H. Lode

Comparison of Pneumococcal Conjugate Polysaccharide and Free Polysaccharide Vaccines in Elderly Adults: Conjugate Vaccine Elicits Improved Antibacterial Immune Responses and Immunological Memory

BACKGROUND High functional antibody responses, establishment of immunologic memory, and unambiguous efficacy in infants suggest that an initial dose of conjugated pneumococcal polysaccharide (PnC) vaccine may be of value in a comprehensive adult immunization strategy. METHODS We compared the immunogenicity and safety of 7-valent PnC vaccine (7vPnC) with that of 23-valent pneumococcal polysaccharide vaccine (PPV) in adults >/=70 years of age who had not been previously vaccinated with a pneumococcal vaccine. One year later, 7vPnC recipients received a booster dose of either 7vPnC (the 7vPnC/7vPnC group) or PPV (the 7vPnC/PPV group), and PPV recipients received a booster dose of 7vPnC (the PPV/7vPnC group). Immune responses were compared for each of the 7 serotypes common to both vaccines. RESULTS Antipolysaccharide enzyme-linked immunosorbent assay antibody concentrations and opsonophagocytic assay titers to the initial dose of 7vPnC were significantly greater than those to the initial dose of PPV for 6 and 5 of 7 serotypes, respectively (P < .01 and P < .05, respectively). 7vPnC/7vPnC induced antibody responses that were similar to those after the first 7vPnC inoculation, and 7vPnC/PPV induced antibody responses that were similar to or greater than antibody responses after administration of PPV alone; PPV/7vPnC induced significantly lower antibacterial responses, compared with those induced by 7vPnC alone, for all serotypes (P < .05). CONCLUSION In adults, an initial dose of 7vPnC is likely to elicit higher and potentially more effective levels of antipneumococcal antibodies than is PPV. In contrast with PPV, for which the induction of hyporesponsiveness was observed when used as a priming dose, 7vPnC elicits an immunological state that permits subsequent administration of 7vPnC or PPV to maintain functional antipolysaccharide antibody levels.

A European care bundle for prevention of ventilator-associated pneumonia

BackgroundOne recent approach to facilitating guideline implementation involves the use of care bundles.MethodsThis document presents a care bundle package addressing VAP prevention in an attempt to promote guideline-compliant practices. Uniquely, the development of these care bundles used a formalised methodology to assess the supporting data, based on multi-criteria decision analysis.ResultsThe resulting VAP care bundles for prevention were: non-ventilatory circuit changes unless specifically indicated, alcohol hand hygiene, appropriately educated and trained staff, incorporation of sedation control and weaning protocols into patient care, and oral care with clorhexidine.ConclusionAdoption of these care bundles should rationalise VAP prevention practises and improve outcomes, such as length of stay.

Safety considerations of fluoroquinolones in the elderly: an update.

The fluoroquinolones ciprofloxacin, levofloxacin, moxifloxacin and gemifloxacin are widely used for the treatment of various types of bacterial infections. Overall, these antibacterial agents can be considered safe and well tolerated drugs. Comparative studies have evaluated the use of quinolones in elderly and younger populations. Although age per se does not seem to decrease their tolerability, specific adverse effects of the quinolones must be considered when they are chosen for antibacterial treatment.Renal function declines consistently with age and doses of renally excreted quinolones (e.g. ofloxacin, levofloxacin, gatifloxacin) need to be adjusted if a clinically relevant reduction of creatinine clearance is identified. Reactions of the gastrointestinal tract, such as nausea, dyspepsia, vomiting or diarrhoea, are among the most often registered adverse drug reactions during therapy with fluoroquinolones. Treatment with a quinolone causes diarrhoea less frequently than treatment with other classes of antimicrobials. Conflicting data have been published with respect to the incidence of Clostridium difficile- associated diarrhoea in quinolone-treated patients. Hypersensitivity reactions, often manifested on the skin, occur less commonly during therapy with quinolones than, for example, during therapy with β-lactam antibacterials.Adverse reactions of the CNS are of particular concern in the elderly population. Given the CNS excitatory effects of quinolones, elderly patients should be monitored carefully for such symptoms. It is likely that many signs of possible adverse reactions, such as confusion, weakness, loss of appetite, tremor or depression, are often mistakenly attributed to old age and remain unreported. Quinolones should be used with caution in patients with known or suspected CNS disorders that predispose to seizures (e.g. severe cerebral arteriosclerosis or epilepsy).Quinolones can cause QT interval prolongation. They should be avoided in patients with known prolongation of the QT interval, patients with un-corrected hypokalaemia or hypomagnesaemia and patients receiving class IA (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) anti-arrhythmic agents.Tendinitis and tendon ruptures are recognized as quinolone-induced adverse effects that can occur during treatment or as late as several months after treatment. Chronic renal diseases, concomitant use of corticosteroids and age >60 years are known risk factors for quinolone-induced tendopathies.Overall, the specific adverse-effect profile of quinolones must be considered when they are chosen for treatment of bacterial infections. Because of physiological changes in renal function and when certain co-morbidities are present, some special considerations are necessary when elderly patients are treated with these drugs.

Mixed community-acquired pneumonia in hospitalised patients

The role of mixed community-acquired pneumonia (CAP) is controversial. The aim of the present study was to determine the incidence, principal microbial patterns, clinical predictors and course of mixed CAP. The current study included 1,511 consecutive hospitalised patients with CAP. Of these, 610 (40%) patients had an established aetiology. One pathogen was demonstrated in 528 patients and 82 (13%) patients had mixed pneumonia. Cases including CAP, by a pyogenic bacteria and a complete paired serology for “atypicals”, revealed that 82 (13%) patients had definite single pyogenic pneumonia and 28 patients (5%) had mixed pyogenic pneumonia. In patients with mixed CAP, Streptococcus pneumoniae was the most prevalent microorganism (44 out of 82; 54%). The most frequent combination was S. pneumoniae with Haemophilus influenzae (17 out of 82; 21%). Influenza virus A and S. pneumoniae (five out of 28; 18%) was the most frequent association in the mixed pyogenic pneumonia group. No clinical predictors for mixed pneumonias could be identified. Patients with mixed pyogenic pneumonia more frequently developed shock when compared with patients with single pyogenic pneumonia (18 versus 4%). In conclusion, mixed pneumonia occurs in >10% of cases with community-acquired pneumonia requiring hospitalisation.

Moxifloxacin Monotherapy Is Effective in Hospitalized Patients with Community-Acquired Pneumonia: The MOTIV Study—A Randomized Clinical Trial

BACKGROUND The aim of this study was to show that sequential intravenous and oral moxifloxacin monotherapy (400 mg once per day) is as efficacious and safe as a combination regimen (intravenous ceftriaxone, 2 g once per day, plus sequential intravenous and oral levofloxacin, 500 mg twice per day) in patients hospitalized with community-acquired pneumonia. METHODS We conducted a prospective, multicenter, randomized, double-blind noninferiority trial. Patients with a Pneumonia Severity Index (PSI) of III-V were stratified on the basis of PSI risk class before randomization. The primary efficacy end point was clinical response at test of cure (4-14 days after the completion of treatment). Secondary efficacy end points were clinical and bacteriological response at end of treatment (days 7-14) and at follow-up assessment (21-28 days after the end of treatment), overall mortality, and mortality attributable to pneumonia. RESULTS Seven hundred thirty-three patients were enrolled in the study (368 in the moxifloxacin arm and 365 in the comparator arm); 49% had a PSI of IV, and 10% had a PSI of V. Of 569 patients (291 in the moxifloxacin arm and 278 in the comparator arm) valid for per-protocol analysis, the overall clinical cure rates at test of cure were 86.9% for moxifloxacin and 89.9% for the comparator regimen (95% confidence interval, -8.1% to 2.2%). Bacteriological success at test of cure was 83.3% for moxifloxacin and 85.1% for the comparator regimen (95% confidence interval, -15.4% to 11.8%). There were no significant differences between moxifloxacin and comparator treatments in the incidence of treatment-emergent adverse events or in mortality. CONCLUSIONS Monotherapy with sequential intravenous/oral moxifloxacin was noninferior to treatment with ceftriaxone plus levofloxacin combination therapy in patients with community-acquired pneumonia who required hospitalization.

Characteristics and outcome of patients with active pulmonary tuberculosis requiring intensive care

Severe tuberculosis (TB) requiring intensive care unit (ICU) care is rare but commonly known to be of markedly bad prognosis. The present study aimed to describe this condition and to determine the mortality rate and risk factors associated with mortality. Patients with confirmed TB admitted to ICU between 1990 and 2001 were retrospectively identified and enrolled. Clinical, radiological and bacteriological data at admission and during hospital stay were recorded. A multivariate analysis was performed to identify the predictive factors for mortality. A total of 58 TB patients (12 females, mean age 48 yrs) admitted to ICU were included. Mean Acute Physiology and Chronic Health Evaluation (APACHE) II score at admission was 13.1±5.6 and 22 of 58 (37.9%) patients required mechanical ventilation. The in-hospital mortality was 15 of 58 (25.9%); 13 (22.4%) patients died in the ICU. The mean survival of patients who died was 53.6 days (range 1–229), with 50% of the patients dying within the first 32 days. The factors independently associated with mortality were: acute renal failure, need for mechanical ventilation, chronic pancreatitis, sepsis, acute respiratory distress syndrome, and nosocomial pneumonia. These data indicate a high mortality of patients with tuberculosis requiring intensive care unit care and identifies new independently associated risk factors.

Quinolone-induced arthropathy: an update focusing on new mechanistic and clinical data

Quinolones possess favourable antibacterial and pharmacokinetic characteristics and are often used as anti-infective agents in adults. They are contraindicated in children and adolescents because they damage weight-bearing joints in juvenile animals. In addition, they possess a tendotoxic potential. Since ciprofloxacin has been used off-label for decades in children and adolescents, it is known today that no pronounced risks for arthropathies or tendinopathies exist in humans. Recently published clinical studies with gatifloxacin in children support this clinical experience. However, a low risk for joint disorders cannot be excluded and tendinopathies are a generally accepted rare adverse effect of quinolones at least in adults. Isolated case reports of arthralgia in children following quinolone therapy have been published and in studies with levofloxacin the incidence of musculoskeletal disorders was significantly greater in levofloxacin-treated patients than in control patients treated with comparator antibiotics. As a consequence, only life-threatening infections for which other antimicrobials cannot be used are possible indications for quinolones in children, for example the use of ciprofloxacin in cystic fibrosis patients with a bronchopulmonary exacerbation, chronic suppurative otitis media caused by Pseudomonas sp., complicated urinary tract infections and enteritis caused by invasive multidrug-resistant pathogens (e.g. Salmonella, Shigella).

Reduced spontaneous apoptosis in peripheral blood neutrophils during exacerbation of COPD.

A major feature of acute exacerbation of chronic obstructive pulmonary disease (COPD) is the accumulation of activated neutrophils in the bronchial tree. This phenomenon can be explained by an increased migration and/or by a prolonged survival due to an inhibition of spontaneous apoptosis. The aim of this study was to assess the apoptotic behaviour of peripheral blood neutrophils in COPD patients during an acute exacerbation. Thirty-six hospitalised COPD patients with an acute exacerbation and 10 healthy volunteers were included. Blood samples were obtained at admission, after 3–5 days and at discharge. Spontaneous apoptosis of isolated neutrophils was measured based on Annexin V‐PE binding and nuclear morphology after culturing for 18 h. At admission, significantly lower rates of spontaneous apoptosis were noted in COPD patients compared with healthy volunteers (mean±sd 31±13% versus 44±18%). The mean percentages of apoptotic neutrophils were 31±13% at admission, 39±15% after 3–5 days and 47±18% at discharge. There was a statistically significant difference between the rates of spontaneous apoptosis on the first day and at discharge. Neither forced expiratory volume in one second <35% predicted, smoking habit, corticosteroid therapy nor evidence of bacterial infection showed any influence on the spontaneous apopotosis in this study. In conclusion, during acute exacerbations of chronic obstructive pulmonary disease, neutrophil granulocytes show a reduced spontaneous apoptosis that increases progressively after treatment and clinical remission. This raises the question of the importance of neutrophil apoptosis in the development and resolution of exacerbations of chronic obstructive pulmonary disease.

Synergistic effects of dexamethasone and quinolones on human-derived tendon cells.

Quinolones and glucocorticoids are frequently used drugs that may cause tendinopathy as a rare adverse effect. We exposed human tenocyte cultures to the steroid dexamethasone alone or in combination with either ciprofloxacin or levofloxacin at concentrations of 3mg/L and 10mg/L. At concentrations corresponding to peak levels in plasma and tissues during therapy (ca. 3-10mg/L), ciprofloxacin caused a significant decrease in collagen type I and the beta(1)-integrin receptor. In contrast, no corresponding effect was induced by 3mg/L levofloxacin. With both quinolones at 3mg/L and 10mg/L, the amount of matrix metalloproteinase-1 (MMP-1) and MMP-13 was increased. In addition, 3mg/L ciprofloxacin and 10mg/L levofloxacin activated caspase-3. Apoptotic changes were confirmed by electron microscopy. Incubation of human tenocytes with dexamethasone decreased the main matrix protein collagen type I, the transmembrane beta(1)-integrin receptor and the cytoskeleton protein vinculin, but only at the high concentrations tested (0.1 microM or 10 microM). Concentrations of 0.1 microM and 10 microM dexamethasone increased the amount of MMPs and activated caspase-3 as an indicator of apoptosis. Combined exposure to quinolones and dexamethasone led to more pronounced effects in tenocyte cultures at most of the analysed endpoints. The clinical observations of an increased risk of quinolone-induced tendinopathy by glucocorticoids are supported by these in vitro data.

Risks associated with the therapeutic use of fluoroquinolones.

Introduction: Quinolones are among the most often prescribed antimicrobial agents. Some types of toxicity observed during therapy with these drugs have gained much attention. Areas covered: Here, we review the potential of the most widely used fluoroquinolones, ciprofloxacin, levofloxacin and moxifloxacin for adverse reactions. The rates of adverse events are similar for quinolones and other antibacterial agents. However, quinolone therapy can be associated with specific risks, which must be weighed against their benefit. In some studies, use of quinolones was associated with Clostridium difficile-associated diarrhea. Patients with impairments of the CNS (e.g., epilepsy or arteriosclerosis) should not be treated with quinolones. They should be avoided in patients with known prolongation of the QT interval or other risk factors for tachyarrhythmia. The risk for quinolone-associated tendinopathy is more pronounced among elderly persons, non-obese patients and individuals with concurrent use of glucocorticoids or chronic renal diseases. Quinolones are contraindicated in children because they cause destruction of the immature joint cartilage in animals. The use in paediatrics is restricted to life-threatening infections. Expert opinion: Changes in the resistance situation and newly recognized adverse reactions require a continuing adjustment of therapeutic recommendations and constant educational efforts in the field of antimicrobial therapy.