1N1 with MRSA. Although the mechanism underlying the sensitivity of ZnD mice to combined H1N1/MRSA infection is unclear, it was noteworthy that this combination exacerbated lung injury as shown by lung epithelial injury markers (increased BAL protein) and decreased genes related to epithelial integrity in Zn-D mice (surfactant protein C and secretoglobins family 1A member 1). As bacterial pneumonia accounts for 25%-50% of morbidity and mortality from influenza A infection, zinc deficiency may be an important pathology component of respiratory tract infections.

Revealing active constituents within traditional Chinese Medicine used for treating bacterial pneumonia, with emphasis on the mechanism of baicalein against multi-drug resistant Klebsiella pneumoniae.

ETHNOPHARMACOLOGICAL RELEVANCE: The emergence of antibiotic-resistant bacteria has rendered it more challenging to treat bacterial pneumonia. Traditional Chinese medicine (TCM) has superior efficacy in the treatment of pneumonia, and it has the unique advantage of antibacterial resistance against multi-drug resistant (MDR) bacteria, but the medication rule and pharmacological mechanism of its antibacterial activity are not clear. AIM OF THE STUDY: This study aims to reveal Chinese medication patterns in treating bacterial pneumonia to select bioactive constituents in core herbs, predict their pharmacological mechanisms and further explore their antibacterial ability against clinically isolated MDR Klebsiella pneumoniae (KP) and their antibacterial mechanisms. MATERIALS AND METHODS: The high-frequency medicinal herbs to treat lung diseases were first screened from Pharmacopoeia of the People's Republic of China (ChP.), and then bioactive compounds in core herbs and targets for compounds and disease were collected. Potential targets, signaling pathways, and drugs' core components were determined by constructing protein-protein interaction network, enrichment analysis and "component-target-pathway-disease" network were mapped by Cytoscape 3.8.2, and the potential therapeutic value of selected core components was verified by comparing the disease targets in the GEO database with the herbal component targets in the ITCM database. The clinically isolated KP were screened by drug sensitivity tests with meropenem (MEM), polymyxin E (PE), and tigecycline and biofilm-forming assay; broth microdilution, chessboard methods and biofilm morphology and permeability experiments were employed to determine the antibacterial, bactericidal and biofilm inhibition ability of selected bioactive constituents alone and in combination with antibiotics; The mechanism of bioactive components on quorum sensing (QS) genes LuxS and LuxR was predicted by molecular docking and tested by RT-PCR. RESULTS: The 13 core Chinese medicines were obtained by mining ChP., and 615 potential targets of core herbal medicine were screened, and the PI3K-Akt signaling pathway might play crucial roles in the therapeutic process. In-vitro experiments revealed that the selected core compounds, including forsythoside B, baicalin, baicalein, and forsythin, all have antibacterial activity, in which baicalein had the strongest ability and a synergistic effect in combination with MEM or PE. Their synergy exhibited a stronger effect on biofilms of MDR KP, inhibiting biofilm formation, disrupting formed biofilms, and removing the residual structures of dead bacteria. Baicalein was predicted to have stable binding capacity to LuxS and LuxR genes by molecular docking, and RT-PCR results verified that the combination of baicalein with MEM or PE was effective in inhibiting the expression of QS genes (LuxS and LuxR) and consequently suppressing biofilm formation. CONCLUSION: The core Chinese herbal medicine in the ChP. to treat lung diseases has a multi-component, multi-target, and multi-pathway synergy to improve bacterial pneumonia. Experimental studies have confirmed that the bioactive compound baicalein was able to combat MDR KP alone and synergistic with MEM or PE, inhibited and disrupted biofilms via regulating LuxS and LuxR genes, and further disturbed quorum sensing system to promote the therapeutic efficacy, which provides a new pathway and rationale for treating MDR KP-induced bacterial pneumonia.

Treatable traits and challenges in the clinical management of non-tuberculous mycobacteria lung disease in people with cystic fibrosis.

INTRODUCTION: Over the last ten years an increasing prevalence and incidence of non-tuberculous mycobacteria (NTM) has been reported among patients with cystic fibrosis (CF) Viviani (J Cyst Fibros, 15(5):619-623, 2016). NTM pulmonary disease has been associated with negative clinical outcomes and often requires pharmacological treatment. Although specific guidelines help clinicians in the process of diagnosis and clinical management, the focus on the multidimensional assessment of concomitant problems is still scarce. MAIN BODY: This review aims to identify the treatable traits of NTM pulmonary disease in people with CF and discuss the importance of a multidisciplinary approach in order to detect and manage all the clinical and behavioral aspects of the disease. The multidisciplinary complexity of NTM pulmonary disease in CF requires careful management of respiratory and extra-respiratory, including control of comorbidities, drug interactions and behavioral factors as adherence to therapies. CONCLUSIONS: The treatable trait strategy can help to optimize clinical management through systematic assessment of all the aspects of the disease, providing a holistic treatment for such a multi-systemic and complex condition.

Manganese-Based Nanoparticle Vaccine for Combating Fatal Bacterial Pneumonia.

Bacterial pneumonia is the leading cause of death worldwide among all infectious diseases. However, currently available vaccines against fatal bacterial lung infections, e.g., pneumonic plague, are accompanied by limitations, including insufficient antigen-adjuvant co-delivery and inadequate immune stimulation. Therefore, there is an urgent requirement to develop next-generation vaccines to improve the interaction between antigen and adjuvant, as well as enhance the effects of immune stimulation. This study develops a novel amino-decorated mesoporous manganese silicate nanoparticle (AMMSN) loaded with rF1-V10 (rF1-V10@AMMSN) to prevent pneumonic plague. These results suggest that subcutaneous immunization with rF1-V10@AMMSN in a prime-boost strategy induces robust production of rF1-V10-specific IgG antibodies with a geometric mean titer of 315,844 at day 42 post-primary immunization, which confers complete protection to mice against 50 × LD50 of Yersinia pestis (Y. pestis) challenge via the aerosolized intratracheal route. Mechanistically, rF1-V10@AMMSN can be taken up by dendritic cells (DCs) and promote DCs maturation through activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and production of type I interferon. This process results in enhanced antigen presentation and promotes rF1-V10-mediated protection against Y. pestis infection. This manganese-based nanoparticle vaccine represents a valuable strategy for combating fatal bacterial pneumonia.

The pharmacokinetic evaluation of omadacycline (Oral Only Dosing Regimen) for the treatment of Community-Acquired Bacterial Pneumonia (CABP).

INTRODUCTION: Omadacycline is a new analog of the tetracycline class active against atypical bacteria, as well as against staphylococci, including methicillin-resistant strains, and Streptococcus pneumoniae. AREAS COVERED: This review has summarized the available clinical evidence on the use of oral omadacycline in the treatment of community-acquired pneumonia (CAP) and described the mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) parameters in healthy and special populations and the latest research on omadacycline. EXPERT OPINION: The available clinical evidence on oral omadacycline for the treatment of CAP shows that its properties provide reliable empirical coverage for pathogens such as Haemophilus influenzae, Moraxella catarrhalis, and species of Legionella, Chlamydia, and Mycoplasma. Omadacycline is also active against methicillin-resistant Staphylococcus aureus (MRSA); penicillin-resistant and multidrug-resistant Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae; and vancomycin-resistant Enterococcus spp. A dose of 450 mg orally once daily is recommended, followed by a maintenance dose of 300 mg orally once daily. Importantly, omadacycline does not require dose adjustment for patients based on BMI, age, gender, or renal or hepatic impairment.

Biocompatible Gallium Nanodots against Drug-Resistant Bacterial Pneumonia and Liver Abscess.

Resistant bacterial infection remains a severe public health threat, and conventional antibiotic drugs work poorly in effectively treating infectious diseases. Here, we developed gallium-based nanodots (Ga NDs), consisting of specific disruption of bacterial iron ability, to treat multidrug-resistant (MDR) Gram-negative bacteria-infected diseases. The Ga NDs significantly suppress the proliferation of two typical MDR bacteria strains (P. aeruginosa and ESBL E. coli) compared with clinically used antibacterial drugs, including penicillin and levofloxacin. Ga NDs could also disrupt the biofilms of these two bacterial strains. In P. aeruginosa infected pneumonia and ESBL E. coli infected acute liver abscess models, the Ga NDs enable substantial inhibition of bacterial growth and reduce the organs' inflammation that resulted in significant improvement of survival. Further, the Ga NDs demonstrated excellent biocompatibility and biosafety characteristics. Together, we believe that our gallium containing nanotherapeutics are expected to be developed into promising alternative therapies to combat drug-resistant bacterial infection.

Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).

BACKGROUND: An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. METHODS: The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046. FINDINGS: Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group. INTERPRETATION: Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. FUNDING: Entasis Therapeutics and Zai Lab.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses Evaluating Omadacycline Dosing Regimens for the Treatment of Patients with Community-Acquired Bacterial Pneumonia Arising from Streptococcus pneumoniae and Haemophilus influenzae.

Omadacycline, a novel aminomethylcycline with in vitro activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and Haemophilus influenzae, is approved in the United States to treat patients with community-acquired bacterial pneumonia (CABP). Using nonclinical pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy and in vitro surveillance data for omadacycline against S. pneumoniae and H. influenzae, and a population pharmacokinetic model, PK-PD target attainment analyses were undertaken using total-drug epithelial lining fluid (ELF) and free-drug plasma exposures to evaluate omadacycline 100 mg intravenously (i.v.) every 12 h or 200 mg i.v. every 24 h (q24h) on day 1, followed by 100 mg i.v. q24h on day 2 and 300 mg orally q24h on days 3 to 5 for patients with CABP. Percent probabilities of PK-PD target attainment on days 1 and 2 by MIC were assessed using the following four approaches for selecting PK-PD targets: (i) median, (ii) second highest, (iii) highest, and (iv) randomly assigned total-drug ELF and free-drug plasma ratio of the area under the concentration-time curve to the MIC (AUC/MIC ratio) targets associated with a 1-log10 CFU reduction from baseline. Percent probabilities of PK-PD target attainment based on total-drug ELF AUC/MIC ratio targets on days 1 and 2 were ≥91.1% for S. pneumoniae for all approaches but the highest target and ≥99.2% for H. influenzae for all approaches at MIC90s (0.12 and 1 µg/mL for S. pneumoniae and H. influenzae, respectively). Lower percent probabilities of PK-PD target attainment based on free-drug plasma AUC/MIC ratio targets were observed for randomly assigned and the highest free-drug plasma targets for S. pneumoniae and for all targets for H. influenzae. These data provided support for approved omadacycline dosing regimens to treat patients with CABP and decisions for the interpretive criteria for the in vitro susceptibility testing of omadacycline against these pathogens.

Etiology and efficacy of anti-microbial treatment for community-acquired pneumonia in adults requiring hospital admission in Ukraine.

BACKGROUND AND AIM: Empiric therapy of community-acquired pneumonia (CAP) remains the standard care and guidelines are mostly based on published data from the United States or Europe. In this study, we determined the bacterial etiology of CAP and evaluated the clinical outcomes under antimicrobial treatment of CAP in Ukraine. METHODS: A total of 98 adult subjects with CAP and PORT risk II-IV were recruited for the study. The sputum diagnostic samples were obtained from all patients for causative pathogen identification. Subjects were randomly assigned in a 1:1 ratio to receive delafloxacin 300 mg (n=51) or moxifloxacin 400 mg (n=47) with blinding placebo. The switch to oral treatment was after a minimum of 6 IV doses according to clinical criteria. The total duration of antibacterial treatment was 5-10 days. In vitro susceptibility of pathogens to delafloxacin and other comparator antibiotics was determined. RESULTS: The most frequently isolated pathogens in adults with CAP were S. pneumoniae - 19.5%, M. pneumoniae - 15.3%, H. influenzae - 13.2%, S. aureus - 10.5%, K. pneumoniae - 10.1%, and H. parainfluenzae - 6.4%. All isolates of S. pneumoniae, S. aureus, M. pneumoniae had sufficient susceptibility to appropriate antibiotics. 9.0% of H. influenzae strains were susceptible to azithromycin. 94.8 % of patients had a successful clinical response to delafloxacin at the end of treatment and 93.9 % - at test-of-cure. CONCLUSIONS: In Ukraine, the major bacterial agents that induced CAP in adults were S. pneumoniae, M. pneumoniae, H. influenzae, S. aureus, K. pneumoniae, H. parainfluenzae, E. cloacae, L. pneumophila. Delafloxacin is a promising effective antibiotic for monotherapy for CAP in adults and could be used in cases of antimicrobial-resistant strains.

The holy basil administration diminishes the NF-kB expression and protects alveolar epithelial cells from pneumonia infection through interferon gamma.

Bacterial pneumonia is one of the most important causes of mortality in the United States. The bacteria Klebsiella pneumoniae (KP) accounts for a significant proportion of community and hospital-acquired infections. Here, we determine that the holy basil (Ocimum sanctum) extract improves cell viability and dampens the proinflammatory cytokine response in an in vitro model of pneumonia. For this, A549, a human alveolar basal epithelial cell line, was subjected to a lethal KP model following a 24-hr pretreatment with basil extract. Bacteremia, cell viability, apoptosis, MTT assay, phagocytic capacity, cytokines, and Khe gene expression were assessed in these cells following pneumonia. Cell morphology analysis showed that holy basil protected A549 cells from KP infection-mediated effects by inhibiting cell death due to apoptosis. Additionally, in the presence of basil, A549 cells demonstrated significantly higher bactericidal capacity and phagocytosis. Administration of holy basil led to reduced expression of hypoxia-inducible factor-1/2a, nuclear factor kappa B, and Khe in the KP-infected cells while increasing interferon (IFN)-γ expression. Our results suggest that basil significantly reduced cell death in the setting of KP infection, likely via attenuation of cytokine and IFN-γ mediated signaling pathways. Holy basil is a promising therapeutic agent for managing and treating bacterial pneumonia based on its potency.

Clinical and microbiological outcomes, by causative pathogen, in the ASPECT-NP randomized, controlled, Phase 3 trial comparing ceftolozane/tazobactam and meropenem for treatment of hospital-acquired/ventilator-associated bacterial pneumonia.

OBJECTIVES: In the ASPECT-NP trial, ceftolozane/tazobactam was non-inferior to meropenem for treating nosocomial pneumonia; efficacy outcomes by causative pathogen were to be evaluated. METHODS: Mechanically ventilated participants with hospital-acquired/ventilator-associated bacterial pneumonia were randomized to 3 g ceftolozane/tazobactam (2 g ceftolozane/1 g tazobactam) q8h or 1 g meropenem q8h. Lower respiratory tract (LRT) cultures were obtained ≤36 h before first dose; pathogen identification and susceptibility were confirmed at a central laboratory. Prospective secondary per-pathogen endpoints included 28 day all-cause mortality (ACM), and clinical and microbiological response at test of cure (7-14 days after the end of therapy) in the microbiological ITT (mITT) population. RESULTS: The mITT population comprised 511 participants (264 ceftolozane/tazobactam, 247 meropenem). Baseline LRT pathogens included Klebsiella pneumoniae (34.6%), Pseudomonas aeruginosa (25.0%) and Escherichia coli (18.2%). Among baseline Enterobacterales isolates, 171/456 (37.5%) were ESBL positive. For Gram-negative baseline LRT pathogens, susceptibility rates were 87.0% for ceftolozane/tazobactam and 93.3% for meropenem. For Gram-negative pathogens, 28 day ACM [52/259 (20.1%) and 62/240 (25.8%)], clinical cure rates [157/259 (60.6%) and 137/240 (57.1%)] and microbiological eradication rates [189/259 (73.0%) and 163/240 (67.9%)] were comparable with ceftolozane/tazobactam and meropenem, respectively. Per-pathogen microbiological eradication for Enterobacterales [145/195 (74.4%) and 129/185 (69.7%); 95% CI: -4.37 to 13.58], ESBL-producing Enterobacterales [56/84 (66.7%) and 52/73 (71.2%); 95% CI: -18.56 to 9.93] and P. aeruginosa [47/63 (74.6%) and 41/65 (63.1%); 95% CI: -4.51 to 19.38], respectively, were also comparable. CONCLUSIONS: In mechanically ventilated participants with nosocomial pneumonia owing to Gram-negative pathogens, ceftolozane/tazobactam was comparable with meropenem for per-pathogen 28 day ACM and clinical and microbiological response.

Delafloxacin for the treatment of adult patients with community-acquired bacterial pneumonia.

INTRODUCTION: Delafloxacin is a novel fluoroquinolone with peculiar characteristics such as a weak acid character, frequent in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA), and a low potential for resistance selection compared with other fluoroquinolones. AREAS COVERED: The present narrative review summarizes the available data on the use of delafloxacin for the treatment of community-acquired bacterial pneumonia (CABP). EXPERT OPINION: Delafloxacin is a novel fluoroquinolone with a unique profile and some interesting characteristics for the treatment of CABP, such as its marked activity against gram-positive bacteria, including MRSA, the possible use as monotherapy (owing to anti-Gram-negative and anti-atypical bacteria activity), the retained activity against many Gram-positive organisms resistant to other fluoroquinolones, and the availability of both oral and intravenous formulations. The results of the DEFINE-CABP phase-3 randomized controlled trial have shown noninferiority of delafloxacin vs. moxifloxacin for the treatment of CABP, thereby providing a further option for this indication. Against this background, future post-marketing experiences remain of crucial importance for further refining the place in therapy of delafloxacin in the real-life management algorithms of CABP, either as first-line option or step-down/outpatient treatment.

La pneumopathie aigue bactérienne communautaire du sujet âge en pneumologie au centre hospitalier et universitaire du point-g, Bamako-mali / Community acute bacterial pneumonitis of the subject age in pulmonology at the Point-g hospital and university center, Bamako- Mali

Introduction : Les pneumopathies aiguës bactériennes (PAB) communautaires sont des infections respiratoires basses aiguës, non suppurées, non tuberculeuses du parenchyme pulmonaire acquises au sein de la communauté. Elles ont une présentation clinique atypique et un mauvais pronostic chez le sujet âgé. Matériels et Méthodes : Il s'agissait d'une étude transversale prospective menée au service de pneumologie du centre hospitalier universitaire (CHU) du Point-G, du 30 Octobre 2018 au 30 Septembre 2019. L'objectif était de déterminer les particularités cliniques, étiologiques, thérapeutiques et évolutives de la PAB chez le sujet âgé. Ont été inclus tout âge ≥ 65 ans, présentant des signes cliniques et radiologiques d'une PAB Résultats : Durant la période d'étude 85 patients répondaient aux critères d'inclusion sur 178 hospitalisés. Le sex-ratio était de 3/1. Environ 2/3 étaient tabagiques et 11% était positif au VIH. La fièvre n'était pas constante enregistrée dans 51,76% des cas. Les signes respiratoires étaient dominés par la toux (96, 47%), la dyspnée (94, 11%) et extra respiratoires par le trouble de la conscience. Le Klebsiellapneumoniae était le germe le plus retrouvé. L'antibiotique le plus utilisé était l'amoxicilline-acide clavulanique. La durée moyenne d'hospitalisation était de 9 jours. La mortalité était de 19%. Conclusion: La PAB chez le sujet âgé est d'une symptomatologie clinique frustre. Elle est grave avec une surmortalité

Introduction: Community-acquired acute bacterial pneumonia (ABP) is an acute, non-suppurative, non-tuberculosis lower respiratory infection of the lung parenchyma acquired within the community. They have an atypical clinical presentation and a poor prognosis in the elderly. Materials and Methods: This was a prospective cross-sectional study conducted in the Pneumology department of the University Hospital Center (CHU) of Point-G, from October 30, 2018, to September 30, 2019. The objective was to determine the clinical, etiological, therapeutic and progression of BAP in the elderly. Were included any age ≥ 65 years, presenting clinical and radiological signs of a PAB. Results During the study period, 85 patients met the inclusion criteria out of 178 hospitalized. The sex ratio was 3/1. About 2/3 were smokers and 11% were HIV positive. Fever was not constant recorded in 51.76% of cases. Respiratory signs were dominated by cough (96.47%), dyspnea (94.11%) and extra respiratory by impaired consciousness. Klebsiella pneumoniae was the most found germ. The most commonly used antibiotic was amoxicillin-clavulanic acid. The average length of hospitalization was 9 days. Mortality was 19%. Conclusion: The PAB in the elderly is of a frustrating clinical symptomatology. It is serious with excess mortality

Clinical and bacterial characteristics of Pseudomonas aeruginosa affecting the outcome of patients with bacteraemic pneumonia.

Few studies have assessed the clinical and bacterial characteristics of Pseudomonas aeruginosa (PA) bacteraemic pneumonia (BP) episodes. This study analysed all non-duplicate PA-BP episodes from a tertiary hospital in 2013-2017. Epidemiology, clinical data, antimicrobial therapy and outcomes were recorded. Whole-genome sequencing was performed on PA blood isolates. The impact on early and late overall mortality of host, antimicrobial treatment and pathogen factors was assessed by multivariate logistic regression analysis. Of 55 PA-BP episodes, 32 (58.2%) were caused by extensively drug-resistant (XDR) PA. ST175 (32.7%) and ST235 (25.5%) were the most frequent high-risk clones. ß-Lactamases/carbapenemases were detected in 29 isolates, including blaVIM-2 (27.2%) and blaGES type (25.5%) [blaGES-5 (20.0%), blaGES-1 (3.6%) and blaGES-20 (1.8%)]. The most prevalent O-antigen serotypes were O4 (34.5%) and O11 (30.9%). Overall, an extensive virulome was identified in all isolates. Early mortality (56.4%) was independently associated with severe neutropenia (aOR = 4.64, 95% CI 1.11-19.33; P = 0.035) and inappropriate empirical antimicrobial therapy (aOR = 5.71, 95% CI 1.41-22.98; P = 0.014). Additionally, late mortality (67.3%) was influenced by septic shock (aOR = 8.85, 95% CI 2.00-39.16; P = 0.004) and XDR phenotype (aOR = 5.46, 95% CI 1.25-23.85; P = 0.024). Moreover, specific genetic backgrounds [ST235, blaGES, gyrA (T83I), parC (S87L), exoU and O11 serotype] showed significant differences in patient outcomes. Our results confirm the high mortality associated with PA-BP. Besides relevant clinical characteristics and inappropriate empirical therapy, bacteria-specific genetics factors, such as XDR phenotype, adversely affect the outcome of PA-BP.

Orientin mediates protection against MRSA-induced pneumonia by inhibiting Sortase A.

Drug-resistant pathogenic Staphylococcus aureus (S. aureus) has severely threatened human health and arouses widespread concern. Sortase A (SrtA) is an essential virulence factor of S. aureus, which is responsible for the covalent anchoring of a variety of virulence-related proteins to the cell wall. SrtA has always been regarded as an ideal pharmacological target against S. aureus infections. In this research, we have determined that orientin, a natural compound isolated from various medicinal plants, can effectively inhibit the activity of SrtA with an IC50 of 50.44 ± 0.51 µM. We further demonstrated that orientin inhibited the binding of S. aureus to fibrinogen and diminished biofilm formation and the attaching of Staphylococcal protein A (SpA) to the cell wall in vitro. Using the fluorescence quenching assay, we demonstrated a direct interaction between orientin and SrtA. Further mechanistic studies revealed that the residues Glu-105, Thr-93, and Cys-184 were the key sites for the binding of SrtA to orientin. Importantly, we demonstrated that treatment with orientin attenuated S. aureus virulence of in vivo and protected mice against S. aureus-induced lethal pneumonia. These findings indicate that orientin is a potential drug to counter S. aureus infections and limit the development of drug resistance.

An overview of cilastatin + imipenem + relebactam as a therapeutic option for hospital-acquired and ventilator-associated bacterial pneumonia: evidence to date.

Introduction: Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are prevalent nosocomial infections with a worrisomely increasing prevalence of multidrug-resistant causative organisms, including those with resistance to carbapenems. The addition of relebactam, a ß-lactamase inhibitor, to imipenem treatment restores the antimicrobial activity against the most of multidrug-resistant Gram-negative bacteria, including some carrying ß-lactamase enzyme-type carbapenemases.Areas covered: The aim of this article is to summarize the current evidence regarding imipenem/relebactam for the treatment of HAP/VAP. The authors discuss its chemistry, pharmacokinetics/pharmacodynamics, microbiology, tolerance and clinical efficacy. The results of clinical trials have demonstrated an efficacy of imipenem/relebactam similar to that of its comparator for the treatment of patients with HAP/VAP. Different studies have also shown its good safety profile, which is better than that of the combination of other ß-lactams with other antibiotics.Expert opinion: This drug should be incorporated as a new therapeutic option for the treatment of patients with HAP/VAP, especially as an alternative treatment in patients with confirmed infections caused by multidrug-resistant Gram-negatives.

Lefamulin efficacy and safety in a pooled phase 3 clinical trial population with community-acquired bacterial pneumonia and common clinical comorbidities.

BACKGROUND: Lefamulin, a first-in-class pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia (CABP), was noninferior to moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) 1 intravenous-to-oral switch study and the LEAP 2 oral-only study. Using pooled LEAP 1/2 data, we examined lefamulin efficacy/safety overall and within subgroups of patients presenting with comorbidities typical in CABP management. METHODS: In LEAP 1, adults with CABP were randomized to receive intravenous lefamulin (150 mg every 12 h) for 5‒7 days or moxifloxacin (400 mg every 24 h) for 7 days, with optional intravenous-to-oral switch if predefined improvement criteria were met. In LEAP 2, adults with CABP were randomized to receive oral lefamulin (600 mg every 12 h) for 5 days or moxifloxacin (400 mg every 24 h) for 7 days. Both studies assessed early clinical response (ECR) at 96 ± 24 h after first study drug dose and investigator assessment of clinical response (IACR) at test-of-cure (5‒10 days after last dose). Pooled analyses of the overall population used a 10% noninferiority margin. RESULTS: Lefamulin (n = 646) was noninferior to moxifloxacin (n = 643) for ECR (89.3% vs 90.5%, respectively; difference - 1.1%; 95% CI - 4.4 to 2.2); IACR success rates at test-of-cure were similarly high (≥ 85.0%). High efficacy with both lefamulin and moxifloxacin was also demonstrated across all well-represented patient subgroups, including those with advanced age, diabetes mellitus, a history of cardiovascular diseases (e.g., hypertension, congestive heart failure, or arrhythmia) or chronic lung diseases (e.g., asthma or chronic obstructive pulmonary disease), elevated liver enzymes, or mild-to-moderate renal dysfunction. No new safety signals were identified. CONCLUSIONS: Lefamulin may provide a valuable intravenous/oral monotherapy alternative to fluoroquinolones or macrolides for empiric treatment of patients with CABP, including cases of patients at risk for poor outcomes due to age or various comorbidities. TRIAL REGISTRATION: ClinicalTrials.gov LEAP 1 (NCT02559310; Registration Date: 24/09/2015) and LEAP 2 (NCT02813694; Registration Date: 27/06/2016).

[Cupping treatment combined with antibiotics for bacterial pneumonia in children: a randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy of cupping treatment combined with antibiotics and antibiotics alone for bacterial pneumonia in children. METHODS: A total of 72 children with bacterial pneumonia were randomly divided into an observation group (36 cases, 1 case dropped off) and a control group (36 cases). The children in the control group were treated with intravenous drip of cefodizine sodium [80 mg/(kg•d)] for 7 days. Based on the treatment of the control group, the children in the observation group were treated with cupping treatment on the bladder meridian of the back on the first day and the fourth day of antibiotic treatment; each cupping treatment was given for 5-10 min; the treatment of observation group was given for 7 days. The days for complete fever reduction, TCM syndrome scores and Canadian acute respiratory illness flu scale (CARIFS) scores before and after treatment were observed, and the clinical efficacy was evaluated. RESULTS: The days for complete fever reduction in the observation group were shorter than that in the control group (P<0.05). After treatment, the TCM syndrome scores and CARIFS scores in the two groups were reduced (P<0.05), and the cough score, expectoration score, lung auscultation score of TCM syndrome and cough score, runny nose score and sore throat score of CARIFS in the observation group were lower than those in the control group (P<0.05). The cured rate in the observation group was 97.1% (34/35), which had no significant difference with 91.7% (33/36) in the control group (P>0.05). CONCLUSION: Cupping treatment combined with antibiotics has similar efficacy with antibiotics alone for bacterial pneumonia in children, but shows better effect in shortening the duration of fever and improving pulmonary symptoms.

Lianhuaqingwen capsule inhibits influenza-induced bacterial adhesion to respiratory epithelial cells through down-regulation of cell adhesion molecules.

ETHNOPHARMACOLOGICAL RELEVANCE: Influenza virus infection is widely believed to cause mild symptoms, but can lead to high mortality and severe disease complicated by secondary bacterial pneumonia. Traditional Chinese medicine (TCM) has been proposed as a promising agent to treat respiratory viral infections. A herbal formula Lianhuaqingwen capsule (LHQW) comprising two prescriptions: Maxing Shigan decoction and Yinqiao San, has been used clinically to treat respiratory infection with immune regulatory effects. However, little is known about the capacity of LHQW against influenza-induced secondary bacterial pneumonia. AIM OF STUDY: This study aimed to evaluate the efficacy and underlying mechanism of LHQW on influenza A virus A/PR/8/34 (PR8) secondary methicillin-resistant Staphy-lococcus aureus (MRSA) infection. METHODS: The anti-adhesion activity of LHQW against PR8-induced MRSA infection was assessed in human lung epithelial (A549) cells and the effect of LHQW on the expression of intracellular adhesion molecule 1 (ICAM-1) was detected. Also, the mRNA expression levels of inflammatory cytokines upon lipopolysaccharide (LPS) stimulation in PR8-infected A549 cells were determined. The body weight change, survivals, viral titers, colonies and the pathological parameters after LHQW treatment in severe pneumonia model have all been systematically determined. RESULTS: LHQW significantly reduced the adhesion of MRSA to PR8-infected A549 cells in a dose-dependent manner by suppressing the up-regulation of bacterial receptors. LHQW also markedly declined the overexpression of IL-6, IL-8, and TNF-α induced by LPS stimulated-A549 cells following influenza virus infection. Furthermore, the abnormal changes of lung index in dual-infection mice were relieved after administered with LHQW in preventive and therapeutic mode, but with no significantly difference (P > 0.05). LHQW could not effectively improve survival rate or prolong the survival time of mice (P > 0.05). LHQW (1000 mg/kg/d) administered prophylactically significantly decreased the lung viral titers (P < 0.05), slightly downregulated IL-6 but TNF-α, IL-1ß levels and improved lung pathological inflammation including neutrophil infiltration, necrosis, which is consistent with the expression of inflammatory factors. CONCLUSIONS: LHQW inhibited influenza-induced bacterial adhesion by down-regulating the adhesion molecules with the improvement trend on severe pneumonia, indicating that it can be used as an adjuvant medication in severe viral-bacterial pneumonia therapy rather than as a single medication.