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Background: Patients with drug-resistant HIV often require complex antiretroviral regimens. However, combining fixed-dose combination tablets such as tenofovir-disoproxil-fumarate, emtricitabine, and cobicistat-boosted elvitegravir (TDF/FTC/EVG/cobi) with darunavir (DRV) can provide a simple, once-daily (QD), 2-tablet regimen for patients with drug-resistant HIV. Primary objective was to determine the percentage of patients with HIV-1 RNA <40 copies/mL at 48 weeks., Methods: We performed a retrospective chart review of patients initiated on TDF/FTC/EVG/cobi plus DRV., Results: Among the 21 included patients, prior resistance showed a median of 2 nucleoside reverse transcriptase inhibitor mutations, 1 nonnucleoside reverse transcriptase mutation, and 1 protease inhibitor mutation. At week 48, 14 (67%) patients achieved HIV-1 RNA <40 copies/mL, 1 patient experienced viral rebound, and 6 (29%) had missing data or discontinued therapy. No patient discontinued for adverse events., Conclusion: According to this observational study, QD TDF/FTC/EVG/cobi plus DRV is considered safe, well tolerated, and generally effective in suppressing HIV drug-resistant virus.

Infections have been recognized as significant causes of cardiac diseases for many decades. Various microorganisms have been implicated in the etiology of these diseases involving all classes of microbial agents. All components of the heart structure can be affected by infectious agents, i.e. pericardium, myocardium, endocardium, valves, autonomic nervous system, and some evidence of coronary arteries. A new breed of infections have evolved over the past three decades involving cardiac implants and this group of cardiac infectious complications will likely continue to increase in the future, as more mechanical devices are implanted in the growing ageing population. This article will review the progress made in the past decade on understanding the pathobiology of these infectious complications of the heart, through advances in genomics and proteomics, as well as potential novel approach for therapy.An up-to-date, state-of-the-art review and controversies will be outlined for the following conditions: (i) perimyocarditis; (ii) infective endocarditis; (iii) cardiac device infections; (iv) coronary artery disease and potential role of infections.

We report the first case of human infection with the fungal plant pathogen Macrophomina phaseolina in a Sri Lankan-born Canadian man following a renal transplant in India. The patient subsequently succumbed to invasive infection with Scytalidium dimidiatum. Molecular sequence analysis confirmed the identification of both fungi and revealed that they are related species within the ascomycete family Botryosphaeriaceae. We review the rationale for the recent reclassification of S. dimidiatum as Neoscytalidium dimidiatum and of Nattrassia mangiferae (formerly considered a synanamorph of S. dimidiatum) as Neofusicoccum mangiferae. This and other recent cases illustrate the potential for plant pathogenic fungi to cause invasive human diseases which are refractory to antifungal therapy.

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.

Botulism is a rare paralytic illness resulting from a potent neurotoxin produced by Clostridium botulinum. Botulism in Canada is predominately due to C botulinum type E and affects mainly the First Nations and Inuit populations. The most recent outbreak of botulism in Ontario was in Ottawa in 1991 and was caused by C botulinum type A. We report an outbreak of foodborne type B botulism in Ontario, which implicated home-canned tomatoes. The outbreak was characterized by mild symptoms in two cases and moderately severe illness in one case. The investigation shows the importance of considering the diagnosis of botulism in patients presenting with cranial nerve and autonomic dysfunction, especially when combined with gastrointestinal complaints; it also highlights the importance of proper home canning technique.

A study was performed to determine whether serum antibody to Chlamydial heat-shock protein-60 (CHSP-60) and C-reactive protein (CRP) were associated with the presence of Chlamydia pneumoniae in atheromatous plaques in 75 patients. The mean (+/-SD) ELISA optical density (OD) of anti-CHSP-60 was 0.19+/-0.15 in 54 patients with detectable C. pneumoniae antigen, versus an OD of 0.11+/-0.08 in 21 patients without detectable C. pneumoniae I antigen (P=.008). Higher anti-CHSP-60 at an OD > or =0.12 was present in 38 (70.4%) of patients with detectable C. pneumoniae in atheromas, compared with 5 (23.8%) of patients without C. pneumoniae antigen (P<.001; 2-tailed test). The mean CRP concentration was 7.4+/-10.3 mg/L in patients with detectable C. pneumoniae antigen, versus 5.7+/-6.1 mg/L in those without (P=.556). Immune response to CHSP-60 may play a role in atherogenesis, but CRP serum levels does not appear to be related to C. pneumoniae infection.

Background: Highly active antiretroviral therapy (HAART) is associated with improvement or resolution of several HIV-associated opportunistic infections. Although prophylaxis against disseminated Mycobacterium avium complex infection may be successfully discontinued after a favorable response to HAART, the 1999 guidelines from the U.S. Public Health Service/Infectious Diseases Society of America recommend continuing therapy for disseminated M. avium complex infection, regardless of the response to HAART., Objective: To examine the outcome among patients with disseminated M. avium complex infection whose antimycobacterial therapy was discontinued after a favorable response to HAART., Design: Retrospective chart review between May 2000 and May 2001., Setting: 13 Canadian HIV clinics., Patients: 52 HIV-infected adults (43 men; mean age, 37.3 years) in whom successful antimycobacterial therapy for disseminated M. avium complex infection was discontinued after a favorable virologic response to HAART., Measurements: Survival, survival free of disseminated M. avium complex infection, and CD4(+) cell count responses., Results: At the time of diagnosis of disseminated M. avium complex infection, the median CD4(+) cell count was 0.016 x 10(9) cells/L, and the median plasma HIV RNA level was 90 000 copies/mL (plasma HIV RNA levels were available for only 21 patients). The patients received a median of 32 months of antimycobacterial therapy that included ethambutol plus either clarithromycin or azithromycin. When antimycobacterial therapy was discontinued, the median CD4(+) cell count was 0.23 x 10(9) cells/L and the median plasma HIV RNA level was less than 50 copies/mL. A median of 20 months after discontinuation of antimycobacterial therapy, only 1 patient had developed recurrent M. avium complex disease (37 months after stopping antimycobacterial therapy). This patient had stopped HAART 2 months earlier because of uncontrolled HIV viremia. Twenty months after stopping antimycobacterial therapy, the other 51 patients had a median CD4(+) cell count of 0.288 x 10(9) cells/L; 34 (67%) had undetectable plasma HIV RNA levels, and 8 (15%) had plasma HIV RNA levels of 50 to 1000 copies/mL., Conclusions: Discontinuation of successful disseminated M. avium complex therapy after a successful response to HAART is safe and reduces patients' pill burdens, potential drug adverse effects, drug interactions, and costs of therapy.

Chlamydia pneumoniae may play a role in atherogenesis and vascular diseases, and antibiotics may prove useful in these conditions. Three groups of New Zealand White rabbits (24 per group) were infected via the nasopharynx with C. pneumoniae on three separate occasions (2 weeks apart). Group I was untreated and sacrificed at 12 weeks; group II received clarithromycin at 20 mg/kg/day for 8 days, beginning 5 days after each inoculation (early treatment); and group III received a similar dose of clarithromycin starting 2 weeks after the third inoculation and continued for 6 weeks thereafter (delayed treatment). To test for a possible anti-inflammatory effect of clarithromycin, two other groups of uninfected rabbits (12 animals in each) were fed 0.5% cholesterol-enriched chow, and one of these groups was treated with clarithromycin at 30 mg/kg/day for 6 weeks. Of 23 untreated infected rabbits, 8 developed early lesions of atherosclerosis, whereas 2 of the 24 early-treated group II had similar changes (P = 0.036 [75% efficacy]). However, in the delayed-treatment group, group III, 3 of 24 rabbits developed early lesions of atherosclerosis, thus demonstrating 62.5% reduction compared to the untreated controls (P = 0.07 [trend to statistical significance]). C. pneumoniae antigen was detected in 8 of 23 group I (untreated) rabbits versus 1 of 24 of the early-treated (group II) rabbits and 4 of 24 animals in the delayed group III (P = 0.009 and 0.138, respectively). All of the untreated, cholesterol-fed rabbits had moderate to advanced atherosclerosis (grade III or IV); clarithromycin had no effect on reducing the prevalence of but did reduce the extent of atherosclerosis in the cholesterol-fed rabbits by 17% compared to untreated controls. Thus, clarithromycin administration modified C. pneumoniae-induced atherosclerotic lesions and reduced the ability to detect organism in tissue. Early treatment was more effective than delayed treatment.

Background: Complications of atherosclerosis are the leading cause of mortality in developed countries, and infections may play a role in the pathogenesis. Numerous studies have addressed this issue in the past decade., Types of Studies Reviewed: The author examined peer-reviewed studies and reviews on the role of microbes or infections in atherosclerosis, cardiovascular disease and cerebrovascular disease. He included selected articles on epidemiology, pathology, in vitro experiments, animal models and clinical studies., Results: Cross-sectional and retrospective studies have shown an association between Chlamydia pneumoniae antibodies and cardiovascular disease, but prospective studies have not been as convincing. Studies on the association between cardiovascular disease and periodontal disease or loss of teeth have produced conflicting results. Cytomegalovirus infection is associated mainly with accelerated arteriosclerosis after cardiac transplantation. Infectious agents can induce biological mechanisms important for atherogenesis. Mice and rabbit studies have indicated that C. pneumoniae is capable of initiating or accelerating the progression of atherosclerosis. Limited studies on cytomegalovirus also suggest the ability to induce early changes of atherosclerosis in a rodent model. Preliminary clinical trials of treatment for C. pneumoniae infection suggest a possible short-term benefit, but larger randomized trials for longer periods are in progress., Conclusion and Clinical Implications: Infectious agents may play an important role in atherogenesis, but currently the jury is not in. Further management of cardiovascular disease could change radically if this concept were proven.

Smooth muscle cell (SMC) proliferation and intimal thickening are hallmark features of atherosclerotic disease, and Chlamydia pneumoniae may contribute to atherogenesis by imparting biological effects on SMCs. An in vitro endothelial cell model and a normocholesterolemic rabbit model were used to test the hypothesis that infection with C. pneumoniae induces SMC growth factor production, SMC proliferation, and aortic intimal thickening. Using reverse-transcriptase polymerase chain reaction, it was demonstrated that C. pneumoniae infection of endothelial cells induced platelet-derived growth factor (PDGF)-B messenger RNA expression. In C. pneumoniae-infected rabbits, maximum intimal thickness (MIT) was significantly greater than that in uninfected animals (P< .0001). MIT correlated with the presence of C. pneumoniae antigen (P= .043) and PDGF-B (P= .002) in aortic tissues, and C. pneumoniae antigen was independently correlated with the presence of PDGF-B in aortic tissues (P= .009). These results suggest that C. pneumoniae-induced SMC proliferation and intimal thickening may be mediated through PDGF-B and may be a molecular mechanism by which C. pneumoniae infection could contribute to atherogenesis.

Chlamydia pneumoniae, a respiratory pathogen, has been suggested as a risk factor for cardiovascular disease. Epidemiologic data are very controversial. Histopathologic and microbiologic studies have established an association between atherosclerosis and presence of C. pneumoniae, consistently finding C. pneumoniae DNA and antigens in atherosclerotic arteries. C. pneumoniae has been cultured from atherosclerotic arteries in several centers. An etiologic role for C. pneumoniae in initiation, acceleration of atherosclerosis, and/or acute ischemia remains debatable. In vitro studies have shown that C. pneumoniae can induce foam cell formation, low-density lipoprotein oxidation, and proinflammatory and procoagulant cytokine expression. Animal models of de novo initiation or enhancement of atherosclerosis have been developed. Preliminary trials of secondary prevention of coronary artery disease complications by antimicrobial agents show modest results. Better diagnostic tools, more diverse animal models, and clinical trials of primary prevention are needed. Meanwhile, results of ongoing large clinical trials on secondary prevention are eagerly awaited, but may not be definitive.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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%]).

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.

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.

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.

Vulvovaginal candidiasis (VVC) is a frequent cause of morbidity in women of reproductive age. Most women will experience 1 or 2 episodes in their lifetime, but a smaller population develop chronic recurrent disease. There are few data on cost or pharmacoeconomic considerations in the management of this condition. The disease does not usually result in long term disability, loss of employment or death, but could affect a woman's work performance through irritability, frustration and unhappiness. This review attempts to estimate the least costly programme or regimen (as the efficacy of different regimens is similar) that would be applicable to patients, third-party payers and society. Nonprescription or over-the-counter (OTC) antifungal preparations could have an impact on overall cost in the management of VVC. In the management of infrequent acute VVC, an OTC preparation would be least costly to the healthcare system (provided that the diagnosis was correct). The strategies used to control symptoms in patients with chronic recurrent VVC should be based on the frequency of recurrent episodes. For patients with less than 12 episodes a year, empirical self-treatment at the onset of symptoms with an OTC agent (e.g. intravaginal clotrimazole 500mg) is less costly and preferable to patients than monthly prophylaxis. Patients with a greater frequency of recurrences may benefit from monthly, daily or twice weekly prophylaxis. At present, for very frequent recurrences, intravaginal clotrimazole 200mg twice weekly appears to be as effective as daily oral ketoconazole, and may be safer and less costly. However, because of the lack of prospective controlled studies, most of these recommendations are based on hypothetical reasonings. Furthermore, the disadvantages of OTC antifungals include the potential for overuse and inappropriate use, possibly resulting in the delayed diagnosis and treatment of other conditions. On balance, OTC preparations may provide patients with faster and more economical care, and improve healthcare delivery.

The efficacy of single amphotericin B bladder washout was assessed, and the source of infection was sought, in 47 patients with 62 separate episodes of candiduria. After a single bladder washout, 44 of 62 (71%) candiduria episodes cleared and none of these patients had evidence of invasive disease or kidney infection. Ten (56%) of 18 patients with persistent candiduria had no evidence of invasive disease or kidney infection at autopsy or clinically. The sensitivity of a positive urine culture for Candida spp. after a single amphotericin B bladder washout in predicting kidney infection or invasive candidiasis was 100% (CI = 63-100%); but the specificity was only 81% (CI = 47-100%) and the positive predictive value only 44%.

Absorption of ketoconazole is impaired in patients with achlorhydria. The purpose of this study was to determine the effectiveness of a palatable acidic beverage (Coca-Cola Classic, pH 2.5) in improving the absorption of ketoconazole in the presence of drug-induced achlorhydria. A prospective, randomized, three-way crossover design with a 1-week wash-out period between each treatment was employed. Nine healthy nonsmoking, nonobese volunteers between 22 and 41 years old were studied. Each subject was randomized to receive three treatments: (A) ketoconazole 200-mg tablet with water (control), (B) omeprazole (60 mg) followed by ketoconazole (200 mg) taken with water, and (C) omeprazole (60 mg) followed by ketoconazole (200 mg) taken with 240 ml of Coca-Cola Classic. The pH values of gastric aspirates were checked after omeprazole was administered to confirm attainment of a pH of > 6. Multiple serum samples were obtained for measurements of ketoconazole concentrations by high-pressure liquid chromatography. The mean area under the ketoconazole concentration-time curve from zero to infinity for the control treatment (17.9 +/- 13.1 mg.h/liter) was significantly greater than that for treatment B (3.5 +/- 5.1 mg.h/liter; 16.6% +/- 15.0% of control). The mean peak concentration was highest for the control treatment (4.1 +/- 1.9 micrograms/ml), for which the mean peak concentration showed a significant increase over that for treatment B. The absorption of ketoconazole was reduced in the presence of omeprazole-induced achlorhydria. However, drug absorption was significantly increased, to approximately 65% of the mean for the control treatment, when the drug was taken with an acidic beverage, such as Coca-Cola.

Progressive multifocal leukoencephalopathy (PML) is usually a fatal neurological disease. The natural history of PML in patients with human immunodeficiency virus infection was analyzed. The correlations between CD4+ lymphocyte count, previous diagnosis of AIDS, treatment with cytarabine, and survival time are reported for 28 individuals for whom the diagnosis of PML was confirmed by histopathologic examination. For 16 patients (57%), PML was the AIDS-defining illness. For these 16 patients, the mean (+/- SD) survival time after presentation was 7.5 +/- 7.6 months (range, 1-31 months), whereas that for the 12 patients (43%) for whom AIDS was previously diagnosed was 3.2 +/- 2.8 months (range, 1-11 months) (P = .01). The overall mean (+/- SD) CD4+ cell count was 85 +/- 82/mm3 (range, 12-349/mm3). The mean (+/- SD) survival time for patients with CD4+ cell counts of > or = 90/mm3 at the time of presentation was 9.4 +/- 8.7 months, while that for patients with CD4+ cell counts of < 90/mm3 at the time of presentation was 3.6 +/- 1.8 months (P = .03). The nine patients did not benefit from treatment with cytarabine.

A randomized study was done to compare the efficacy of clarithromycin 250 mg or 500 mg b.i.d., vs. cefaclor 250 mg or 500 mg t.i.d. for 7-14 d in 197 evaluable patients with lower respiratory tract infection. Ninety-five patients received clarithromycin, 88 with acute bronchitis or exacerbation of chronic bronchitis, and 7 with pneumonia. One hundred and two patients received cefaclor, 86 with bronchitis and 16 with pneumonia. Ten patients (10.5%) in the clarithromycin group did not complete the trial, 5 (5.3%) because of adverse event, and 3 (3.2%) because of clinical failure. Similarly, 11 patients (10.8%) did not complete cefaclor, 2 (2%) because of adverse event, and 7 (6.9%) because of clinical failure. Clinical cure or improvement was observed in 90 (94.7%) of patients on clarithromycin vs. 92 (90.2%) on cefaclor, p = 0.66. Bacteriologic cure was seen in 26/36 patients (72.2%) on clarithromycin vs. 28/40 patients (70%) on cefaclor, p = 0.28. Clarithromycin is just as effective as cefaclor for lower respiratory tract infections and is well tolerated.

JC virus DNA was detected by PCR in the cerebrospinal fluid of 17 of 23 (73.9%) patients with confirmed cases of progressive multifocal leukoencephalopathy and 2 of 48 (4.2%) controls without progressive multifocal leukoencephalopathy. The sensitivity and specificity of this PCR were 74 and 95.8%, respectively, while the positive and negative predictive values were 89.5 and 88.5%, respectively.

Current dosage regimens of trimethoprim-sulfamethoxazole used to treat Pneumocystis carinii pneumonia in AIDS patients have been based on data from healthy subjects or patients without AIDS. The clearance and absorption characteristics of the drugs may potentially be different between patients with and without AIDS. This study was conducted to assess the pharmacokinetics of trimethoprim-sulfamethoxazole in critically ill and non-critically ill AIDS patients treated for P. carinii pneumonia. Patients received trimethoprim at 15 mg/kg of body weight and sulfamethoxazole at 75 mg/kg of body weight daily intravenously in three to four divided doses and were switched to the oral route when the regimen was tolerated. Serum samples for determination of drug concentrations were obtained over 12 h after intravenous and oral dosing. The pharmacokinetics of trimethoprim and sulfamethoxazole were compared in eight critically ill versus nine non-critically ill male patients and were as follows, respectively: clearance, 1.88 +/- 0.44 versus 1.73 +/- 0.64 ml/min/kg for trimethoprim and 0.40 +/- 0.12 versus 0.34 +/- 0.11 ml/min/kg for sulfamethoxazole; volume of distribution, 1.6 +/- 0.5 versus 1.5 +/- 0.5 liters/kg for trimethoprim and 0.5 +/- 0.3 versus 0.4 +/- 0.1 liters/kg for sulfamethoxazole; and half-life, 10.9 +/- 7.4 versus 11.3 +/- 4.0 h for trimethoprim, and 15.5 +/- 9.5 versus 14.3 +/- 4.7 h for sulfamethoxazole. No significant differences (P > 0.05) were observed between patient groups, although there was wide intersubject variability. Absorption appeared to be similar between the critically ill and non-critically patients: bioavailability was 97.5% +/- 22.4% versus 101.8% +/- 22.7% for trimethoprim and 86.2% +/- 17.9% versus 99.1% +/- 20.5% for sulfamethoxazole, respectively. Because of the similar pharmacokinetics of trimethoprim-sulfamethoxazole in critically ill and non-critically ill AIDS patients, the two groups of patients may receive similar dosages. Dosage adjustment does not appear to be required when switching from the intravenous to the oral route.

Reinfection from the lower gastrointestinal tract is a possible source of recurrent vulvo-vaginal candidiasis. A prospective study to assess the prevalence of yeast carriage in various orifices (including the rectum) in controls and patients, and the relationship to acute vaginitis, was conducted. Cultures for yeast were obtained from the mouth, rectum, vulva, and vagina every 1-2 months for 1 y from the patients. The prevalence of yeast carriage in healthy controls was 3/37 (8.1%) from the vulva, vagina, and rectum, and 4/37 (10.8%) from the mouth. In patients, yeast carriage during episodes of vaginitis was: from the vagina, 190/193 (98.4%); from the vulva, 107/193 (55.4%); from the rectum, 93/193 (48.2%); and from the mouth, 52/193 (26.9%). During visits without vaginitis, yeast carriage was lower: in the rectum, 59/587 (10.1%); in the vulva, 53/459 (11.6%); in the vagina, 77/587 (13.1%); and in the mouth, 89/587 (15.2%). Yeast in the lower bowel during symptomatic vaginitis is higher (p = 0.0001) than in controls, but not significantly greater during asymptomatic periods. Recurrence of Candida vaginitis is not dependent on yeast reservoir in the lower gut between symptomatic episodes.

Rapid progression of infection with human immunodeficiency virus type 1 (HIV-1) to AIDS after seroconversion is rare; it has been associated with coinfection by cytomegalovirus or human T lymphotrophic virus type I. We describe an alcoholic patient whose condition progressed to AIDS 3 months after HIV-1 seroconversion occurred. Culture of peripheral blood mononuclear cells yielded a syncytium-inducing variant of HIV-1. T lymphocytes showed no spontaneous cytotoxic activity against HIV-infected cells, nor could such activity be demonstrated following stimulation with HIV-1 antigen in the presence of recombinant interleukin-2. We hypothesize that our patient's accelerated course was due to alcohol abuse, which may have suppressed T cell function and stimulated HIV replication.

Objective: To determine the comparative efficacy and cost benefit of prophylactic monthly (perimenstrual) clotrimazole, versus empiric self-treatment with the same agent at the onset of symptoms in recurrent vulvovaginal candidiasis., Design: Prospective, randomised, open cross-over study of women with proven recurrent vulvovaginal candidiasis. Clinical and microbiological assessments were done every two months for 12 months., Setting: Women's Clinic of a University Teaching Hospital., Subjects: Twenty-three otherwise healthy, non-pregnant women with greater than four proven episodes of candida vaginitis in the last year were enrolled into the study., Intervention: Patients were randomised to receive: (1) a single dose of prophylactic clotrimazole 500 mg ovule just before or on the last day of the menses each month for 6 months; (2) or a single dose of clotrimazole 500 mg ovule empirically at the onset of symptoms for 6 months. After the first 6 months patients were crossed-over to the opposite regimen., Main Outcome Measures: Symptoms of recurrent vulvovaginitis during each period, and number of clotrimazole ovules used for each 6 month period. The personal preference of the patients for the two different regimens were assessed at the end of study., Results: During the prophylactic 6 months period of the study, 23 patients had 50 episodes of symptomatic vaginitis (mean 2.2 episodes per patient), versus 86 episodes (mean 3.7 episodes/patient) during the empiric self-treatment 6 months period (P = 0.05). However, during the prophylactic period a total of 168 clotrimazole ovules were used (mean 7.3 per patient), versus 84 ovules (mean 3.6 per patient) during the empiric self-treatment period, p < 0.001. The personal preference of the patients for the type of regimen employed were 17 (73.9%) in favour of the empirical treatment, versus 4 (17.4%) in favour of the prophylactic treatment and 2 (8.7%) no personal preference, p < 0.01., Conclusion: Empiric self-treatment is more cost-effective and preferable to patients than cyclical monthly prophylactic use of 500 mg clotrimazole vaginal ovules.

Patients with HIV infection or AIDS often receive several medications for treatment or prevention of their primary disease and/or associated complications. The objective of this study was to document patterns of drug use in an HIV-positive, outpatient population. Data were collected via one-on-one interviews with 26 HIV-positive patients; prescription and non-prescription drug use, adverse drug reactions and drug allergies were recorded. Anti-retroviral therapy was received by over 90 % of the patients. Over 90% of patients were on anti-infective agents, commonly cotrimoxazole or dapsone, while 27% received acyclovir. At least 70% of patients used three or more prescription medications concurrently. Every patient reported self-medicating with at least one over-the-counter (OTC) product and over half used three or more OTC products concurrently. Adverse reactions, mainly attributable to zidovudine, were reported by over 80% of patients. Non-compliance was a common drug-related issue; over 70% of patients omitted drug doses. In conclusion, the use of multiple medications in the ambulatory HIV-positive patients presents the health care team with potential drug-related problems that may ultimately affect the efficacy and toxicity of therapy. Thus pharmacists may play an active role in the provision of direct care to these patients.

Heart involvement in patients with AIDS has been described in autopsy and clinical series, but the true incidence in HIV-infected patients is not clear. A prospective study was done on 101 unselected HIV-infected patients (71 with AIDS and 30 with pre-AIDS) and 24 healthy controls to assess the prevalence of cardiac abnormalities. Assessment included physical examination, electrocardiogram, two-dimensional echocardiogram, and Doppler studies. At least one abnormality was detected in 41 (40.6%) HIV-infected patients vs. 3 (12.5%) in controls (p = 0.003). Echocardiographic abnormalities were detected in 29 (28.7%) HIV-infected patients and 3 (12.5%) controls (p = 0.04). There were no significant differences in abnormalities on physical examination, electrocardiogram, or Doppler studies. Only six (5.9%) HIV-infected patients had abnormal cardiac findings on physical examination. We found no correlation between HIV staging, CD4 cell count, acute illness, or severity of illness and the presence of cardiac abnormalities. Cardiac abnormalities in HIV-infected patients are more frequent than in healthy controls, but most abnormalities are of no significant clinical consequence.