Coccidioidomycosis: efficacy of new agents and future prospects.

Recent studies have contributed to our understanding of risk factors for severe and potentially life-threatening infections with Coccidioides immitis, allowing a more rational approach to initiation of antifungal therapy for this infection, as well as determining its intensity and duration. A large randomized trial found that itraconazole and fluconazole had similar efficacies in the treatment of progressive nonmeningeal coccidioidomycosis. An animal model of coccidioidal meningitis suggested potential efficacy of systemically administered liposomal amphotericin B. Investigational agents that have activity against C. immitis include posaconazole, voriconazole, caspofungin, and sordarin derivatives.

Azithromycin prophylaxis during a hospitalwide outbreak of a pertussis-like illness.

A questionnaire regarding tolerability and adherence was administered for 5 days to hospital employees who received azithromycin prophylaxis during a hospitalwide outbreak of a pertussis-like illness. Analysis of the 239 responses from those having received prophylactic azithromycin determined that it was well tolerated and accounted for a minimal loss of days worked; 81.5% were fully adherent with the regimen.

N-acetylcysteine replenishes glutathione in HIV infection.

BACKGROUND: Glutathione (GSH) deficiency is common in HIV-infected individuals and is associated with impaired T cell function and impaired survival. N-acetylcysteine (NAC) is used to replenish GSH that has been depleted by acetaminophen overdose. Studies here test oral administration of NAC for safe and effective GSH replenishment in HIV infection. DESIGN: Oral NAC administration in a randomized, 8-week double-blind, placebo-controlled trial followed by optional open-label drug for up to 24 weeks. SUBJECTS: HIV-infected, low GSH, CD4 T cells < 500 micro L(-1), no active opportunistic infections or other debilitation; n = 81. Study conducted prior to introduction of protease inhibitors. RESULTS: Whole blood GSH levels in NAC arm subjects significantly increased from 0.88 mM to 0.98 mM, bringing GSH levels in NAC-treated subjects to 89% of uninfected controls (P = 0.03). Baseline GSH levels in the placebo group (0.91) remained essentially the same during the 8 week placebo-controlled trial. T cell GSH, adjusted for CD4 T cell count and beta2-microglobulin levels, also increased in the NAC-treated subjects (P = 0.04). Adverse effects were minimal and not significantly associated with NAC ingestion. CONCLUSION: NAC treatment for 8 weeks safely replenishes whole blood GSH and T cell GSH in HIV-infected individuals. Thus, NAC offers useful adjunct therapy to increase protection against oxidative stress, improve immune system function and increase detoxification of acetaminophen and other drugs. These findings suggest that NAC therapy could be valuable in other clinical situations in which GSH deficiency or oxidative stress plays a role in disease pathology, e.g. rheumatoid arthritis, Parkinson's disease, hepatitis, liver cirrhosis, septic shock and diabetes.

Human immunodeficiency virus on the web: a guided tour.

Through the efforts of thousands of individuals, the World Wide Web has become a gold mine of information about HIV. In this article, we describe approximately 90 Web sites that are among the most useful to clinicians and researchers with regard to HIV. Web sites were classified according to their content and target audience and were judged according to their adherence to accepted standards of medical Internet publishing. Selected Web sites were categorized into the following groups: (1) sites with comprehensive coverage of HIV treatment and its management, (2) on-line peer-reviewed journals, (3) proceedings of scientific meetings, (4) sites with HIV-related textbooks, manuals, and guidelines, (5) government publications, (6) research databases, (7) information on clinical trials, (8) sites with comprehensive information for laypersons, and (9) sites with information related to specific medical complications of HIV infection.

Hyperimmune products in the prevention and therapy of infectious disease: a report of a hyperimmune products expert advisory panel.

This paper reviews a meeting at which basic pathophysiology of infections, mechanisms of action of hyperimmune products and pharmacokinetic and pharmacodynamic parameters, as well as currently available hyperimmunes and their potential new targets and uses, were discussed. A hyperimmune product was defined as either a monoclonal antibody or a polyclonal preparation enriched with antibody directed against one or more particular targets. A number of issues were emphasised, including: resistant bacterial pathogens, such as Staphylococcus aureus and Streptococcus pyogenes; the role of hyperimmune intravenous globulins in the prevention of sepsis in low birthweight infants; hepatitis B virus infection associated with liver transplantation; combination therapy; the potential role of hyperimmunes in the prevention and treatment of hepatitis C virus; and the use of immunoglobulins for the prophylaxis of Epstein-Barr virus-related lymphoproliferative disease. Routes of administration were also discussed. It was concluded that the development of hyperimmunes faces numerous obstacles. It was agreed that the use of hyperimmunes in clinical trials must be standardised; clinical trials must be large enough to have sufficient power to demonstrate efficacy with clear-cut end-points, and means need to be developed, in conjunction with regulatory agencies, for the feasible evaluation of combination products. However, progress in all these aspects will provide a wide range of hyperimmunes for future use.

Evolution of the clinical manifestations of infection during the course of febrile neutropenia in patients with malignancy.

The impact of a standardized set of diagnostic interventions on the further management of 968 episodes of fever in neutropenic cancer patients who did not respond to initial therapy was assessed prospectively. At the onset of fever, 65% of patients had no additional signs of infection, whereas skin and soft tissue infections were present in 12%, and clinical sepsis and gastrointestinal infections in 8% each. After 72 h, 41% of the fevers still remained unexplained. New foci of infection emerged in 11% of the cases involving mainly the lungs, skin and soft tissues, and urinary tract. The presence of a lower respiratory tract infection or a microbiologically defined infection of any sort was associated with higher mortality than other types of infection were. Changes in initial antibiotic therapy were based on the results of the diagnostic measures specified in the protocol in only 15% of the cases.

Mexiletine for HIV-infected patients with painful peripheral neuropathy: a double-blind, placebo-controlled, crossover treatment trial.

Although mexiletine, an antiarrhythmic with local anesthetic properties, has been reported to relieve discomfort in diabetic neuropathy, its usefulness in the treatment of HIV-related painful peripheral neuropathy (PPN) has not been determined. The tolerance and effectiveness of mexiletine in HIV-related PPN were assessed in 22 patients who were randomized to receive mexiletine (maximum dose, 600 mg/day) or placebo for 6 weeks, followed by the alternative intervention for 6 weeks after a 1-week washout period. The daily pain response was assessed using a visual analogue scale card in 19 patients who received at least 2 weeks of the drug, 16 of whom were crossed-over to receive the alternate agent. No statistically significant difference was found between the mean daily pain scores for patients receiving mexiletine versus placebo, irrespective of the order in which the agents were received. Comparing the mean individual daily pain scores for each phase of study, 5 patients (31%) had significantly less pain while receiving mexiletine compared with their response to placebo, 5 patients (31%) had significantly less pain while receiving placebo, and no difference was noted in 6 patients (38%). Crossover and multivariate analyses for repeated measures showed no apparent difference in the response to mexiletine versus placebo. Dose-limiting adverse events occurred in 39% of those receiving mexiletine, but only 1 patient (5%) discontinued placebo. Mexiletine was only modestly well tolerated despite its relatively brief period of administration, and no evidence was found to support its benefit in HIV-related PPN. Although a first-drug effect was not demonstrated, a powerful placebo effect was seen in some patients.

The prevalence of measles antibody in human immunodeficiency virus-infected patients in northern California.

The seroprevalence of measles (rubeola) antibody in 619 human immunodeficiency virus (HIV)-infected adults was determined by a standard ELISA. Risk factors for a lack of antibody and presumed susceptibility to measles were examined. Whereas overall, 9.8% of patients (60) were found to lack antibody, 17.8% of those born within the United States in 1957 or later were antibody-negative. Multivariate analysis showed that absence of measles antibody was significantly associated with younger age (born in 1957 or later) (odds ratio [OR], 8.15; 95% confidence interval [CI], 3.7-21.5; P < .0001) and birth within the United States (OR, 4.72; 95% CI, 1.7-19.7; P = .0045). Neither minority status, stage of HIV infection, CD4 cell count, nor a history of opportunistic infection bore any relationship to the presence of antibody. While progression of HIV disease does not affect measles serostatus, younger HIV-infected patients, especially those born in the United States in 1957 or later, are at the greatest risk for measles.

Immunomodulatory treatment of Mycobacterium avium complex bacteremia in patients with AIDS by use of recombinant granulocyte-macrophage colony-stimulating factor.

Eight AIDS patients with Mycobacterium avium complex (MAC) bacteremia were randomized to receive azithromycin with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) for 6 weeks to examine the effect of GM-CSF administration on clearance of mycobacteremia and on monocyte function. Superoxide anion production was significantly increased ex vivo in monocytes from patients receiving GM-CSF but not in those from patients receiving azithromycin alone. Relative to monocytes obtained from untreated healthy controls, median differences in viable intracellular MAC at 2, 4, and 6 weeks were -0.76, -0.94, and -0.47 log10 cfu/mL of lysate for cells from patients receiving GM-CSF versus -0.15, -0.11, and -0.19 log10 cfu/mL for cells from patients receiving azithromycin alone. Although no effect on mycobacteremia was detected, the administration of GM-CSF to AIDS patients with MAC bacteremia resulted in activation of their blood monocytes, as evidenced by increased superoxide anion production and enhanced mycobactericidal activity. GM-CSF deserves further investigation in the treatment of mycobacterial infections.

Treatment of Pneumocystis carinii pneumonia in adults with AIDS.

Trimethoprim-sulfamethoxazole remains the treatment of choice in patients with Pneumocystis carinii pneumonia (PCP) requiring intravenous therapy. Those patients who require intravenous therapy who cannot tolerate or who fall therapy with trimethoprim-sulfamethoxazole may be treated with either pentamidine or trimetrexate (plus folinic acid), with or without orally administered dapsone. The toxicity of the former drug makes trimetrexate-based therapy the preferred second choice for parenteral use. Treatment with trimethoprim-sulfamethoxazole, dapsone-trimethoprim, or clindamycin-primaquine is approximately of equivalent efficacy, but variable toxicity, in patients with mild to moderate PCP for whom an oral route of administration is appropriate. Atovaquone, formulated as an oral suspension, is also effective, but, in the absence of additional data, must be considered as second line therapy. Adjunctive corticosteroid therapy is indicated for patients with [PAO2-PaO2] more than 30 mm Hg or PaO2 less than 70 mm Hg [corrected] while breathing ambient air in the absence of contraindications. Recognition of the apparent fungal nature of P carinii as well as improved understanding of the pathophysiology of PCP will lead to further improvements in antipneumocystis therapy.

Glutathione deficiency is associated with impaired survival in HIV disease.

Glutathione (GSH), a cysteine-containing tripeptide, is essential for the viability and function of virtually all cells. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV-infected subjects. Specifically, we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2-3 years after baseline data collection (Kaplan-Meier and logistic regression analyses, P < 0.0001 for both analyses). This finding, supported by evidence demonstrating that oral administration of the GSH prodrug N-acetylcysteine replenishes GSH in these subjects and suggesting that N-acetylcysteine administration can improve their survival, establishes GSH deficiency as a key determinant of survival in HIV disease. Further, it argues strongly that the unnecessary or excessive use of acetaminophen, alcohol, or other drugs known to deplete GSH should be avoided by HIV-infected individuals.

Travels with HIV: the compliance and health of HIV-infected adults who travel.

We examined the effects of travel on the health of a group of HIV-infected adults (n = 89) cared for in a public hospital HIV clinic. In a period of 2 years, 45% travelled to a median of 3 US destinations for at least one week and 20% travelled to at least one international destination for a mean duration of 20 days. At the time of completion of the survey, the majority of these patients were severely immunosuppressed (median CD4+ count, 120/mm3). A physician was consulted concerning travel before 53% of the trips, but only one person consulted a travel medicine expert. All but one patient (98%) who was receiving medical therapy carried sufficient supplies of medication; 95% estimated their compliance with medication at 75% or better. None of the travellers to developing countries received gamma globulin, but one received yellow fever vaccine. Fifteen travellers (43%) became ill either during their trip or immediately thereafter; 3 required hospitalization. While most illnesses were not severe, 4 patients developed potentially life-threatening infections including coccidioidomycosis, cryptococcosis, PCP, and bacterial pneumonia. This survey provides information by which the clinician can anticipate the health care needs of HIV-infected patients who travel. HIV-infected patients should be more aware of the necessity for medical counsel prior to travel.

Aspergillus fumigatus infection of an automatic internal cardiac defibrillator.

We report a patient without immune compromise with infection of an automatic internal cardiac defibrillator patch due to Aspergillus fumigatus presenting 8 years after implantation. The mechanism of infection was unknown, but symptoms began 1 month after laser uvulopalatopharyngoplasty was performed for sleep apnea. The patches were surgically removed and the patient was treated sequentially with amphotericin B and itraconazole. He remains without evidence of infection 12 months after the completion of therapy.

Early identification of neutropenic patients at risk of grampositive bacteraemia and the impact of empirical administration of vancomycin.

The aim of this multicentre randomised trial was to determine whether it was possible to predict grampositive bacteraemia, and whether the empirical use of vancomycin would lead to reduced morbidity and mortality. 35 of 113 patients (31%; confidence interval, CI 8.5), who presented with a skin or soft tissue infection and had received empirical vancomycin in addition to either ceftazidime or piperacillin-tobramycin, had initial bacteraemia with a single gram-positive bacterium compared with 135 of the 784 (17%; CI 2.6), who presented with another infection and who had been given ceftazidime or piperacillin-tobramycin without vancomycin (P < 0.001). Empirical vancomycin resulted in a higher rate of eradication (P = 0.033, relative risk 1.2), but not a better clinical outcome and was associated with more toxicity (P = 0.042, relative risk 1.6). Irrespective of the initial treatment regimen, fever lasted an average of 8 days, the empirical regimen was modified in more than 50% of cases and mortality attributed to gram-positive infection was less than 2%. Incorporating vancomycin in the initial empirical antibiotic regimen for febrile neutropenic patients does not appear necessary, even for skin and soft tissue infections associated with gram-positive bacteraemia.

Treatment of Mycobacterium avium complex infection: do the results of in vitro susceptibility tests predict therapeutic outcome in humans?

The ability of various in vitro methods of antibiotic susceptibility testing to predict therapeutic outcome in patients infected with Mycobacterium avium complex (MAC) was evaluated. Pretreatment bloodstream MAC isolates from 38 patients with AIDS, previously treated in a randomized fashion with either ethambutol, rifampin, or clofazimine, were tested by three conventional methods using broth or agar, as well as by cocultivation with macrophages. The results obtained with each method were compared with the quantitatively determined bacteriologic response to the administration of the single agent in humans. None of the conventional in vitro susceptibility methods was predictive of therapeutic outcome, while the results of cocultivation with macrophages were of moderate predictive value. The positive predictive value of a response in humans based on a response in macrophages (defined by > or = to 1.0 log reduction in baseline colony counts after 5 days of treatment) was 74%. The negative predictive value was 82%.

Treatment of Myocardium avium complex infection: does the beige mouse model predict therapeutic outcome in humans?

To determine the predictive value of a standard murine model in the treatment of disseminated Myocardium avium complex (MAC) infection, beige mice were infected with MAC strains isolated from human immunodeficiency virus-infected patients and treated with the same antibiotic (ethambutol, clofazimine, or rifampin) that had been administered to the subject from whom that strain had been recovered. While ethambutol had the greatest bacteriologic efficacy in humans (mean decrease +/-SD, 1.0+/-0.5 log 10 cfu/mL of blood), clofazimine had the greatest bacteriostatic efficacy in mice (mean decrease +/- SD, 2.8 +/- 0.7 log(10) cfu/g of tissue). A linear correlation was not observed between bacteriostatic activity in mouse liver or spleen and the degree of bacteriologic response in humans (P > or = to .1). Odds ratios for a response in humans based on a bacteriologic response in mice were not significant for each agent (P > or = to .1, all cases).

Genotypic analysis of pseudoepidemic due to contamination of Hanks' balanced salt solution with Candida parapsilosis.

A cluster of isolates of Candida parapsilosis recovered from clinical specimens was demonstrated, by both classical and molecular epidemiological techniques, to have resulted from contamination in the laboratory. The source of the pseudoepidemic was a repeatedly utilized contaminated container of Hanks' balanced salt solution used in specimen processing. The patterns of restriction fragment length polymorphisms of DNA extracted from the clinical and environmental isolates were identical to each other but composed a newly identified unique C. parapsilosis DNA type.

Disseminated acanthamoeba infection in patients with AIDS: case reports and review.

Acanthamoeba infection has been described as an opportunistic infection in persons with AIDS. We report two cases of patients with AIDS and acanthamoeba infection and review the manifestations of this protozoan infection in patients infected with human immunodeficiency virus. The diagnosis of this infection requires a high index of suspicion because the clinical and histologic manifestations may be confused with those of disseminated fungal or algal disease. Clinicians and laboratory personnel should be aware of this potentially fatal condition so that appropriate diagnostic studies can be performed and treatment can be urgently administered. Early initiation of therapy may alter the clinical outcome of the disease.