Biomedical subjects

Charles Feldman

Publications and source records attributed to Charles Feldman.

At least 19 recordsLinked to original sources

PubMed2007

HIV and pneumococcal disease.

PURPOSE OF REVIEW: To describe the impact of highly active antiretroviral therapy on the burden of pneumococcal disease and advances in our understanding of the impact of HIV on this disease. RECENT FINDINGS: Although highly active antiretroviral therapy has reduced the burden of pneumococcal disease among HIV-infected adults, these infections remain far more common than in HIV uninfected adults. HIV-infected adults who smoke or have comorbidities are at particular risk. In the absence of highly active antiretroviral therapy, pneumococcal meningitis has emerged in Africa as a major disease burden with a high mortality among HIV-infected children and adults. Conjugate pneumococcal vaccine protects HIV-infected infants from pneumococcal pneumonia. In the United States, where conjugate vaccine is given to children, herd immunity has reduced the burden of invasive pneumococcal disease among HIV-infected adults. SUMMARY: The pneumococcus remains a significant cause of morbidity and mortality among HIV-infected children and adults, both in developed and in developing countries.

Anti-Retroviral Agents↗

PubMed2006

Guideline for the management of nosocomial infections in South Africa.

OBJECTIVE: To write a guideline for the management and prevention of nosocomial infections in South Africa in view of the following: Nosocomial infections are a common and increasing problem globally, including South Africa. Widely varying standards of prevention and management of these important infections. Increasing and emerging antimicrobial resistance among commonly isolated pathogens. The significant economic burden of these infections on the health care system as well as their impact on patient morbidity and mortality. The main aims of the guideline are to provide recommendations for the initial choice of antimicrobial agents and the appropriate management of these infections encompassing the following conditions: (i) nosocomial pneumonia, health care-associated pneumonia and ventilator-associated pneumonia; (ii) nosocomial bloodstream infections; (iii) nosocomial intravascular infections; (iv) nosocomial urinary tract infections; (v) nosocomial intra-abdominal infections; and (vi) nosocomial surgical skin and soft-tissue infections. EVIDENCE: Working group of clinicians from relevant disciplines, following detailed literature review. RECOMMENDATIONS: These include details of the likely pathogens, an appropriate diagnostic approach, antibiotic treatment options and appropriate preventive strategies. ENDORSEMENT: The guideline document was endorsed by the South African Thoracic Society, the Critical Care Society of Southern Africa and the Federation of Infectious Diseases Societies of Southern Africa.

Anti-Infective Agents↗

PubMed2005

Neutrophils potentiate platinum-mediated injury to human ciliated epithelium in vitro.

Exposure to platinum salts, such as may occur in the platinum refining industry, can be associated with the development of airway disorders such as asthma. However, there have been no studies investigating the direct effects of platinum salts on human ciliated epithelium. We have investigated the effects of platinic chloride on human ciliated epithelium, obtained by brushing the inferior nasal turbinate of healthy human volunteers. Ciliary beat frequency was measured using a phototransistor technique, and damage to the structural integrity of the epithelium was measured using a visual scoring index. Platinic chloride at concentrations between 0.25 and 25 microM caused a dose-dependent slowing of ciliary beating and damage to the structural integrity of the epithelium. These direct injurious effects were not affected by catalase, but were almost completely attenuated by preincubation of the epithelium with cysteine. The effects of platinic chloride on ciliary beating and structural integrity were enhanced by the presence of neutrophils and were partially attenuated by preincubation of the epithelial strips with catalase, suggesting that the direct effects of the metal were enhanced in this experimental system by reactive oxidants produced by activated neutrophils. This study documents that platinum salts have an injurious effect on human ciliated epithelium in vitro. If such effects also occur in vivo they may play a role, at least partly, in the pathogenesis of airway disorders that may manifest in exposed workers.

Acridines↗

PubMed2005

Pneumonia associated with HIV infection.

PURPOSE OF REVIEW: Pneumonia occurs commonly in HIV-infected patients and this review highlights some of the recent findings in the epidemiology, pathogenesis, clinical features, treatment and prevention of this condition. RECENT FINDINGS: Pneumonia remains an important cause of morbidity and mortality in HIV-infected patients. A number of factors have been identified that increase the risk of pneumonia. Cigarette smoking increases the risk of lung colonization, as well acute pneumonia due to Pneumocystis jiroveci, and has been documented to produce significant depression of the phagocytic function of alveolar macrophages in HIV-infected patients, which may underlie this risk. Legionella pneumophila infections appear to be uncommon in HIV-infected patients, while pneumonia with Streptococcus pneumoniae continues to occur with regularity, including infections with antibiotic-resistant isolates. Pneumocystis pneumonia occurs with a low incidence in patients receiving HAART, once the CD4 count increases to over 200 microl. Studies of invasive pneumococcal infections (predominantly pneumonia) indicate that in critically ill cases, including HIV-seropositive patients, combination antibiotic therapy is associated with a lower mortality than monotherapy. The 23-polyvalent pneumococcal vaccine has been shown to reduce the risk of pneumococcal infection in HIV-infected adults receiving HAART, and a 9-valent conjugate pneumococcal vaccine has been shown to reduce the incidence of radiologically confirmed pneumonia in HIV-seropositive and HIV-seronegative children. SUMMARY: Pneumonia remains an important condition in HIV-infected patients, but recent studies demonstrate that antibiotic prophylaxis, the introduction of HAART, recognition of specific risk factors, new antibiotic treatment strategies and effective vaccines should serve to decrease its impact.

AIDS-Related Opportunistic Infections↗

PubMed2005

Altered PBP 2A and its role in the development of penicillin, cefotaxime, and ceftriaxone resistance in a clinical isolate of Streptococcus pneumoniae.

We report the unusual involvement of altered PBP 2A in the development of beta-lactam resistance in Streptococcus pneumoniae. This was investigated amid three identical serotype 14 isolates (designated isolates 1, 2, and 3, respectively) of pneumococci cultured successfully from the blood of a human immunodeficiency virus-seropositive child with recurrent pneumonia. The passage of this strain through its human host induced several changes in the bacterium, which is typical of the adaptive and evolving nature of the pneumococcus. An efflux resistance mechanism, which conferred increased ciprofloxacin resistance, was induced in isolates 2 and 3. In addition, faster growth rates and larger capsules were also observed for these isolates, with respect to isolate 1. Notably, compared to isolates 1 and 2, isolate 3 showed a decrease in penicillin, cefotaxime, and ceftriaxone resistance. This change was associated with the replacement of an altered PBP 2A for an unaltered PBP 2A. In all likelihood, these events produced a strain which evolved into a fitter and more virulent type, isolate 3, that resulted in an aggravated pneumococcal infection and ultimately in the patient's death.

Cefotaxime↗

PubMed2004

Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia.

Retrospective studies have suggested that combination antibiotic therapy for severe bacteremic pneumococcal pneumonia may reduce mortality. We assessed this issue in a prospective, multicenter, international observational study of 844 adult patients with bacteremia due to Streptococcus pneumoniae. The effect of combination antibiotic therapy versus monotherapy on mortality was examined by univariate analyses and by logistic regression models. The 14-day mortality was not significantly different for the two groups. However, among critically ill patients, combination antibiotic therapy was associated with lower 14-day mortality (23.4 versus 55.3%, p = 0.0015). This improvement in survival was independent of country of origin, intensive care unit support, class of antibiotics, or in vitro activity of the antibiotics prescribed. Combination antibiotic therapy improved survival among critically ill patients with bacteremic pneumococcal illness.

Adolescent↗

PubMed2004

Effects of platinum and palladium ions on the production and reactivity of neutrophil-derived reactive oxygen species.

This study was designed to investigate the effects of platinum, as hydrogen hexachloroplatinate (Pt; 0.0025-25 microM), on the production of reactive oxygen species (ROS) by human neutrophils in vitro. ROS were measured by lucigenin-enhanced chemiluminescence (LECL). Addition of Pt to neutrophils was accompanied by a lag phase of about 1 min, followed by a linear dose-related increase in LECL, which peaked at around 4 min and achieved statistical significance at concentrations of 0.025 microM Pt and higher. Interestingly, Pt-mediated enhancement of LECL was not associated with meaningful alterations in neutrophil oxygen consumption, assembly of NADPH oxidase, or cytosolic Ca2+ and was completely attenuated by superoxide dismutase and inhibitors of NADPH oxidase, but not by catalase or scavengers of hydroxyl radical, and was undetectable with cells from individuals with chronic granulomatous disease. Exposure of alpha1-proteinase inhibitor to Pt-treated neutrophils resulted in inactivation of elastase-inhibitory capacity, underscoring the potential toxicity of neutrophil/Pt interactions. The pro-oxidative actions of Pt were mimicked by palladium (Pd), but not by cisplatin or rhodium. These observations demonstrate that Pt and Pd potentiate the reactivity, as opposed to the generation of neutrophil-derived oxidants, an activity that may contribute to airway inflammation in occupationally and possibly environmentally exposed individuals.

Adenosine Triphosphate↗

PubMed2004

Gender as a risk factor for both antibiotic resistance and infection with pediatric serogroups/serotypes, in HIV-infected and -uninfected adults with pneumococcal bacteremia.

Among 1022 adults with either pneumococcal bacteremia or meningitis, 85.5% of women and 74.7% of men were infected with human immunodeficiency virus (HIV). A multivariable regression analysis found more pediatric serogroups/serotypes (odds ratio [OR], 1.59 [95% confidence interval [CI], 1.18-2.15]) and more penicillin-nonsusceptible strains (OR, 1.65 [95% CI, 1.06-2.59]) in women than in men; it was also found that bacteremic women were more likely to be infected with HIV (OR, 1.85 [95% CI, 1.26-2.71]) and to be younger (OR, 1.72 [95% CI, 1.25-2.36]) than were men. Thus, conjugate pneumococcal vaccination of children may reduce, in particular, both antibiotic resistance and the burden of conjugate vaccine serotype pneumococcal disease in young, HIV-infected women.

Adolescent↗

PubMed2004

Clinical relevance of antimicrobial resistance in the management of pneumococcal community-acquired pneumonia.

Streptococcus pneumoniae remains the most common bacterial cause of community-acquired pneumonia, and these infections are associated with significant morbidity and mortality worldwide. A major concern is the increasing incidence of antibiotic resistance among pneumococcal isolates, which, in the case of certain of the antibiotic classes, has been associated with treatment failure. Yet despite multiple reports of infections with penicillin-resistant pneumococcal isolates, no cases of bacteriologic failure have been documented with the use of penicillin or ampicillin in the treatment of pneumonia caused by penicillin-resistant pneumococci. Current prevalence and levels of penicillin resistance among pneumococal isolates in most areas of the world do not indicate a need for substantial treatment changes with regard to the use of the penicillins. For infections with penicillin-sensitive strains, penicillin or an aminopenicillin in a standard dosage will still be effective for treatment. In the cases of strains with intermediate resistance, beta-lactam agents are still considered appropriate treatment, although higher dosages are recommended. Infections with isolates of high-level penicillin resistance should be treated with alternative agents such as the third-generation cephalosporins or the new antipneumococcal fluoroquinolones. In the case of the cephalosporins, pharmacodynamic/pharmacokinetic parameters help predict which of those agents are likely to be successful, and the less active agents should not be used. Debate continues in the literature with regard to the impact of macrolide resistance on the outcome of pneumococcal pneumonia, with some investigators providing evidence of an "in vivo-in vitro paradox," referring to discordance between reported in vitro resistance and clinical success of macrolides/azalide in vivo. However, several cases of macrolide/azalide treatment failure have been documented, and many clinicians recommend that these agents not be used on their own in areas with a high prevalence and levels of macrolide/azalide resistance. However, evidence is emerging to show beneficial effects on outcome with combination therapy, especially that of a beta-lactam agent and a macrolide given together to sicker, hospitalized patients with pneumococcal pneumonia. In an attempt to prevent the emergence of resistance, it has been recommended by some that the new fluoroquinolones not be used routinely as first-line agents in the treatment of community-acquired pneumonia; instead, they say, these agents should be reserved for patients who are allergic to the commonly used beta-lactam agents, for infections known to be or suspected of being caused by highly resistant strains, and for patients in whom initial therapy has failed.

Anti-Bacterial Agents↗

PubMed2004

Appropriate management of lower respiratory tract infections in primary care.

Respiratory tract symptoms are one of the major reasons for consultations with general practitioners. Most patients present because of symptoms that distress them or their family, or for reassurance that the symptoms do not represent something serious, or in order to receive medication. Many patients believe that their symptoms are due to an infection and expect to receive an antibiotic. These expectations influence the doctor's prescribing such that many patients will receive antibiotics even if the general practitioner considers these not to be required. This article describes the principles of rational antibiotic prescribing for lower respiratory tract infections in primary care, including disorders such as acute bronchitis, acute exacerbations of chronic obstructive pulmonary disease (COPD) and community-acquired pneumonia.

Journal Article↗

PubMed2004

Pneumolysin potentiates oxidative inactivation of alpha-1-proteinase inhibitor by activated human neutrophils.

This study was designed to investigate the effects of the Streptococcus pneumoniae-derived, pro-inflammatory toxin, pneumolysin (8.37 and 41.75 ng/ml), on the oxidative inactivation of alpha-1-protease inhibitor (API) by chemoattractant-activated human neutrophils in vitro. The elastase inhibitory capacity (EIC) of API in supernatants from unstimulated neutrophils, neutrophils treated with pneumolysin only, or with the chemoattractant FMLP (1 microM) only, or the combination of the toxin with FMLP was measured by a colorimetric procedure based on the activity of added porcine elastase. The EIC of API was unaffected by exposure to pneumolysin only, unstimulated neutrophils, or neutrophils treated with pneumolysin only. However, exposure to FMLP-activated neutrophils resulted in a reduction of the EIC of API, which was significantly (P<0.05) augmented by pneumolysin (mean reductions of 16%, 43% and 83% for FMLP only and in combination with 8.37 and 41.75 ng/ml pneumolysin, respectively), and was attenuated by wortmannin (1 microM), an inhibitor of NADPH oxidase, the oxidant-scavenger methionine (100 microM), and depletion of Ca2+ from the cell-suspending medium. These pro-proteolytic interactions of pneumolysin with chemoattractant-activated neutrophils may contribute to the invasiveness of the pneumococcus.

Adult↗

PubMed2004

Global strategies to prevent bacterial pneumonia in adults with HIV disease.

We examined the peer-reviewed literature on the burden of bacterial pneumonia and the effectiveness of interventions for its prevention among HIV-infected adults in developed and developing countries. Bacterial pneumonia rates were up to 25-fold higher among HIV-infected adults than in the general community, with rates increasing as CD4+ T-cell count decreases. In developed countries, cohort studies showed that highly active antiretroviral therapy (HAART) had the most consistent effect on reducing pneumonia. In a prospective cohort and case-control studies from these regions, pneumococcal polysaccharide vaccine reduced pneumococcal disease in certain subgroups, particularly those with higher CD4+ T cells/microL. In patients with fewer than 200 CD4+ T cells/microL, antimicrobial prophylaxis was usually effective in reducing pneumonia. In sub-Saharan Africa, randomised controlled trials concluded that co-trimoxazole prophylaxis decreased rates of bacterial pneumonia, but pneumococcal polysaccharide vaccine prevented neither pneumonia nor invasive pneumococcal disease. Although not yet fully evaluated in Africa, based on experience in industrialised nations, use of HAART in Africa may have substantial potential to prevent bacterial pneumonia.

AIDS-Related Opportunistic Infections↗

PubMed2004

Docosahexaenoic acid and eicosapentaenoic acid antagonize the proinflammatory interactions of pneumolysin with human neutrophils.

Pneumolysin (4.18 ng/ml)-mediated influx of Ca(2+) and augmentation of the chemoattractant-activated generation of reactive oxidants was antagonized by pretreatment of human neutrophils with the omega-3 polyunsaturated fatty acids docosahexaenoic acid and eicosapentaenoic acid (1.25 to 5 microg/ml). These agents may have potential in attenuating the proinflammatory properties of this pneumococcal toxin.

Bacterial Proteins↗

PubMed2003

An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome.

We performed a prospective, international, observational study of 844 hospitalized patients with blood cultures positive for Streptococcus pneumoniae. Fifteen percent of isolates had in vitro intermediate susceptibility to penicillin (minimum inhibitory concentration [MIC], 0.12-1 microg/mL), and 9.6% of isolates were resistant (MIC, >or=2 microg/mL). Age, severity of illness, and underlying disease with immunosuppression were significantly associated with mortality; penicillin resistance was not a risk factor for mortality. The impact of concordant antibiotic therapy (i.e., receipt of a single antibiotic with in vitro activity against S. pneumoniae) versus discordant therapy (inactive in vitro) on mortality was assessed at 14 days. Discordant therapy with penicillins, cefotaxime, and ceftriaxone (but not cefuroxime) did not result in a higher mortality rate. Similarly, time required for defervescence and frequency of suppurative complications were not associated with concordance of beta-lactam antibiotic therapy. beta-Lactam antibiotics should still be useful for treatment of pneumococcal infections that do not involve cerebrospinal fluid, regardless of in vitro susceptibility, as determined by current NCCLS breakpoints.

Adolescent↗

PubMed2003

Pneumolysin in the immunopathogenesis and treatment of pneumococcal disease.

Recent insights into the immunopathogenesis of pneumococcal infection, a common and significant cause of morbidity and mortality, have implicated pneumolysin as being a prominent virulence factor, which may play a role in microbial colonization, invasion and dissemination, as well as tissue inflammation. Being a highly immunogenic polypeptide produced by all clinically relevant pneumococcal isolates, pneumolysin is recognized as a potential carrier protein for polysaccharide conjugate vaccines, while in the setting of acute disease, promising pneumolysin-directed pharmacological strategies include, among others, macrolides and corticosteroids.

Animals↗

PubMed2002

Pneumolysin activates the synthesis and release of interleukin-8 by human neutrophils in vitro.

The effects that the Streptococcus pneumoniae-derived, proinflammatory toxin, pneumolysin (8.37 and 41.75 ng/mL), has on the production of interleukin (IL)-8 and tumor-necrosis factor (TNF)-alpha by human neutrophils have been investigated in vitro. Total and extracellular IL-8 and TNF-alpha were assayed by enzyme-linked immunosorbent assay, and flow cytometry and colorimetric procedures were used to detect intracellular cytokine and cytokine messenger RNA, respectively. Treatment of neutrophils with pneumolysin either alone or in combination with the chemotactic tripeptide, N-formyl-l-methionyl-l-leucyl-l-phenylalanine (1 microM), resulted in a time-dependent (maximal at 6 h) increase in synthesis and release of IL-8 but not of TNF-alpha, which was associated with increased expression of IL-8 messenger RNA transcripts and was abrogated by either cycloheximide (10 microg/mL) or depletion of Ca(2+) from the cell-suspending medium. These interactions between the toxin and neutrophils may contribute to the exaggerated pulmonary inflammatory responses caused by pneumolysin-producing strains of the pneumococcus.

Bacterial Proteins↗

PubMed2002

The role of pneumolysin in the pathogenesis of Streptococcus pneumoniae infection.

In addition to being cytotoxic for eukaryotic cells, recent research has clearly indicated that pneumolysin at sub-cytolytic concentrations potentiates the proinflammatory activities of neutrophils and macrophages. Together these cytotoxic and proinflammatory activities of the toxin are likely to contribute to the virulence of the pneumococcus, particularly in facilitating adherence, invasion and dissemination of this important microbial pathogen. Pneumolysin-based vaccine strategies, although in the early stages of development and evaluation, show promise in reducing the severity of pneumococcal disease.

Antibodies, Bacterial↗

PubMed2002

Prevalence of anti-mycolic acid antibodies in patients with pulmonary tuberculosis co-infected with HIV.

Isolation and purification of mycolic acids from Mycobacterium tuberculosis have allowed them to be applied as antigen in an ELISA-based assay to detect specific antibodies in human sera. Tuberculosis patients have previously been shown to contain antimycolic acids antibodies. The aim of this study was to determine whether human immunodeficiency virus (HIV) co-infection increases false-negative testing rate and whether other random diseases for which hospitalisation is normally required will contribute to false-positive results. Sera from 118 human subjects were tested for the presence of antibodies to mycolic acids; 59 were patients with proven pulmonary tuberculosis and 59 were control hospitalised patients without evidence of tuberculosis. Each group consisted of HIV-seropositive and HIV-seronegative subjects. The endpoint was the detection of specific antibodies to mycolic acids in the sera, before and after precipitation of immune complexes. The two groups of subjects were well matched for age, gender, race and HIV status. On average, humans infected with Mycobacterium tuberculosis showed a specific antibody response to mycolic acids that was not affected by low CD4 T-lymphocyte counts in HIV-seropositive patients but was compromised by various other serious diseases.

Adolescent↗