Survival benefit associated with clarithromycin in severe community-acquired pneumonia: A matched comparator study.

Although analysis of retrospective studies has documented survival benefit from the addition of a macrolide to the treatment regimen for community-acquired pneumonia (CAP), no data are available to determine if there is differential efficacy between members of the macrolide family. In order to investigate this, an analysis was undertaken of data from 1174 patients with CAP who met the new Sepsis-3 definitions and were enrolled prospectively in the data registry of the Hellenic Sepsis Study Group. Four well-matched treatment groups were identified with 130 patients per group: clarithromycin and ß-lactam; azithromycin and ß-lactam; respiratory fluoroquinolone and ß-lactam monotherapy. The primary endpoint was comparison of the effects of clarithromycin with ß-lactam monotherapy on 28-day mortality. The secondary endpoint was resolution of CAP. Mortality rates for the clarithromycin, azithromycin, respiratory fluoroquinolone and ß-lactam groups were 20.8%, 33.8% (P=0.026 vs clarithromycin), 32.3% (P=0.049 vs clarithromycin) and 36.2% (P=0.009 vs clarithromycin), respectively. After stepwise Cox regression analysis among all groups, clarithromycin was the only treatment modality associated with a favourable outcome (hazard ratio 0.61; P=0.021). CAP resolved in 73.1%, 65.9% (P=0.226 vs clarithromycin), 58.5% (P=0.009 vs clarithromycin) and 61.5% (P=0.046 vs clarithromycin) of patients, respectively. It is concluded that the addition of clarithromycin to the treatment regimen of patients with severe CAP leads to better survival rates.

Progression into sepsis: an individualized process varying by the interaction of comorbidities with the underlying infection.

BACKGROUND: Development of sepsis is a process with significant variation among individuals. The precise elements of this variation need to be defined. This study was designed to define the way in which comorbidities contribute to sepsis development. METHODS: Three thousand five hundred nine patients with acute pyelonephritis (AP), community-acquired pneumonia (CAP), intraabdominal infections (IAI) or primary bacteremia (BSI) and at least two signs of the systemic inflammatory response syndrome were analyzed. The study primary endpoint was to define how comorbidities as expressed in the Charlson's comorbidity index (CCI) and the underlying type of infection contribute to development of organ dysfunction. The precise comorbidities that mediate sepsis development and risk for death among 18 comorbidities recorded were the secondary study endpoints. RESULTS: CCI more than 2 had an odds ratio of 5.67 for sepsis progression in patients with IAI between significantly higher than AP and BSI. Forward logistic regression analysis indicated seven comorbidities that determine transition into sepsis in patients with AP, four comorbidities in CAP, six comorbidities in IAI and one in BSI. The odds ratio both for progression to sepsis and death with one comorbidity or with two and more comorbidities was greater than in the absence of comorbidities. CONCLUSIONS: The study described how different kinds of infection vary in the degree to which they lead to sepsis. The number of comorbidities that enhances the risk of sepsis and death varies depending on the underlying infections.

Effects of the 34C>T Variant of the AMPD1 Gene on Immune Function, Multi-Organ Dysfunction, and Mortality in Sepsis Patients.

INTRODUCTION: Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C>T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown. METHODS: The effects of the presence of the 34C>T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n = 285; replication cohort n = 212) and ventilator-associated pneumonia (VAP, n = 117; n = 33) and control patients without infection (n = 101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort. RESULTS: The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1-3.7); P = 0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P = 0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0-3.1), P = 0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-α by LPS-stimulated monocytes was attenuated (P = 0.005), indicative of a more pronounced immunoparalytic state in these patients. CONCLUSIONS: Presence of the AMPD1 34C>T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti-inflammatory effects of adenosine may account for this observation.

Bloodstream infections and sepsis in Greece: over-time change of epidemiology and impact of de-escalation on final outcome.

BACKGROUND: Choice of empirically prescribed antimicrobials for sepsis management depends on epidemiological factors. The epidemiology of sepsis in Greece was studied in two large-periods. METHODS: Sepsis due to bloodstream infections (BSI) from July 2006 until March 2013 was recorded in a multicenter study in 46 departments. Patients were divided into sepsis admitted in the emergencies and hospitalized in the general ward (GW) and sepsis developing after admission in the Intensive Care Unit (ICU). The primary endpoints were the changes of epidemiology and the factors related with BSIs by multidrug-resistant (MDR) pathogens; the secondary endpoint was the impact of de-escalation on antimicrobial therapy. RESULTS: 754 patients were studied; 378 from 2006-2009 and 376 from 2010-2013. Major differences were recorded between periods in the GW. They involved increase of: sepsis severity; the incidence of underlying diseases; the incidence of polymicrobial infections; the emergence of Klebsiella pneumoniae as a pathogen; and mortality. Factors independently related with BSI by MDR pathogens were chronic hemofiltration, intake of antibiotics the last three months and residence into long-term care facilities. De-escalation in BSIs by fully susceptible Gram-negatives did not affect final outcome. Similar epidemiological differences were not found in the ICU; MDR Gram-negatives predominated in both periods. CONCLUSIONS: The epidemiology of sepsis in Greece differs in the GW and in the ICU. De-escalation in the GW is a safe strategy.

The level of endotoxemia in sepsis varies in relation to the underlying infection: Impact on final outcome.

Former studies of our group have shown that the innate and adaptive immune status may differ in relation with the causative infection. To this same end, it was investigated if kinetics of circulating lipopolysaccharide (LPS) leading to inflammatory response may differ. Blood was sampled from 189 patients with sepsis and 206 with severe sepsis/shock starting 24h from advent of sepsis and repeating on day 3. Serum LPS was measured by Limulus Amebocyte Lysate (LAL) assay. From 59 patients, circulating monocytes were isolated and incubated in the absence/presence of LPS. Concentrations of tumor necrosis factor-alpha (TNFα) were measured in supernatants by an enzyme immunoassay. In either category of severity, circulating LPS was greater among sufferers from primary Gram-negative bacteremia (BSI) and from community-acquired pneumonia (CAP) than sufferers from other underlying infections. LPS were greater among patients with BSI compared to patients with secondary Gram-negative bacteremia and patients without bacteremia. Greater decrease of circulating LPS over 48h was recorded for survivors compared to non-survivors only within sufferers from BSI and CAP. Significant endotoxemia was considered for patients with serum LPS within the upper quartile of distribution; their monocytes were less potent for release of TNFα. It is concluded that endotoxemia in sepsis varies greatly with the underlying infection; this is related with immunoparalysis of monocytes with implications on final outcome.

Polymicrobial bloodstream infections: Epidemiology and impact on mortality.

The aim of this study was to investigate the impact of polymicrobial bloodstream infections (pBSIs) on the outcome of sepsis in an area where antimicrobial resistance is of concern. This was a retrospective analysis of data collected prospectively from patients developing BSI outside of an intensive care unit (non-ICU patients) or after ICU admission. Demographics and clinical characteristics were compared for patients with pBSI versus monomicrobial BSI (mBSI) and following stratification by ICU or non-ICU and severity of sepsis status. Possible risk factors for adverse outcome were explored by multivariate analysis, and outcomes were measured by Cox regression analysis. Among 412 patients with BSI, 47 patients (11.4%) with pBSI were recorded; compared with patients with mBSI, they had significantly higher APACHE II scores and presented more frequently with severe sepsis/septic shock. The all-cause 28-day mortality was significantly higher for pBSI versus mBSI (38.3% vs. 24.7%; P=0.033), whereas appropriateness of treatment was comparable (78.7% vs. 86.6%). Primary bacteraemia by combinations of Enterococcus faecalis, Klebsiella pneumoniae and Acinetobacter baumannii was predominant among pBSIs; in mBSIs, urinary tract infections by Escherichia coli, K. pneumoniae or Pseudomonas aeruginosa predominated. Multivariate analysis demonstrated pBSI as a significant contributor to 28-day mortality (HR=1.86; P=0.039), along with presence of two or more co-morbidities (HR=2.35; P=0.004). In conclusion, pBSIs differed epidemiologically from mBSIs, with the emergence of enterococcal species, and portended an almost two-fold increased risk of 28-day mortality. Prospective studies are warranted to elucidate possibly modifiable factors.

The functional role of natural killer cells early in clinical sepsis.

Although much information is available for the function of circulating monocytes when signs of sepsis are apparent, little is known for natural killer (NK) cells. NK cells were isolated from 10 healthy controls and from 103 patients with sepsis within the first 24 h from diagnosis. NK cells were stimulated with lipopolysaccharide for cytokine production. Release of tumor necrosis factor-alpha and of interleukin (IL)-6 was below the limit of detection. Release of IL-23 and of interferon-gamma (IFNγ) was significantly greater among patients than among healthy volunteers. Release of IFNγ was pronounced in septic shock. Patients were divided into two subgroups based on the ratio of IFNγ to IL-23 released by the NK cells after stimulation: those with ratio ≤5 and 28-day survival 13.5%, and those with ratio >5 and 28-day survival 29.4% (p: 0.048). It is concluded that early after clinical development of sepsis, NK cells remain active for the production of IFNγ. Their activity is associated with the final outcome.

Bartonella quintana endocarditis as a cause of severe aortic insufficiency and heart failure.

We describe the case of a 26-year-old man who developed severe aortic valve insufficiency due to a culturenegative endocarditis, leading to severe heart failure. The diagnosis of Bartonella quintana endocarditis was suspected from the clinical presentation and serological immunofluorescence assay, and was confirmed by polymerase chain reaction analysis of excised valve tissue after aortic valve replacement. The aim of this report is to illustrate B. quintana endocarditis as an important cause of culture-negative endocarditis that presents challenges in its clinical, diagnostic and therapeutic management.