The Skin Microbiota in Patients Hospitalized for Cellulitis and Association With Outcome.

BACKGROUND: The skin microbiota plays a key role in the pathogenesis of several skin diseases, but its role in cellulitis remains unknown. We investigated the skin microbiota in patients with cellulitis, studied whether its analysis could help determine the causative pathogen, and explored whether skin microbiota composition was associated with clinical outcomes. METHODS: We prospectively included 58 patients hospitalized for cellulitis. Skin swabs obtained from the lesion sites were compared with swabs from identical sites on the contralateral unaffected limbs and with swabs obtained from 19 age- and sex-matched control subjects without cellulitis. Bacterial profiling of the skin microbiota was performed by interspacer profiling (IS-pro). RESULTS: A large interpersonal variation in the skin microbiota composition of patients hospitalized with cellulitis was observed. Firmicutes were the dominant phylum, and Staphylococcus and Streptococcus the dominant genera. In most patients, a strong correlation between the microbiota of the affected lesion and the microbiota of the unaffected, contralateral limb was seen. Overall, the composition of the cellulitis microbiota could not be distinguished from the skin microbiota of controls. No consistent association could be found between traditional culture results and skin microbiota signatures in patients with cellulitis. Lastly, we found that neither microbiota composition nor diversity were associated with clinical parameters and outcomes in patients with cellulitis. CONCLUSIONS: In this exploratory study on the skin microbiota in patients hospitalized with cellulitis, we were unable to identify a typical cellulitis microbiota. The diagnostic and prognostic information that could be derived from skin microbiota profiling in this patient cohort was limited. CLINICAL TRIALS REGISTRATION: NCT02032654.

Antibiotic-induced gut microbiota disruption during human endotoxemia: a randomised controlled study.

OBJECTIVE: The gut microbiota is essential for the development of the intestinal immune system. Animal models have suggested that the gut microbiota also acts as a major modulator of systemic innate immunity during sepsis. Microbiota disruption by broad-spectrum antibiotics could thus have adverse effects on cellular responsiveness towards invading pathogens. As such, the use of antibiotics may attribute to immunosuppression as seen in sepsis. We aimed to test whether disruption of the gut microbiota affects systemic innate immune responses during endotoxemia in healthy subjects. DESIGN: In this proof-of-principle intervention trial, 16 healthy young men received either no treatment or broad-spectrum antibiotics (ciprofloxacin, vancomycin and metronidazole) for 7 days, after which all were administered lipopolysaccharide intravenously to induce a transient sepsis-like syndrome. At various time points, blood and faeces were sampled. RESULTS: Gut microbiota diversity was significantly lowered by the antibiotic treatment in all subjects. Clinical parameters, neutrophil influx, cytokine production, coagulation activation and endothelial activation during endotoxemia were not different between antibiotic-pretreated and control individuals. Antibiotic treatment had no impact on blood leucocyte responsiveness to various Toll-like receptor ligands and clinically relevant causative agents of sepsis (Streptococcus pneumoniae, Klebsiella pneumoniae, Escherichia coli) during endotoxemia. CONCLUSIONS: These findings suggest that gut microbiota disruption by broad-spectrum antibiotics does not affect systemic innate immune responses in healthy subjects during endotoxemia in humans, disproving our hypothesis. Further research is needed to test this hypothesis in critically ill patients. These data underline the importance of translating findings in mice to humans. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT02127749; Pre-results).

Comparing short to standard duration of antibiotic therapy for patients hospitalized with cellulitis (DANCE): study protocol for a randomized controlled trial.

BACKGROUND: Recommended therapy duration for patients hospitalized with cellulitis is 10-14 days. Unnecessary use of antibiotics is one of the key factors driving resistance. Recent studies have shown that antibiotic therapy for cellulitis in outpatients can safely be shortened, despite residual inflammation. This study will compare in hospitalized patients the safety and effectiveness of shortening antibiotic therapy for cellulitis from 12 to 6 days. METHODS/DESIGN: In a multicenter, randomized, double-blind, non-inferiority trial, adult patients admitted with cellulitis will be included. Cellulitis is defined as warmth, erythema, and induration of the skin and/or subcutaneous tissue, with or without pain (including erysipelas). All patients will initially be treated with intravenous flucloxacillin, and will be evaluated after 5-6 days. Those who have improved substantially (defined as being afebrile, and having a lower cellulitis severity score) will be randomized at day 6 between additional 6 days of oral flucloxacillin (n = 198) or placebo (n = 198). Treatment success is defined as resolution of cellulitis on day 14 (disappearance of warmth and tenderness, improvement of erythema and edema), without the need of additional antibiotics for cellulitis by day 28. Secondary endpoints are relapse rate (up to day 90), speed of recovery (using a cellulitis severity score until day 28, and VAS scores on pain and swelling until day 90), quality of life (using the SF-36 and EQ-5D questionnaires) and costs (associated with total antibiotic use and health-care resource utilization up to day 90). DISCUSSION: Inclusion is planned to start in Q2 2014. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02032654) and the Netherlands Trial Register (NTR4360).

Clinical consequences of increased ciprofloxacin and gentamicin resistance in patients with Escherichia coli bacteraemia in the Netherlands.

BACKGROUND: Escherichia coli is a common cause of bacteraemia and is increasingly resistant to ciprofloxacin and gentamicin. The primary objective of this study was to investigate how often this leads to inadequate initial antimicrobial treatment. Secondary goals were to determine factors associated with inadequate empirical therapy and to assess its impact on mortality and length of stay. METHODS: All patients with an E. coli bacteraemia hospitalized in 2008 were identified retrospectively. Initial antimicrobial therapy and clinical outcomes of all patients with an isolate resistant to gentamicin and/or ciprofloxacin (cases) were compared to those of a group of randomly selected patients in whom a gentamicin and ciprofloxacin susceptible E. coli was isolated (controls). RESULTS: One hundred and thirty-six unique patients had E. coli bacteraemia. Of these, 34 patients were identified as cases and were compared to 34 controls. Among the cases, 97% of the E. coli was resistant to ciprofloxacin and 44% to gentamicin. Resistance to amoxicillin was high in both cases (94%) and controls (65%). In 41% of the cases initial antimicrobial therapy was inadequate, compared to only 3% in the controls. The majority of inadequately treated cases had a biliary focus (64%). Infections in cases were more often healthcare-associated than infections in controls (62% vs 26%). E. coli with the same resistance pattern had been isolated before in adequately treated cases more often than in inadequately treated cases. Mortality did not differ significantly between cases and controls. CONCLUSIONS: Neither ciprofloxacin nor amoxicillin should be used as empirical therapy in patients with a presumed E. coli bacteraemia.

Clinical Characteristics and Outcomes of Patients With Cellulitis Requiring Intensive Care.

Importance: Cellulitis is a commonly occurring skin and soft tissue infection and one of the most frequently seen dermatological diseases in the intensive care unit (ICU). However, clinical characteristics of patients with cellulitis requiring intensive care treatment are poorly defined. Necrotizing fasciitis is often confused for cellulitis at initial presentation and is considered to be more severe and thus has previously been described in more detail. Objective: To describe the clinical presentation and outcomes of patients with ICU-necessitating cellulitis and to compare them with patients with necrotizing fasciitis. Design, Setting, and Participants: This prospective cohort study includes all ICU admissions from 2 tertiary hospitals in the Netherlands. Of 2562 sepsis admissions, 101 had possible, probable, or definite cellulitis or soft tissue infections. Retrospective review identified severe cellulitis was the reason for ICU admission in 23 patients, necrotizing fasciitis in 31 patients, and other diagnoses in 47 patients. Main Outcomes and Measures: Patient and disease characteristics, cultured pathogens, lengths of stay, and short-term and long-term mortality. Results: Overall, 54 patients with cellulitis (n = 23; mean [SD] age, 57.2 [17.7] years) or necrotizing fasciitis (n = 31; mean [SD] age, 54.3 [13.5]) were included in this study. Patients with cellulitis were found to be less severely ill than patients with necrotizing fasciitis. This is reflected in rates of shock (7 [30.4%] vs 19 [61.3%]; P = .03), need for mechanical ventilation (12 [52.2%] vs 19 [93.5%]; P = .003) and slightly lower mean Sequential Organ Failure Assessment scores (8 vs 10; P = .046). Median (interquartile range [IQR]) Acute Physiology and Chronic Health Evaluation IV scores did not differ significantly (82 [75-98] vs 76 [70-96]; P = .16). Patients with cellulitis had more chronic comorbidities than patients with necrotizing fasciitis (20 [87.0%] vs 17 [54.8%]; P = .02), especially cardiovascular insufficiencies (10 [43.5%] vs 4 [12.9%]; P = .02) and immunodeficiencies (9 [39.1%] vs 3 [9.7%]; P = .02). Among patients with cellulitis and patients with patients with necrotizing fasciitis, Staphylococcus aureus (10 [43.5%] vs 4 [12.9%]; P = .02), Streptococcus pyogenes (2 [8.7%] vs 19 [61.3%]; P < .001) and Escherichia coli (4 [17.4%] vs 5 [16.2%]; P = .90) were the most frequently observed pathogens. Median (IQR) length of ICU stay was shorter for patients with cellulitis vs patients with necrotizing fasciitis (3 [2-5] vs 5 [3-11]; P = .01), while median (IQR) hospital length of stay did not differ significantly (22 [10.25-32] vs 36 [14.25-40]; P = .16); and the in-hospital mortality rate (26.1% vs 22.6%, P > .99) and 90-day mortality rate (30.4% vs 22.6%; P = .54) were similar. Conclusions and Relevance: Patients with cellulitis patients are seldom admitted to the ICU. However, while these patients are less critically ill on admission than patients with necrotizing fasciitis, they have more chronic comorbidities and most notably similar short-term and long-term mortality. Trial Registration: clinicaltrials.gov Identifier: NCT01905033.

Host innate immune responses to sepsis.

The immune response to sepsis can be seen as a pattern recognition receptor-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. Invasive infection triggers both pro-inflammatory and anti-inflammatory host responses, the magnitude of which depends on multiple factors, including pathogen virulence, site of infection, host genetics, and comorbidities. Toll-like receptors, the inflammasomes, and other pattern recognition receptors initiate the immune response after recognition of danger signals derived from microorganisms, so-called pathogen-associated molecular patterns or derived from the host, so-called danger-associated molecular patterns. Further dissection of the role of host-pathogen interactions, the cytokine response, the coagulation cascade, and their multidirectional interactions in sepsis should lead toward the development of new therapeutic strategies in sepsis.