Impact of treating Staphylococcus aureus nasal carriers on wound infections in cardiac surgery.

Staphylococcus aureus is a common cause of postoperative wound infections, and nasal colonization by this organism is an important factor in the development of infections. Treatment with mupirocin can eradicate the organism in the short term, and prophylactic treatment of colonized patients may prevent postoperative S. aureus infections. A double-blind, randomized, placebo-controlled trial was performed to determine whether nasal mupirocin administered pre-operatively to S. aureus carriers reduces the rates of sternal and leg wound infections after cardiac surgery. The study enrolled 263 patients with nasal S. aureus undergoing elective cardiac surgery at St. Michael's Hospital, Toronto, Canada. Patients were assessed for infections in the immediate postoperative period and two months later. Two hundred and fifty-seven patients were included in the intention-to-treat analysis and re-analysed according to the actual treatment applied. Wound infections occurred in 17 (13.5%) mupirocin recipients and 11 (9.1%) placebo recipients (P=0.319), with seven (5.4%) and six (4.7%) sternal infections, respectively. Two (1.6%) wound infections were acquired postoperatively in the mupirocin group, neither of which were caused by S. aureus. The placebo group had three (2.4%) nosocomial wound infections, with two (1.6%) S. aureus bacteraemias (P=0.243). Among patients receiving mupirocin, 106 (81.5%) cleared S. aureus compared with 59 (46.5%) patients receiving placebo (P<0.0001). There was no significant difference between intention-to-treat and actual treatment groups. Prophylactic intranasal mupirocin administered to S. aureus carriers did not reduce the rates of overall surgical site infections by S. aureus, and only showed a trend towards decreased incidence of nosocomial S. aureus infections.

Transfusion-transmitted babesiosis in Ontario: first reported case in Canada.

Babesiosis has only recently been reported in Canada, but a number of transfusion-transmitted cases of this infection have been reported from the United States. We present a case of transfusion-transmitted babesiosis that occurred in Canada. Canadian physicians must consider babesiosis in the differential diagnosis of patients who experience fever or a hemolytic reaction after blood transfusion. Prompt recognition and treatment are important, because Babesia infections can be severe or fatal in certain risk groups. Better strategies to prevent transfusion-transmitted babesiosis are required.

Emerging relations between infectious diseases and coronary artery disease and atherosclerosis.

Cardiovascular disease is the leading cause of death in developed countries. The cause is multifactorial. A substantial proportion of patients with coronary artery disease (CAD) do not have traditional risk factors. Infectious diseases may play a role in these cases, or they may intensify the effect of other risk factors. The association of CAD and Chlamydia pneumoniae infection is firmly established, but causality is yet to be proven. The link with other infectious agents or conditions, such as cytomegalovirus, herpes simplex virus, Helicobacter pylori and periodontitis, is more controversial. Cytomegalovirus infection is more strongly linked than native CAD to coronary artery restenosis after angioplasty and to accelerated CAD after cardiac transplantation. However, new data on this topic are appearing in the literature almost every month. The potential for novel therapeutic management of cardiovascular disease and stroke is great if infection is proven to cause or accelerate CAD or atherosclerosis. However, physicians should not "jump the gun" and start using antibiotic therapy prematurely for CAD. The results of large randomized clinical trials in progress will help establish causality and the benefits of antimicrobial therapy in CAD.

Antibiotics effects in a rabbit model of Chlamydia pneumoniae-induced atherosclerosis.

The association of Chlamydia pneumoniae infection with the complications of atherosclerosis, cardiovascular disease, and stroke are well established. C. pneumoniae infection of New Zealand White rabbit respiratory tract can result in early changes of atherosclerosis of the aorta that are not produced by sham infection or by Mycoplasma pneumoniae (which result in similar lung pathology). Early institution of antimicrobials with antichlamydial activity (azithromycin, clarithromycin, moxifloxacin, and doxycycline) within 5 days of infection can largely prevent the aortic lesions (75%-85% efficacy). Early treatment is also effective in suppressing the IgG antibody response to C. pneumoniae. However, delayed treatment (6 weeks after infection) with azithromycin was ineffective in aborting vascular changes but clarithromycin was partially effective (62.5% reduction). These studies support but do not prove that C. pneumoniae can cause atherosclerosis. Antibiotics are potentially useful in this model, but the optimum dose and duration of therapy or use of combination of agents remain to be determined.

Value of long-term administration of acyclovir and similar agents for protecting against AIDS-related lymphoma: case-control and historical cohort studies.

Acyclovir or similar agents with activity against Epstein-Barr virus (EBV) theoretically may prevent non-Hodgkin's lymphoma (NHL) in AIDS. A case-control study of 29 patients with AIDS-related NHL and 58 matched control subjects assessed the frequency with which daily acyclovir (>/=800 mg/d) or similar agents were used for > or =1 year. In a historical cohort of 304 patients with AIDS for > or =2 years, the prevalence of NHL was assessed among 3 groups of patients: those who received long-term treatment with high-dose acyclovir (or similar agents) or low-dose or intermittent acyclovir; those treated with ganciclovir/foscarnet for <1 year; and those who had not previously been treated with acyclovir, ganciclovir, or foscarnet. In the case-control study, 22 patients (72.4%) with NHL never received acyclovir or similar drugs versus 19 control subjects (32.8%; P=. 002); 2 patients (6.9%) with NHL received acyclovir (> or =800 mg/d) for > or =1 year versus 27 (46.6%) of control subjects (P=.0001). In the cohort study, 6 (6.8%) of 88 patients who received acyclovir (> or =800 mg/d) for > or =1 year developed NHL versus 15 (15.5%) of 97 patients who received intermittent or lower-dose acyclovir and 30 (25.2%) of 119 patients who never received these agents (P=.002). Long-term administration (>1 year) of high-dose acyclovir or similar agents with anti-EBV activity may prevent NHL in patients with AIDS. A prospective, randomized study is warranted to confirm these results.

Can an antibiotic (macrolide) prevent Chlamydia pneumoniae-induced atherosclerosis in a rabbit model?

There is increasing data implicating Chlamydia pneumoniae in the pathogenesis of atherosclerosis, and antibiotics may theoretically be useful to prevent secondary vascular complications. Three groups of New Zealand White specific-pathogen-free rabbits, fed cholesterol-free chow, were inoculated via the nasopharynx on three occasions, 2 weeks apart, with C. pneumoniae. Group I (n = 23) rabbits were untreated; group II (n = 24) rabbits were treated with azithromycin at 30 mg/kg of body weight daily for 3 days and then once every 6 days, starting 5 days after first inoculation and continuing until sacrifice (early treatment); and group III (n = 24) rabbits were treated with the same dose of azithromycin but initiated 2 weeks after the last inoculation. All animals were sacrificed at 10 to 11 weeks after initial inoculation and examined for signs of atherosclerosis of the aorta. Eight (34.8%) untreated rabbits developed early signs of atherosclerosis, whereas only one (4.2%) in the early-treatment group had such signs (P = 0.02). However, eight rabbits (33.3%) of the delayed-treatment group had atherosclerotic changes of the aorta and no significant reduction compared to untreated rabbits. Early treatment of C. pneumoniae-infected rabbits with azithromycin was highly effective (87%) in preventing atherosclerotic changes, but delayed treatment was ineffective. It is possible that longer or more aggressive antibiotic treatment may be needed to reverse preformed lesions or that antibiotics may not be of value once lesions have formed.

De Novo induction of atherosclerosis by Chlamydia pneumoniae in a rabbit model.

Chlamydia pneumoniae, a bacterial respiratory tract pathogen, has been associated with atherosclerosis in humans. C. pneumoniae infection of the respiratory tracts of rabbits fed a noncholesterol diet induced changes of atherosclerosis of the aorta in 6 (26.1%) of 23 animals after a single inoculum at 3 months. Multiple inocula given three times within 6 weeks resulted in grade III atherosclerosis in 8 (34.8%) of 23 rabbits, with an additional 5 (21. 7%) showing increased myxoid changes in the intima-media junction and exhibiting 8 (34.8%) focal periaortitis. Control animals inoculated with carrier broth (n = 24), HEp-2 cells (n = 12), or another respiratory pathogen, Mycoplasma pneumoniae (n = 32), produced no changes of atherosclerosis after 3 months. The histological changes were dissimilar (fewer foam cells) from those of rabbits fed a 0.5% cholesterol diet but were highly similar to or indistinguishable from changes in rabbits fed a 0.15% cholesterol diet (similar to that of humans). Proinflammatory cytokines and tissue growth factors were more consistently detected in cholesterol-induced aortic lesions than those induced by C. pneumoniae. These data are compatible with de novo induction of atherogenesis by C. pneumoniae in rabbits and suggest that C. pneumoniae may be important in the pathogenesis of atherosclerosis in humans.

Value of animal models for Chlamydia pneumoniae-related atherosclerosis.

Chlamydia pneumoniae is strongly implicated in the pathogenesis of atherosclerosis in human beings. Animal models are important to help establish causality, to understand the mechanism of infection induced atherogenesis, to examine interaction of other factors or variables, to explore treatment regimens and their efficacy, and to help develop a vaccine for prevention. To date, the rabbit model is the only animal model shown to develop de novo atherosclerotic changes with C pneumoniae infection. However, the mouse model may be useful to show enhancement with other factors such as hypercholesterolemia and to explore pathogenic mechanisms. In our studies, we have shown that C pneumoniae respiratory infection in the rabbit results in early atherosclerotic changes in 26% with single inoculation and in 35% after triple inoculation, but sham infection or infection with Mycoplasma pneumoniae does not result in similar changes. Early treatment (5 days after inoculation) with 30 mg/kg per day azithromycin once every 6 days was 87% effective in preventing atherosclerotic changes, but delayed treatment (6 weeks after inoculation) was ineffective. Further studies are needed with longer or more aggressive regimens or possible combination of agents to determine whether it is possible to reverse preformed lesions. An effective vaccine for prevention of C pneumoniae -induced pneumonia and possibly atherosclerotic lesions in human beings would have tremendous application and would circumvent the shortcomings of antibiotic therapy.

In vivo cytokine and neuroendocrine responses to endotoxin in human immunodeficiency virus-infected subjects.

The cytokine and neuroendocrine host responses to experimental challenge with lipopolysaccharide (LPS) were studied in human immunodeficiency virus (HIV)-infected subjects and uninfected control subjects. Elevations in circulating concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 were significantly greater in HIV-infected subjects than control subjects after LPS challenge. All subjects showed a significant increase in circulating concentrations of adrenocorticotropin, cortisol, and norepinephrine after LPS challenge, but there was not a significant difference between the responses of these hormones in the HIV-infected and -uninfected subjects. Compared with the control subjects, the HIV-infected subjects had a significantly reduced IL-10 response and a reduced IL-1 receptor antagonist response. It is concluded that the TNF-alpha, IL-6, IL-8, and IL-10 cytokine responses to LPS in vivo are disrupted in HIV subjects but that this is not related to disruption of the hypothalamo-pituitary-adrenal axis.

Does in vitro susceptibility to rifabutin and ethambutol predict the response to treatment of Mycobacterium avium complex bacteremia with rifabutin, ethambutol, and clarithromycin? Canadian HIV Trials Network Protocol 010 Study Group.

The in vitro susceptibilities of baseline Mycobacterium avium complex (MAC) blood isolates from 86 patients with AIDS who were treated with clarithromycin, ethambutol, and rifabutin were determined to examine whether these results predict bacteriologic response to treatment. No patient received prior prophylaxis with clarithromycin or azithromycin. Minimum inhibitory concentrations (MICs) of clarithromycin for all isolates were < or = 2 micrograms/mL. The median MIC of rifabutin was between 0.25 and 0.5 microgram/mL, and all isolates were susceptible to < or = 2 micrograms of rifabutin/mL. The median MIC of ethambutol was 4 micrograms/mL, and the MIC90 was 8 micrograms/mL. There was no correlation between ethambutol susceptibility and subsequent bacteriologic clearance. At all time points through week 12, bacteriologic clearance occurred more frequently in patients with isolates for which MICs of rifabutin were lower, but this difference was statistically significant only at week 2. Susceptibility testing for baseline MAC isolates from AIDS patients not previously treated with clarithromycin or azithromycin does not appear to be useful in guiding therapy.

Integrative aspects of a human model of endotoxemia.

The production of tumor necrosis factor (TNF)-alpha is a key step in the response to sepsis and has powerful local and systemic effects on the host. These systemic responses include a complex cascade of centrally mediated endocrine and neural responses. An integrative model of these regulatory cytokine-neuroendocrine interactions in humans is presented. The rapid kinetics of these responses are illustrated by data showing the response of normal human subjects to experimental endotoxemia. Appreciation of the integrative biology of the in vivo response to experimental endotoxemia can provide a framework for the design of experiments aimed at examining the effects of physical training paradigms on particular cytokine and neuroendocrine pathways.

Active immunization of patients with HIV infection: a study of the effect of VaxSyn, a recombinant HIV envelope subunit vaccine, on progression of immunodeficiency.

Infection with the human immunodeficiency virus (HIV) leads to a progressive immunodeficiency characterized by decreasing levels of CD4+ T lymphocytes. VaxSyn, a vaccine based on the recombinant envelope glycoprotein subunit (rgp160) of HIV-1IIIB, was used to immunize HIV-infected patients to determine whether its administration was beneficial with respect to slowing disease progression. A 3-year multicenter, randomized, placebo-controlled, double-blinded, efficacy and safety trial of repeated immunization with VaxSyn was used to evaluate the long-term impact on the progression of immunodeficiency. VaxSyn in alum, or alum alone, was given to 278 HIV-infected asymptomatic individuals with initial CD4 counts of > or =500 cells/mm3. Clinical findings, the CD4 count, and both virological and immunological parameters were followed. No significant differences were observed between the treatment and placebo control groups in rate of CD4 T cell decline, time to initiation of antiretroviral therapy, incidence of opportunistic infections, HIV RNA plasma viremia, HIV viral infectivity as measured by quantitative HIV coculture assay, and death. This study revealed no effect on either clinical or laboratory virological parameters from the administration of VaxSyn.

Chlamydia pneumoniae, cytomegalovirus, and herpes simplex virus in atherosclerosis of the carotid artery.

BACKGROUND: Chlamydia pneumoniae and the herpes viruses cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) have been associated with human atherosclerosis in seroepidemiological and separate histopathological studies. We investigated the concurrent presence of these microorganisms in patients undergoing carotid endarterectomy. METHODS AND RESULTS: Endarterectomy specimens from 76 patients with carotid artery stenosis were stained for C. pneumoniae, CMV, and HSV-1 particles with specific IgG monoclonal antibodies by the avidin-biotin-peroxidase method. IgG antibodies to CMV and C. pneumoniae were also measured in the serum. These were correlated with plaque morphology and the presence of the microorganisms in the atherosclerotic plaques. C. pneumoniae was detected in 54 (71%) (95% confidence interval [CI], 59.5% to 80.9%), CMV was detected in 27 (35.5%) (CI, 24.9% to 47.3%), and HSV-1 was detected in 8 (10.5%) (CI, 4.7% to 19.7%) versus none of 20 (0%) control normal carotid artery and aortic tissue (autopsy) specimens (CI, 0% to 16.8%) (P<.001 for CMV and C. pneumoniae). At least one microorganism was detected in 59 of the specimens (77.6%) (CI, 66.6% to 86.4%), with a single microorganism present only in 35 (46%), two microorganisms present in 18 (23.7%) (CI, 14.7% to 34.8%), and all three present in 6 (7.9%) (CI, 3.0% to 16.4%). Atherosclerotic plaques with thrombosis were more likely to have C. pneumoniae (80.4%) or CMV (57.8%) than were plaques without thrombosis (56.7% and 16.7%, respectively; P=.04 and .007). There was no correlation between the presence of CMV and C. pneumoniae in the atherosclerotic vessels and serum antibody titers. CONCLUSIONS: C. pneumoniae and CMV are commonly detected in atherosclerotic plaques of the carotid arteries, but their presence cannot be predicted by measuring serum antibodies. The presence of these microorganisms may predispose to a greater risk of thrombosis in the plaques, but further studies are needed to confirm this observation.

The efficacy of exit site povidone-iodine ointment in the prevention of early peritoneal dialysis-related infections.

Infections are the main complications of peritoneal dialysis, and currently there is no established method for prevention. A prospective, randomized, single-blind study was performed to evaluate the efficacy of regular application of povidone-iodine ointment at the catheter site (during the entire time on the study) in peritoneal dialysis. One hundred twenty patients were randomized; three were excluded for not completing the study. Sixty-one patients received application of povidone-iodine and 56 patients received standard care. Povidone-iodine ointment was effective in delaying infectious complications, with a lower proportion of treated patients having infections (exit site and peritonitis) within 140 days of starting dialysis compared with the controls (P = 0.04, Wilcoxon test). This protective benefit was lost after 140 days on dialysis. Staphylococcus aureus infections developed in only two (3.3%) of the treated patients compared with 10 (21.4%) of the controls (P = 0.009), despite the higher rate of S aureus nasal carriage in the treated group (22 of 61 patients [36%] v 14 of 56 patients [25%]).

Asymptomatic oral carriage of Candida albicans in patients with HIV infection.

OBJECTIVE: To assess the relationship of asymptomatic carriage of Candida albicans and clinically apparent thrush in patients with HIV infection. DESIGN: Prospective, longitudinal, controlled study. SETTING: The HIV clinic at St. Michael's Hospital, University of Toronto. PARTICIPANTS: One hundred and twenty-seven patients with HIV-infection were divided into 3 groups according to the CD4+ lymphocyte count, and 37 healthy volunteers served as controls. INTERVENTIONS: Determination of blood type, baseline CD4+ lymphocyte count in patients with HIV infection, and immunophenotyping. Samples of saliva (2 mL) were obtained from each patient and control. MAIN OUTCOME MEASURES: Carrier status, clinical presence of thrush, the association between carriage of C. albicans and blood type, secretor status and history of oral infection. RESULTS: In patients with HIV infection and C albicans colonization no correlation was found with blood type or secretor status of blood group antigen in the saliva. The frequency of oral carriage of yeast was greater in patients infected with HIV than in controls, but the difference was not significant for asymptomatic subjects with a CD4+ lymphocyte count greater than 500/microL. Persistent carriage of yeast and development of clinical thrush were associated with lower CD4+ counts. Clinical thrush developed only in patients with persistent asymptomatic carriage of C. albicans and CD4+ counts less than 500/microL. CONCLUSION: The greater risk of oral colonization with C. albicans in patients with HIV infection partly explains the high prevalence of thrush found in this group.

Rabbit model for Chlamydia pneumoniae infection.

A rabbit model was established for Chlamydia pneumoniae infection that may be helpful to understand the pathogenesis of disease in humans. Twelve, pathogen-free, 1-month-old New Zealand White rabbits were inoculated with 1.0 x 10(7) to 5.0 x 10(7) CFU of purified C. pneumoniae (ATCC strain VR 1310) via the nasopharynx (1 rabbit died immediately postinoculation, and 11 were available for study). Five controls were inoculated with the carrier buffer. Ten of the 11 study rabbits demonstrated serological evidence of acute infection (immunoglobulin G antibodies, 1:8 to > 1:16), with the weakest response at 7 days and the strongest response at 28 days, whereas none of the controls showed any seroconversion. Study animals were sacrificed in batches of three, on days 7, 14, 21, and 28, but controls were sacrificed on days 7 and 28. Two-thirds of the animals demonstrated evidence of bronchiolitis and pneumonia on days 7 and 14 and resolution by day 21. Two study rabbits demonstrated, on histology, early and intermediate lesions of atherosclerosis: one animal (day 7) showed the accumulation of foamy macrophages (fatty streak) in the arch of the aorta, and the other animal (day 14) showed spindle cell proliferation of smooth muscle cells (intermediate lesion). Focal periaortitis was seen in the same animal (day 7). C. pneumoniae elementary bodies were demonstrated by immunocytochemical stain in the lungs (n = 2), liver (n = 3), spleen (n = 5), and aorta (n = 2), one of which corresponded to the intermediate lesion. C. pneumoniae was cultured from the lungs (n = 2), liver (n = 2), spleen (n = 2), and aortic arch (n = 1). All histopathological, immunocytochemical, and cultural studies were negative in the controls. Hence, the rabbit provides a useful animal model for the study of C. pneumoniae infection and its complications, particularly atherosclerosis.

The effect of exercise on lymphocyte redistribution and leucocyte function in asymptomatic HIV-infected subjects.

This study was undertaken to examine the responsiveness of circulating leucocyte and lymphocyte populations to the physiological demands of exercise in asymptomatic HIV-infected subjects with CD4+ counts greater than 500/microliter. Thirteen subjects infected with HIV and 14 control subjects underwent 20 min of defined moderate exercise at estimated 65% of their maximal ventilatory capacity on a bicycle ergometer. Blood samples were obtained for serum cortisol, norepinephrine, lymphocyte subsets (CD4, CD8, CD19, CD16-CD56), and phagocytic function at rest immediately after exercise and 20 min following the cessation of the exercise. The HIV-infected subjects had increased circulating concentrations of CD8 cells (p = .007) and CD16-CD56+ NK cells (p = .02) in response to the exercise, whereas the control group did not. There was a greater increase in monocyte respiratory burst activity following recovery from exercise in the control subjects (p = .016) but not in the HIV-infected subjects. The control subjects experienced an increase in serum cortisol in response to the exercise (p = .006), but the HIV-infected subjects did not. Our results show that the changes in the distribution and function of circulating leucocytes and adrenal neuroendocrine responses to moderate exercise differ in asymptomatic HIV-infected and control subjects.

A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group.

BACKGROUND: Bacteremia with the Mycobacterium avium complex is common in patients with the acquired immunodeficiency syndrome (AIDS), but the most effective treatment for this infection remains unclear. METHODS: We randomly assigned 229 patients with AIDS and M. avium complex bacteremia to receive either rifampin (600 mg daily), ethambutol (approximately 15 mg per kilogram of body weight daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily) (the four-drug group) or rifabutin (600 mg daily), ethambutol (as above), and clarithromycin (1000 mg twice daily) (the three-drug group). In the three-drug group the dose of rifabutin was reduced by half after 125 patients were randomized, because 24 of 63 patients had uveitis. RESULTS: Among 187 patients who could be evaluated, blood cultures became negative more often in the three-drug group than in the four-drug group (69 percent vs. 29 percent, P<0.001). Among patients treated for at least four weeks, the bacteremia resolved more frequently in the three-drug group (78 percent vs. 40 percent, P<0.001). In the three-drug group, bacteremia resolved more often with the 600-mg dose of rifabutin than with the 300-mg dose (P=0.025), but the latter regimen was more effective than the four-drug regimen (P<0.05). The median survival was 8.6 months in the three-drug group and 5.2 months in the four-drug group (P = 0.001). The median Karnofsky performance score was higher in the three-drug group than in the four-drug group from week 2 to week 16 (P<0.05). Mild uveitis developed in 3 of the 53 patients receiving the 300-mg dose of rifabutin, an incidence about one quarter that observed with the 600-mg dose (P<0.001). CONCLUSIONS: In patients with AIDS and M. avium complex bacteremia, treatment with the three-drug regimen of rifabutin, ethambutol, and clarithromycin leads to resolution of the bacteremia more frequently and more rapidly than treatment with rifampin, ethambutol, clofazimine, and ciprofloxacin, and survival rates are better.