Robert E. McCabe

Influence of coinfection with hepatitis C virus on morbidity and mortality due to human immunodeficiency virus infection in the era of highly active antiretroviral therapy.

To ascertain the impact of hepatitis C virus (HCV) infection on human immunodeficiency virus (HIV) disease progression and associated death in the era of highly active antiretroviral therapy (HAART), we examined mortality rates, the presence of other diseases, and antiretroviral use in an observational cohort of 823 HIV-infected patients with and without HCV coinfection during the period of January 1996 through June 2001. Analyses were used to compare patient characteristics, comorbid conditions, and survival durations in HIV-infected and HIV-HCV-coinfected patients. HIV-HCV-coinfected persons did not have a statistically greater rate of acquired immunodeficiency syndrome or of renal or cardiovascular disease, but they did have more cases of cirrhosis and transaminase elevations. There were proportionately more deaths in the HIV-HCV-coinfected group. Age, baseline CD4+ cell count, and duration of HAART were significantly associated with survival, but HCV infection was not. HAART use was a strong predictor of increased duration of survival, suggesting that treatment is more important to survival than is HCV coinfection status.

Effect of Antiidiotypic Antibodies to HLA on Graft Survival in Renal-Allograft Recipients

Although the presence in the recipient of preformed antibodies to HLA antigens in the kidney of a renal-transplant donor may be associated with early graft failure, such grafts are often well tolerated. We have investigated the possibility that anti-anti-HLA (antiidiotypic) antibodies influence the outcome of renal transplantation in recipients with a history of presensitization to their donors HLA antigens. A retrospective analysis of 20 such cases showed that in 10 patients the transplanted kidney was rejected within one month, whereas in the remaining 10 the graft was tolerated for more than a year. Nine of the 10 patients in whom the graft was tolerated had anti-anti-HLA antibodies at the time of transplantation. Nine of the 10 patients in whom the graft was rejected had antibodies that potentiated, rather than blocked, the cytotoxic activity of anti-donor-HLA antibodies. These results suggest that patients with anti-anti-HLA antibodies specific for a potential donor can safely undergo transplantation, despite a prior history of anti-HLA antibodies. At the time of transplantation, patients who have antibodies that potentiate the cytotoxic activity of a historically positive serum are at high risk of graft rejection within a short period. Taking these considerations into account may improve the reliability of cross-matching in renal transplantation.

Hepatitis A and B Vaccination Practices for Ambulatory Patients Infected with HIV

Few studies exist of adherence to guidelines for vaccination of persons infected with human immunodeficiency virus (HIV), especially in the era of highly active antiretroviral therapy (HAART). In a retrospective, cross-sectional analysis in the HIV Outpatient Study sites, 198 (32.4%) of 612 patients eligible for hepatitis B vaccine received at least 1 dose. In multivariate analysis, hepatitis B vaccination was associated with HIV risk category, education level, and number of visits to the HIV clinic per year. Among 716 patients eligible for hepatitis A vaccine, 167 (23.3%) received > or =1 dose. Response to hepatitis B vaccination was associated with higher nadir CD4+ cell counts (P=.008) and HIV RNA levels less than the level of detection (P=.04), although some response was documented at all CD4+ levels. Although there were low rates of complete hepatitis vaccination in this cohort of ambulatory patients, prompt efforts to vaccinate patients entering care, receipt of antiretroviral therapy, and practice reminder systems may enhance vaccination practices.

Open lung biopsy in patients with acute leukemia

The results of open lung biopsy in 15 patients with acute leukemia, pulmonary infiltrates, neutropenia, and fever were reviewed. The patients averaged 26 hospital days of neutropenia and 20 hospital days of fever before open lung biopsy, and all patients received broad-spectrum antibacterial agents (mean 17 days) before open lung biopsy. Nine (67 percent) received amphotericin B prior to open lung biopsy (mean 22 days). Open lung biopsy yielded a specific clinically helpful diagnosis in six patients, but only two of these patients survived the hospitalization during which open lung biopsy was performed. Open lung biopsy detected fungus in four patients and leukemic infiltrates in two patients. Management was appropriately modified in these patients. In nine patients, a specific diagnosis of the pulmonary infiltrate was not obtained by open lung biopsy. Antimicrobial regimens were not changed substantially for these patients. In six patients, the results of open lung biopsy may have been misleading. Two patients had pulmonary fungal diseases at autopsy, undetected by open lung biopsy eight days and five weeks prior to death. Another patient had invasive aspergillosis and one had cytomegalovirus pneumonitis not detected by open lung biopsy. Two patients had false-positive preliminary histologic reports of pulmonary infection. On the basis of this experience, in this specific population of patients, open lung biopsy was often of little help in directing medical therapy or influencing clinical outcome.

Perinephric abscess. Modern diagnosis and treatment in 47 cases

The records of 47 patients with a perinephric abscess diagnosed from 1975 to 1986 at 8 San Francisco Bay Area hospitals were reviewed. The mean age was 51 years. Fifty-five percent were females and 45%, males. The left kidney was affected in 47% of cases, the right kidney in 40%, both in 4%, and a transplanted pelvic kidney in 9%. Fever (55%), chills or diaphoresis (47%), flank pain (40%), abdominal pain (40%), and nausea or vomiting (32%) were the most common presenting symptoms. About half the patients had symptoms for 1 week or less and 12% had no symptoms. Fever was documented before diagnosis in 88% of patients. Abdominal mass (13%) or tenderness (49%), and flank mass (9%) or tenderness (42%) were seen less frequently, and 11% of patients did not have fever, flank, or abdominal findings. The most frequent underlying conditions included previous urologic surgery (45%), previous urinary tract infection (38%), diabetes mellitus (36%), and urinary tract stones (36%). Cultures of perinephric abscesses yielded gram-negative aerobes in 52% of patients, primarily Escherichia coli. Staphylococcus aureus was isolated in 26% of patients and anaerobes in 17%. A single pathogen was isolated in 71% and multiple isolates in 29%. Of interest and great potential therapeutic importance was culture of anaerobes, primarily Bacteroides spp. in 17%, Enterococcus spp. in 7%, and Candida albicans in 7%. Positive blood and urine cultures identified perinephric abscess organisms exactly in 58% and 37% of cases, respectively. Routine laboratory tests such as the white blood cell count and urinalysis were insensitive and non-specific for perinephric abscess. Leukocytosis and anemia at admission were seen in slightly more than half of the patients. For radiologic diagnosis, computerized tomographic scanning was most helpful. Ultrasound and intravenous pyelography were falsely negative in about one-third of cases. Mortality (13%) was low in this series when compared with earlier studies, and probably reflects modern medical care. Six patients (13%) died during hospitalization, 2 of whom had diagnosis of PNA established only at autopsy. Drainage of the perinephric abscess was carried out by open surgical drainage in 64% of patients, percutaneous drainage in 19%, and both in 13%. The initial procedure, whether open surgical drainage or percutaneous catheter drainage, was usually successful. Late complications included nephrocutaneous fistulas in 3 patients and disseminated candidiasis in 1 patient.

A new therapeutic option for the treatment of pneumonia

Patients with bacterial pneumonia often are treated empirically with parenteral broad-spectrum antimicrobials intended to cover potential gram-negative and gram-positive pathogens. However, beta-lactamase-mediated resistance has developed to many of these antimicrobials, particularly third-generation cephalosporins, and has led to the development of fourth-generation agents that are relatively beta-lactamase stable. The purpose of these studies was to compare the efficacy and safety of the fourth-generation agent, cefepime, with that of the third-generation agent, ceftazidime, in the treatment of hospitalized patients with moderate-to-severe bacterial pneumonia. A total of 336 (97 evaluable) patients were enrolled in an open-label study, and 99 (23 evaluable) patients were enrolled in a blinded study of patients with lower respiratory tract infections (LRTI) including pneumonia. Patients were randomized to receive either cefepime 1 g every 12 hours or ceftazidime 1 g every 8 hours given as an intravenous infusion over 30 minutes. Efficacy analysis included the evaluable patients while the safety analysis included all patients. The results in the open-label study were as follows: In patients with pneumonia, clinical response was satisfactory in 58 (85%) of 68 patients in the cefepime group and 21 (72%) of 29 patients in the ceftazidime group. Bacteriologic eradication occurred for 75 (93%) of 81 pathogens and 30 (94%) of 32 pathogens isolated from the 68 cefepime-treated patients and 29 ceftazidime-treated patients, respectively. The results in the blinded study were as follows: In patients with pneumonia, clinical response was satisfactory in 12 (80%) of 15 cefepime patients and in 7 (88%) of 8 ceftazidime patients, and the bacteriologic eradication rates were 85% (17/20 pathogens) and 73% (8/11 pathogens) isolated from the 15 cefepime-treated patients and the eight ceftazidime-treated patients, respectively. Among the most frequent adverse events in both groups were nausea, diarrhea, vomiting, and abdominal pain. Similar adverse events were noted in the 99 patients in the blinded study. These studies indicate that the efficacy and safety of cefepime administered at 1 g twice daily is comparable to that of ceftazidime administered at 1 g three times daily for treatment of hospitalized patients with pneumonia caused by susceptible pathogens.

Current Recommendations and Future Prospects in the Treatment of Toxoplasmosis

SummaryToxoplasma infection is highly prevalent throughout the world and causes disease in diverse populations. Effective treatment regimens are available for each clinical entity of toxoplasma, but problems of incomplete clinical efficacy, drug potency, drug safety, and length of treatment remain. No well-controlled clinical trials in humans have been performed to evaluate the efficacy and safety of treatment.Primary treatment of toxoplasmosis is with the Synergistic combination of pyrimethamine and sulphonamide. This is considered the treatment of choice for severe disease, disease in immunocompromised patients, and congenital toxoplasmosis. Spiramycin, a macrolide antibiotic, is frequently used alone or alternately with pyrimethamine and sulphonamide for pregnant women with the acute acquired infection to prevent congenital toxoplasmosis. Clindamycin is used frequently to treat acute flares of toxoplasmic chorioretinitis and as second-line therapy for toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome (AIDS).Inadequacies in the treatment of toxoplasmosis in immunosuppressed patients, exemplified by experience with AIDS patients, should provide the impetus for well-designed trials to find and evaluate more potent and better-tolerated agents. Classes of new drugs that have been investigated and show some promise include: (a) macrolides (roxithromycin, azithromycin); (b) folic acid antagonists (piritrexim and trimetrexate), and (c) purine analogues (arprinocid). Immunomodulators have attracted interest, and interferon-γ alone and in combination with roxithromycin is effective in murine models. Interleukin-2 is also effective in the murine model.

The effects of cyclosporine on Toxoplasma gondii in vivo and in vitro.

We examined the effect of cyclosporine on Toxoplasma infection in vivo and in vitro. Administration to mice of 150 mg/kg/day cyclosporine variably affected mortality in four separate experiments. IgG (Sabin-Feldman dye test) and IgM enzyme-linked immunosorbent assay antibody titers were significantly depressed in mice treated with cyclosporine. These results suggested the possibility that cyclosporine possesses anti-Toxoplasma activity. Thus, macrophages were incubated with cyclosporine before and after infection with Toxoplasma. Treatment with 0.5, 1, and 5 micrograms cyclosporine/ml during or after challenge of macrophage monolayers with Toxoplasma inhibited replication of Toxoplasma (and resulted in killing of Toxoplasma). The effect of cyclosporine on development of activated macrophages was studied. Cyclosporine administered to mice at a dose of 150 mg/kg/day neither accelerated nor delayed activation of macrophages (assessed by inhibition of Toxoplasma replication in vitro) by i.v. injection of either Corynebacterium parvum or Toxoplasma. Cyclosporine affects mortality variably in murine toxoplasmosis, depresses synthesis of IgG and IgM Toxoplasma antibody in vivo, does not prevent activation of macrophages in vivo, and possesses anti-Toxoplasma activity in vitro and perhaps in vivo. Cyclosporine may be the preferred immunosuppressive agent for recipients of an organ transplant who are at high risk for toxoplasmosis (e.g., seronegative recipients who have received organ from seropositive donors).

Ketoconazole promotes parasitological cure of mice infected with Trypanosoma cruzi

Administration of 120 mg/kg/day of ketoconazole for 9 weeks resulted in parasitological cure of at least 78.5% of mice infected with 10(5) blood trypanosomes of Trypanosoma cruzi, strain Y. These results and the fact that ketoconazole is widely used in humans for prolonged therapy of fungal infections without significant side effects strongly suggest that further evaluation of ketoconazole for treatment of Chagas disease is highly desirable.

Hospital survey of antimicrobial prophylaxis to prevent endocarditis in patients with prosthetic heart valves

The American Heart Association (AHA) has published guidelines for use of prophylactic antibiotics to prevent bacterial endocarditis, but few data are available about physician compliance with these guidelines. A retrospective review was conducted of the use of prophylactic antibiotics in patients with prosthetic heart valves who were undergoing diagnostic or operative procedures or heart catheterization at three hospitals. Compliance with AHA recommendations was only 30 percent (14 of 46) for procedures considered high risk for patients with prosthetic heart valves. Six (23 percent) of 26 patients who underwent right or left heart catheterization received prophylactic antibiotics (not recommended by AHA). Antibiotics were given to 42 (74 percent) of 57 patients who underwent surgical procedures considered at low risk of bacteremia, but only 33 (58 percent) received antibiotics that cover organisms commonly present at the site of the procedure. The results indicate that clinicians frequently do not administer prophylactic antibiotics in patients with prosthetic heart valves who are undergoing invasive procedures or do not follow published AHA guidelines when antibiotics are administered.