Cumulative clinical experience from over a decade of use of levofloxacin in community-acquired pneumonia: critical appraisal and role in therapy

Levofloxacin is the synthetic L-isomer of the racemic fluoroquinolone, ofloxacin. It interferes with critical processes in the bacterial cell such as DNA replication, transcription, repair, and recombination by inhibiting bacterial topoisomerases. Levofloxacin has broad spectrum activity against several causative bacterial pathogens of community-acquired pneumonia (CAP). Oral levofloxacin is rapidly absorbed and is bioequivalent to the intravenous formulation such that patients can be conveniently transitioned between these formulations when moving from the inpatient to the outpatient setting. Furthermore, levofloxacin demonstrates excellent safety, and has good tissue penetration maintaining adequate concentrations at the site of infection. The efficacy and tolerability of levofloxacin 500 mg once daily for 10 days in patients with CAP are well established. Furthermore, a high-dose (750 mg) and short-course (5 days) of once-daily levofloxacin has been approved for use in the US in the treatment of CAP, acute bacterial sinusitis, acute pyelonephritis, and complicated urinary tract infections. The high-dose, short-course levofloxacin regimen maximizes its concentration-dependent antibacterial activity, decreases the potential for drug resistance, and has better patient compliance

Staphylococcus aureus Surface Protein SdrE Binds Complement Regulator Factor H as an Immune Evasion Tactic

Similar to other highly successful invasive bacterial pathogens, Staphylococcus aureus recruits the complement regulatory protein factor H (fH) to its surface to inhibit the alternative pathway of complement. Here, we report the identification of the surface-associated protein SdrE as a fH-binding protein using purified fH overlay of S. aureus fractionated cell wall proteins and fH cross-linking to S. aureus followed by mass spectrometry. Studies using recombinant SdrE revealed that rSdrE bound significant fH whether from serum or as a purified form, in both a time- and dose-dependent manner. Furthermore, rSdrE-bound fH exhibited cofactor functionality for factor I (fI)-mediated cleavage of C3b to iC3b which correlated positively with increasing amounts of fH. Expression of SdrE on the surface of the surrogate bacterium Lactococcus lactis enhanced recruitment of fH which resulted in increased iC3b generation. Moreover, surface expression of SdrE led to a reduction in C3-fragment deposition, less C5a generation, and reduced killing by polymorphonuclear cells. Thus, we report the first identification of a S. aureus protein associated with the staphylococcal surface that binds factor H as an immune evasion mechanism

Staphylococcus aureus Protein A Disrupts Immunity Mediated by Long-Lived Plasma Cells

Infection with Staphylococcus aureus does not induce long-lived protective immunity for reasons that are not completely understood. Human and murine vaccine studies support a role for antibodies in protecting against recurring infections, but S. aureus modulates the B cell response through expression of Staphylococcal Protein A (SpA), a surface protein that drives polyclonal B cell expansion and induces cell death in the absence of co-stimulation. In this murine study, we show that SpA altered the fate of plasmablasts and plasma cells (PCs) by enhancing the short-lived extrafollicular response and reducing the pool of bone marrow (BM)-resident long-lived PCs (LLPCs). The absence of LLPCs was associated with a rapid decline in antigen-specific, class-switched antibody. In contrast, when previously inoculated mice were challenged with isogenic Δspa S. aureus, cells proliferated in the BM survival niches and sustained long-term antibody titers. The effects of SpA on PC fate were limited to the secondary response, as antibody levels and the formation of B cell memory occurred normally during the primary response in mice inoculated with either WT or Δspa S. aureus. Thus, failure to establish long-term protective antibody titers against S. aureus was not a consequence of diminished formation of B cell memory; instead, SpA reduced the proliferative capacity of PCs that entered the BM, diminishing the number of cells in the long-lived pool

Risk factors for nosocomial pneumonia comparing adult critical-care populations

The purpose of the study was to examine risk factors for nosocomial pneumonia in the surgical and medical/respiratory intensive care unit (ICU) populations. In a public teaching hospital, all cases of nosocomial pneumonia in the surgical and medical/respiratory ICUs (n = 20, respectively) were identified by prospective surveillance during a 5-yr period from 1987-1991. Each group of ICU cases was compared with 40 ICU control patients who did not acquire pneumonia, and analyzed for 25 potential risk factors. Surgical ICU patients were found to have consistently higher rates of nosocomial pneumonia than medical ICU patients (RR = 2.2). The strongest predictor for nosocomial pneumonia in both the surgical and medical/respiratory ICU groups was found to be prolonged mechanical ventilation (> 1 d) resulting in a 12-fold increase in risk over nonventilated patients. APACHE III score was found to be predictive of nosocomial pneumonia in the surgical ICU population, but not in the medical/respiratory ICU population. We conclude that certain groups deserve special attention for infection control intervention. Surgical ICU patients with high APACHE scores and receiving prolonged mechanical ventilation may be at the greatest risk of acquiring nosocomial pneumonia of all hospitalized patients

Acquisition of Complement Inhibitor Serine Protease Factor I and Its Cofactors C4b-Binding Protein and Factor H by Prevotella intermedia

Infection with the Gram-negative pathogen Prevotella intermedia gives rise to periodontitis and a growing number of studies implies an association of P. intermedia with rheumatoid arthritis. The serine protease Factor I (FI) is the central inhibitor of complement degrading complement components C3b and C4b in the presence of cofactors such as C4b-binding protein (C4BP) and Factor H (FH). Yet, the significance of complement inhibitor acquisition in P. intermedia infection and FI binding by Gram-negative pathogens has not been addressed. Here we show that P. intermedia isolates bound purified FI as well as FI directly from heat-inactivated human serum. FI bound to bacteria retained its serine protease activity as shown in degradation experiments with 125I-labeled C4b. Since FI requires cofactors for its activity we also investigated the binding of purified cofactors C4BP and FH and found acquisition of both proteins, which retained their activity in FI mediated degradation of C3b and C4b. We propose that FI binding by P. intermedia represents a new mechanism contributing to complement evasion by a Gram-negative bacterial pathogen associated with chronic diseases

Cardiac Troponin Release is Associated with Biomarkers of Inflammation and Ventricular Dilatation During Critical Illness.

INTRODUCTION: Troponin release is common during critical illness. We hypothesized that there was an association between cardiac troponin T (cTnT) and biomarkers of systemic inflammation and ventricular dilatation. METHODS: In an observational prospective cohort study, we enrolled consecutive adult patients admitted for non-cardiac reasons to the Intensive Care Unit (ICU) in 2 tertiary care centers. We measured cTnT, C-reactive protein (CRP), Interleukin-6 (IL-6), procalcitonin (PCT) and N-terminal pro brain natriuretic peptide (NT-proBNP) daily in the first week, and on alternate days in the second week. Using a peak cTnT cut-off ≥15ng/L and concomitant changes on electrocardiogram (ECG), patients were categorised as "definite myocardial infarction (MI)", "possible MI", "cTnT rise only" or "no cTnT rise". Within each group, associations between CRP, IL-6, PCT, NT-proBNP and cTnT were investigated using mixed effect models. RESULTS: 172 patients were included in the analysis of whom 84% had a cTnT rise ≥15ng/L. 21 patients (12%) had a definite MI, 51 (30%) had a possible MI and 73 (42%) had a cTnT rise only. At time of peak cTnT, 71% of patients were septic and 67% were on vasopressors.Multivariable analysis showed a significant association between cTnT and IL-6 in all patients with a cTnT rise independent of age, gender, renal function and cardiovascular risk factors. In patients without a definite MI, cTnT levels were significantly associated with PCT and NT-proBNP values. In patients without elevated cTnT levels, there was no associated NT-proBNP rise. CONCLUSIONS: In ICU patients admitted for non-cardiac reasons, serial cTnT levels were independently associated with markers of systemic inflammation and NT-proBNP

The impact of dental caries and its treatment by conventional or biological approaches on the oral health-related quality of life of children and carers

Background The effect of untreated dental caries and the approaches taken to its treatment have not been extensively elucidated in children. Aim To investigate the impact of untreated dental caries on children aged 4–9 years and whether its treatment with either a conventional or a biological approach influenced the oral health-related quality of life (OHRQoL) of the children and their carers. Design Children (n = 110) and their carers attending two specialist centres for treatment of carious primary teeth completed the Early Childhood Oral Health Impact Scale and the Self-reported Scale of Oral Health Outcomes for 5-year-old Children at baseline prior to dental treatment and at 3–6 months following completion of dental care. Dental treatment was provided using either a conventional or a biological approach. Results Dental caries showed a negative impact on the child and family's OHRQoL (P = 0.001). Children reported difficulty eating (55.5%), sleeping (40%), and avoiding smiling because of how the teeth looked (27.3%). More than half of the parents reported their child had toothache. Parents perceived difficulty eating (40.9%), being irritable (38.2%), and difficulty drinking (30.9%) as being impacts of caries on their child's OHRQoL. In addition, approximately half the parents reported feeling a sense of guilt because of their child's dental disease. Following dental treatment, participants reported significant improvement in their overall health status (P = 0.001). Children's age, gender, or the treatment approach were not statistically significantly associated with changes in OHRQoL of the child or carer. Children and parents who initially reported greater impacts of untreated dental caries demonstrated greater improvements in their overall oral health status (P < 0.0001). Conclusion Dental caries was associated with negative impacts on children and parents' quality of life. Treatment of caries improved the quality of life of children and families significantly, irrespective of whether the treatment was provided by a conventional or a biological approach

Septic cardiomyopathy

Depression of left ventricular (LV) intrinsic contractility is constant in patients with septic shock. Because most parameters of cardiac function are strongly dependent on afterload, especially in this context, the cardiac performance evaluated at the bedside reflects intrinsic contractility, but also the degree of vasoplegia. Recent advances in echocardiography have allowed better characterization of septic cardiomyopathy. It is always reversible providing the patient's recovery. Unlike classic cardiomyopathy, it is not associated with high filling pressures, for two reasons: improvement in LV compliance and associated right ventricular dysfunction. Although, it is unclear to which extent it affects prognosis, a hyperkinetic state is indicative of a profound and persistent vasoplegia associated with a high mortality rate. Preliminary data suggest that the hemodynamic response to a dobutamine challenge has a prognostic value, but large studies are required to establish whether inotropic drugs should be used to treat this septic cardiac dysfunction