Exebacase is Active In Vitro in Pulmonary Surfactant and is Efficacious Alone and Synergistic with Daptomycin in a Mouse Model of Lethal Staphylococcus aureus Lung Infection

Exebacase (CF-301) is a novel antistaphylococcal lysin (cell wall hydrolase) in Phase 3 of clinical development for the treatment of Staphylococcus aureus bacteremia including right-sided endocarditis used in addition to standard of care antibiotics. In the current study, the potential for exebacase to treat S. aureus pneumonia was explored in vitro using bovine pulmonary surfactant (Survanta®) and in vivo using a lethal murine pneumonia model. Exebacase was active against a set of methicillin-sensitive and methicillin-resistant S. aureus (MSSA and MRSA, respectively), with an MIC 90 of 2 μg/mL (n=18 strains), in the presence of a surfactant concentration (7.5%) inhibitory to the antistaphylococcal antibiotic, daptomycin, which is inactive in pulmonary environments due to specific inhibition by surfactant. In a rigorous test of the ability of exebacase to synergize with antistaphylococcal antibiotics, exebacase synergized with daptomycin in the presence of surfactant in vitro, resulting in daptomycin MIC reductions up to 64-fold against 9 MRSA and 9 MSSA strains. Exebacase was also observed to facilitate binding of daptomycin to S. aureus and elimination of biofilm-like structures formed in the presence of surfactant. Exebacase (5 mg/kg, q24d, administered intravenously for 3 days) was efficacious in a murine model of staphylococcal pneumonia, resulting in 50% survival compared to 0% survival in vehicle control; exebacase in addition to daptomycin (50 mg/kg, q24d, 3 days) resulted in 70% survival, compared to 0% survival in the daptomycin alone control. Overall, exebacase in active in pulmonary environments and may be appropriate for development as a treatment for staphylococcal pneumonia.

Prognostic factors of severe community-acquired staphylococcal pneumonia in France

PurposeStaphylococcus aureus causes severe forms of community-acquired pneumonia (CAP), namely staphylococcal pleuropneumonia in young children and staphylococcal necrotising pneumonia in older patients. Methicillin resistance, the Panton-Valentine leukocidin (PVL) toxin, as well as less specific factors have been associated with poor outcome in severe CAP, but their respective roles are unclear.MethodsA prospective multicentre cohort study of severe staphylococcal CAP was conducted in 77 paediatric and adult intensive care units in France between January 2011 and December 2016. After age-clustering, risk factors for mortality, including pre-existing conditions, clinical presentation, laboratory features, strain genetic lineage, PVL, other virulence factors, and methicillin resistance were assessed using univariate and multivariable Cox and LASSO regressions.ResultsOf 163 included patients, aged one month to 87 years, 85 (52.1%) had PVL-positive CAP; there were 20 (12.3%) patients aged <3 years (hereafter “toddlers”), among whom 19 (95%) had PVL-positive CAP. The features of PVL-positive CAP in toddlers matched with the historical description of staphylococcal pleuropneumonia, with a lower mortality (n=3/19, 15%) compared to PVL-positive CAP in older patients (n=31/66, 47%). Mortality in older patients was independently predicted by PVL-positivity (hazard ratio 1.81, 95% CI, 1.03 to 3.17) and methicillin resistance (2.37, 95% CI 1.29 to 4.34) independently from S. aureus lineages and the presence of other virulence determinants.ConclusionPVL was associated with staphylococcal pleuropneumonia in toddlers and was a risk factor for mortality in older patients with severe CAP, independently of methicillin resistance, S. aureus genetic background and other virulence factors.

Molecular Amplification Assays Accuracy for Diagnosis of Staphylococcal Pneumonia: a Systematic Review and Meta-analysis

Rapid and accurate identification of staphylococcal pneumonia is crucial for effective antimicrobial stewardship. We performed a meta-analysis to evaluate the diagnostic value of nucleic acid amplification tests (NAAT) from lower respiratory tract (LRT) samples of suspected pneumonia patients for avoiding superfluous empirical methicillin-resistant Staphylococcus aureus (MRSA) treatment. PubMed, Scopus, Embase, Web of Science, and the Cochrane library database were searched from inception to September 02, 2020. Data analysis was carried out using a bivariate random-effects model to estimate pooled sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR). Of 1808 citations, 24 publications comprising 32 datasets met our inclusion criteria. Twenty-two studies (n = 4630) assessed the accuracy of NAAT for methicillin-sensitive S. aureus (MSSA) detection, while ten studies (n = 2996) demonstrated the accuracy of NAAT for MRSA detection. The pooled NAAT sensitivity and specificity for all MSSA detection was higher [sensitivity: 0.91 (95% confidence interval [CI] 0.89–0.94), specificity: 0.94 (95% CI 0.94–0.95)] as compared to MRSA [sensitivity: 0.75 (95% CI 0.69–0.80), specificity: 0.88 (95% CI 0.86–0.89)] in lower respiratory tract (LRT) samples. NAAT pooled sensitivity differed marginally among differing LRT samples, including sputum, endotracheal aspirate (ETA), and bronchoalveolar lavage (BAL). Noticeably, NAAT pooled specificity against microbiological culture was consistently ≥88% across various types of LRT samples. A meta-regression and subgroup analysis of study design, sample condition, and patient selection method could not explain the heterogeneity (P >0.05) in the diagnostic efficiency. This meta-analysis has demonstrated that NAAT can be applied as the preferred initial test for timely diagnosis of staphylococcal pneumonia in LRT samples for successful antimicrobial therapy.

Staphylococcal pneumonia as a complication of cellulitis

Introduction: Cellulitis is less common local infection caused by staphylococci but may be accompanied by severe symptoms. Aim: The authors present a case of a 25-year-old woman with cellulitis in the lower jaw area, who had a complication in the form of purulent pneumonia with numerous abscesses and pleurisy. Case study: The patient, 25-year-old woman, was admitted to Clinic of Dermatology in Olsztyn due to painful swelling of her cheek, jaw and chin on the right side. The physical examination revealed crackles in the lung base and the chest X-ray image showed numerous circular shadows in the lung fields. In addition, there was fluid in the left pleural cavity. Intensive antibiotic therapy was used in the treatment for 14 days and improvement in the skin lesion was achieved. Cough and radiological changes also subsided. Results and discussion: Pneumonia usually develops as a result of the aspiration of the microorganism from the upper respiratory tract or through the bloodstream. Staphylococcal methicillin resistant Staphylococcus aureus (MRSA) infections are a particular problem. Poor hygiene conditions, close contact, contaminated material and damaged skin are some of the risk factors for the spread of MRSA infection in the population of non-hospitalized patients. In this patient, such a predisposing factor was alcohol and an attempt to remove a purulent lesion on her own in unsanitary conditions. Conclusions: It should be remembered that skin infections may lead to complications in the form of staphylococcal pneumonia.

Getting the wind knocked out of him – Report of a broncho-cutaneous fistula caused by staphylococcal pneumonia, and review of literature

A broncho-cutaneous fistula (BCF) refers to the formation of an abnormal fistulous connection between the tracheobronchial tree and the cutaneous surface of skin. A rare occurrence in and of itself, the disease entity may have varied etiologies, and may or may not be associated with a broncho-pleural fistula. We describe a case of a young patient who developed a BCF as a complication of a necrotizing pneumonic process, and his subsequent clinical course. In so doing, we review the clinical features of this peculiar disease entity, analyzing the available medical literature similarities in etiology and variations in management strategies described in the literature thus far.

Child with community acquired staphylococcal pneumonia complicated by bilateral pneumothorax

Community acquired Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia usually present in children with some comorbidity and may have fulminant course in these children. In this case report authors have described a healthy child with MRSA pneumonia complicated by bilateral pneumothorax.

Risk factors of severity in community-acquired staphylococcal pneumonia

Background Staphylococcus aureus causes severe forms of community-acquired pneumonia (CAP), namely staphylococcal pleuropneumonia in young children and staphylococcal necrotizing pneumonia in older patients. Methicillin resistance and the Panton-Valentine leukocidin (PVL) toxin have both been associated with poor outcome in severe CAP, but their respective roles are unclear. Methods Prospective multicenter cohort study of severe staphylococcal CAP conducted in 77 pediatric and adult intensive care units in France between January 2011 and December 2016. Clinical features and outcomes were compared between toddlers (<3 years of age) and older patients with PVL-positive CAP; and between older patients with PVL-negative or PVL-positive CAP. Risk factors for mortality were identified using multivariate Cox regression. Results Of 163 included patients, aged one month to 87 years, 85 (52.1%) had PVL-positive CAP; there were 20 (12.3%) toddlers, among whom 19 (95%) had PVL-positive CAP. The features of PVL-positive CAP in toddlers matched with the historical description of staphylococcal pleuropneumonia, with a lower mortality (n = 3/19, 15%) compared to PVL-positive CAP in older patients (n=31/66, 47%). Mortality in older patients was independently predicted by PVL-positivity (hazard ratio 1.81, 95% CI, 1.03 to 3.17) and methicillin resistance (2.37, 95% CI 1.29 to 4.34). As genetic diversity was comparably high in PVL-positive and PVL-negative isolates, confounding by microbial population structure was unlikely. Conclusion PVL was associated with staphylococcal pleuropneumonia in toddlers and was a risk factor for mortality in older patients with severe CAP, independently of methicillin resistance. Funded by the French ministry of Health (PHRC 2010-A01132-37)