Clostridium difficile infection in children: epidemiology and risk of recurrence in a low-prevalence country.

Clostridium difficile infection (CDI) is increasingly found in children worldwide, but limited data are available from children living in southern Europe. A 6-year retrospective study was performed to investigate the epidemiology, clinical features, treatment, and risk of recurrence in Italy. Data of children with community- and hospital-acquired CDI (CA-CDI and HA-CDI, respectively) seen at seven pediatric referral centers in Italy were recorded retrospectively. Annual infection rates/10,000 hospital admissions were calculated. Logistic regression was used to investigate risk factors for recurrence. A total of 177 CDI episodes was reported in 148 children (83 males, median age 55.3 months), with a cumulative infection rate of 2.25/10,000 admissions, with no significant variability over time. The majority of children (60.8 %) had CA-CDI. Children with HA-CDI (39.2 %) had a longer duration of symptoms and hospitalization (p = 0.003) and a more common previous use of antibiotics (p = 0.0001). Metronidazole was used in 70.7 % of cases (87/123) and vancomycin in 29.3 % (36/123), with similar success rates. Recurrence occurred in 16 children (10.8 %), and 3 (2 %) of them presented a further treatment failure. The use of metronidazole was associated with a 5-fold increase in the risk of recurrence [odds ratio (OR) 5.18, 95 % confidence interval (CI) 1.1-23.8, p = 0.03]. Short bowel syndrome was the only underlying condition associated with treatment failure (OR 5.29, 95 % CI 1.17-23.8, p = 0.03). The incidence of pediatric CDI in Italy is low and substantially stable. In this setting, there is a limited risk of recurrence, which mainly concerns children treated with oral metronidazole and those with short bowel syndrome.

Obesity: impact of infections and response to vaccines.

Obesity is a common condition that has rapidly increased in both the industrialised and developing world in recent decades. Obese individuals show increased risk factors for severe infections and significant immune system dysregulation that may impair the immune response to vaccines. The main aim of this paper was to review the current knowledge regarding the association between obesity and the risk and outcome of infections as well as immune response to vaccines. The results showed that obesity is a highly complex clinical condition in which the functions of several organ and body systems, including the immune system, are modified. However, only a small minority of the biological mechanisms that lead to reduced host defences have been elucidated. Relevant efforts for future research should focus on obese children, as the available data on this population are scarce compared with the adult population. Even if most vaccines are given in the first months of life when obesity is rare, some vaccines require booster doses at preschool age, and other vaccines, such as the influenza vaccine, are recommended yearly in the obese population, but it is not known whether response to vaccines of obese patients is impaired. The reduced immune response of obese patients to vaccination can be deleterious not only for the patient but also for the community.

Hexavalent vaccines for immunization in paediatric age.

Despite the potential for protection against a broad spectrum of pathogens, the availability of an increased number of effective vaccines could lead to a significant reduction in vaccination coverage as the result of issues with implementation of new vaccines within existing protocols. To overcome these problems, the development of combined vaccines has been promoted. The use of combined vaccines offers a number of potential benefits, including a reduction in the number of patient visits, reduced complications associated with multiple intramuscular injections, decreased costs of stocking and administering separate vaccines, and a lowering of the risk of delayed or missed vaccinations. The hexavalent vaccine includes antigens against diphtheria, tetanus, acellular pertussis (DTaP), hepatitis B (HBsAg), poliomyelitis (P1, P2, P3) and Haemophilus influenzae type B (Hib) infections. The primary goal of this review is to discuss the immunogenicity, efficacy, safety and tolerability of several hexavalent preparations that are either commercially available or still under development.

Preventing influenza in younger children.

Influenza is common in infants and children: attack rates vary from 23% to 48% each year during inter-pandemic periods, and are even higher during pandemics. Severe cases occur more frequently in children with underlying chronic diseases; however, epidemiological studies have clearly shown that influenza also causes an excess of medical examinations, drug prescriptions and hospitalizations in otherwise healthy children (particularly those aged <5 years), as well as a considerable number of paediatric deaths. Childhood influenza also has a number of social and economic consequences. However, many European health authorities are still reluctant to include influenza vaccinations in their national vaccination programmes for healthy children because, among other things, there are doubts concerning their real ability to evoke a protective immune response, especially in children in the first years of life. New hope for the solution of these problems has come from the introduction of vaccines containing more antigens and the possibility of intradermal administration. However, further studies are needed to establish whether universal influenza vaccination in the first years of life should be recommended, and with which vaccine.

Efficacy of increasing dosages of clarithromycin for treatment of experimental Mycoplasma pneumoniae pneumonia.

OBJECTIVES: Mycoplasma pneumoniae respiratory infection is a common cause of acute respiratory infection in children and adults. We evaluated the efficacy of increasing dosages of clarithromycin for the optimized therapy of M. pneumoniae respiratory infection in a mouse model. METHODS: BALB/c mice were intranasally inoculated once with M. pneumoniae or SP4 broth (control). Groups of mice were treated with increasing dosages of clarithromycin (10, 25 or 75 mg/kg/day) or placebo subcutaneously daily. Groups of mice were evaluated after 1, 2, 3, 6 and 12 days of therapy. Outcome variables included quantitative M. pneumoniae culture, histopathological score of the lungs, bronchoalveolar lavage (BAL) cytokine/chemokine/growth factor concentrations and plethysmography after aerosolized methacholine to assess airway hyperresponsiveness. RESULTS: Elevated dosages of clarithromycin resulted in greater antimicrobial efficacy with significantly reduced M. pneumoniae quantitative cultures (P < 0.05), as well as greater improvement in markers of disease severity with significantly reduced lung histopathology scores, BAL cytokine concentrations and airway hyperresponsiveness (P < 0.05). CONCLUSIONS: Escalated dosing of clarithromycin resulted in significantly greater therapeutic efficacy in the treatment of experimental M. pneumoniae respiratory infection.

Tigecycline therapy significantly reduces the concentrations of inflammatory pulmonary cytokines and chemokines in a murine model of Mycoplasma pneumoniae pneumonia.

Mycoplasma pneumoniae is one of the causative agents of atypical community-acquired pneumonia. Tigecycline belongs to a new class of glycylcycline antimicrobials that have activity against a wide range of microorganisms, including in vitro activity against M. pneumoniae. We investigated the effect of tigecycline on microbiologic, histologic, and immunologic indices in a murine model of M. pneumoniae pneumonia. BALB/c mice were inoculated intranasally with M. pneumoniae and treated subcutaneously with tigecycline or placebo for 6 days. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniae culture, lung histopathologic score (HPS), BAL cytokine and chemokine concentrations (tumor necrosis factor alpha [TNF-alpha], gamma interferon [IFN-gamma], interleukin 1beta [IL-1beta], IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 [p40/p70], granulocyte-macrophage colony-stimulating factor, MIP-1alpha, MIG, KC, MCP-1, and IP-10). BAL M. pneumoniae concentrations in mice treated with tigecycline (MpTige) tended to be reduced compared with mice treated with placebo (MpPl); however this did not reach statistical significance. The lung HPS was significantly lower, as well as the parenchymal-pneumonia subscore, in the MpTige mice than in the MpPl mice. MpTige mice had significantly lower BAL cytokine concentrations of IL-1beta, IL-12 (p40/p70), IFN-gamma, and TNF-alpha; of the chemokines, MIG, MIP-1alpha, and IP-10 were statistically lower in MpTige mice. While tigecycline treatment demonstrated a modest microbiologic effect, it significantly improved lung histologic inflammation and reduced pulmonary cytokines and chemokines.

The impact of steroids given with macrolide therapy on experimental Mycoplasma pneumoniae respiratory infection.

BACKGROUND: Systemic steroids have been advocated in addition to antimicrobial therapy for severe Mycoplasma pneumoniae pneumonia. We evaluated the efficacy of clarithromycin, dexamethasone, and combination therapy for M. pneumoniae respiratory infection. METHODS: Mice infected with M. pneumoniae were treated with clarithromycin, dexamethasone, combined clarithromycin/dexamethasone, or placebo daily; mice were evaluated at baseline and after 1, 3, and 6 days of therapy. Outcome variables included M. pneumoniae culture, lung histopathologic score (HPS), and bronchoalveolar lavage cytokine, chemokine, and growth factor concentrations. RESULTS: Clarithromycin monotherapy resulted in the greatest reductions in M. pneumoniae concentrations. After 3 days of treatment, combination therapy significantly reduced lung HPS compared with placebo, clarithromycin, and dexamethasone alone, whereas, after 6 days of therapy, clarithromycin alone and combination therapy significantly reduced lung HPS compared with placebo. Concentrations of interleukin (IL)-12 p40, RANTES, macrophage chemotactic protein-1, and cytokine-induced neutrophil chemoattractant were significantly lower in mice treated with clarithromycin alone and/or combination therapy compared with dexamethasone alone and/or placebo; combination therapy resulted in a significantly greater reduction than clarithromycin alone for IL-12 p40 and RANTES. CONCLUSIONS: Although monotherapy with clarithromycin had the greatest effect on reducing concentrations of M. pneumoniae, combination therapy had the greatest effect on decreasing levels of cytokines and chemokines as well as pulmonary histologic inflammation.

Clinical and socio-economic impact of influenza and respiratory syncytial virus infection on healthy children and their households.

This prospective study compared the clinical and socio-economic impact of laboratory-confirmed influenza and respiratory syncytial virus (RSV) infection on healthy children and their families. Among 1,520 otherwise healthy children aged< 15 years attending the Emergency Department for acute conditions other than trauma, influenza viruses and RSV were found in 234 (15.4%) and 116 (7.6%; p<0.0001) patients, respectively. The fact that influenza has a similar global clinical impact on the community to that of RSV infection, but represents a greater socio-economic burden, may contribute to broadening the acceptance of influenza vaccination.

Pharmacological control of the mevalonate pathway: effect on arterial smooth muscle cell proliferation.

The mevalonate (MVA) pathway is involved in cell proliferation. We investigated drugs acting at different enzymatic steps on rat aorta smooth muscle cell (SMC) proliferation. Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (0.1-10 microM) dose-dependently decreased (up to 90%) SMC proliferation. This effect was prevented by 100 microM MVA, 10 microM all-trans farnesol (F-OH) and 5 microM all-trans geranylgeraniol (GG-OH), precursors of protein prenyl groups, but not by 2-cis GG-OH, precursor of dolichols, squalene and ubiquinone. The same inhibitory effect was obtained with 6-fluoromevalonate (1-50 microM), an inhibitor of MVA-pyrophosphate decarboxylase. Partial recovery of cell proliferation was possible by all-trans F-OH and all-trans GG-OH, but not MVA. Squalestatin 1 (1-25 microM), a potent squalene synthase inhibitor, blocked cholesterol synthesis and slightly inhibited (21% decrease) SMC proliferation only at the highest tested concentration. NB-598 (1-10 microM), a potent squalene epoxidase inhibitor, blocked cholesterol synthesis without affecting SMC proliferation. Finally, the benzodiazepine peptidomimetic BZA-5B (10-100 microM), a specific inhibitor of protein farnesyltransferase, time- and dose-dependently decreased SMC proliferation (up to 62%) after 9 days. This effect of BZA-5B was prevented by MVA and all-trans GG-OH, but not by all-trans F-OH. SMC proliferation was not affected by the closely related compound BZA-7B, which does not inhibit protein farnesyltransferase. Altogether, these findings focus the role of the MVA pathway in cell proliferation and call attention to the involvement of specific isoprenoid metabolites, probably through farnesylated and geranylgeranylated proteins, in the control of this cellular event.