Hydroxyurea in combination with didanosine and stavudine in antiretroviral-experienced HIV-infected subjects with a review of the literature.

The safety and efficacy of hydroxyurea with didanosine in combination with stavudine in nucleoside reverse-transcriptase inhibitor (NRTI)-experienced patients was investigated. Entry criteria included HIV-1 infected, NRTI-experienced adults, with CD4(+) counts 50-550 cells/mm(3) and viral loads >or=12,500 copies/mL. Subjects were treated with didanosine 200 mg twice a day (BID), stavudine 40 mg BID, and hydroxyurea 1000 mg daily for 16 weeks. Thirty-one HIV-1 subjects with mean bDNA viral load 1x10(5) log(10) copies/mL and mean CD4(+) T-cell counts of 231 cells/mm(3) were enrolled. A 1.3 log(10) decrease in mean viral load was seen at 12 weeks of therapy. Prior didanosine use resulted in a more rapid response to therapy compared with prior zidovudine use. Side effects consisting of neutropenia, pancreatitis, and peripheral neuropathy occurred in four subjects and resolved upon withdrawal of therapy. This non-randomized study in subjects with a mean CD4(+) T-cell count of 230 cells/mm(3) demonstrates the antiviral activity of hydroxyurea+didanosine and stavudine. Toxicities related to therapy need to be followed closely. The results support the need for a randomized, prospective study to determine the safety and efficacy of hydroxyurea plus didanosine in antiretroviral-experienced patients with CD4(+) cell counts below 300 cells/mm(3).

DNA fingerprinting of serial Candida albicans isolates obtained during itraconazole prophylaxis in patients with AIDS.

During a randomized double-blind placebo-controlled study testing the efficacy of itraconazole for prophylaxis of systemic and mucosal fungal infections in patients with acquired immune deficiency syndrome, 298 patients were enrolled with 295 evaluable. Of those, 46 patients were considered prophylaxis failures because of recurrent oral or esophageal candidiasis. Oropharyngeal fungal cultures were taken at the time of suspected thrush or Candida esophagitis, but not at baseline. All of the Candida spp. isolates were cultured on CHROMagar Candida medium then identified using API 20 AUX strips. Antifungal susceptibility testing was performed following the National Committee for Clinical Laboratory Standards M-27A guidelines. Sequential isolates were genotyped using randomly amplified polymorphic DNA. Polymerase chain reaction fingerprints were generated using two repetitive sequence primers, (GGA)7 and (GACA)4. The study group consisted of 23 patients, nine from the itraconazole arm and 14 from the placebo arm, who were prophylaxis failures and had more than two C. albicans isolates. Five of 23 had isolates showing a > or =4-fold reduction in susceptibility; four of these patients were in the itraconazole prophylaxis arm and one was in the placebo arm. Three of the five had yeast isolations showing changes in banding patterns over time. Such changes may indicate genetic changes in the same strain that could be linked to acquired resistance to itraconazole, or acquisition of a new strain, or emergence of a previously minor component of the original population.

Does long-term itraconazole prophylaxis result in in vitro azole resistance in mucosal Candida albicans isolates from persons with advanced human immunodeficiency virus infection? The National Institute of Allergy and Infectious Diseases Mycoses study group.

The effects of prolonged itraconazole exposure on the susceptibility of Candida albicans isolates to itraconazole and fluconazole have not been well characterized. A recent placebo-controlled study of long-term itraconazole antifungal prophylaxis in persons with advanced human immunodeficiency virus infection afforded the opportunity to address this question. Mucosal Candida sp. isolates were obtained from subjects who developed oropharyngeal or esophageal candidiasis, and in vitro susceptibilities of the last isolate obtained at removal from the study as a prophylaxis failure were compared in itraconazole and placebo recipients. More subjects in the placebo group (74 of 146 [51%]) than in the itraconazole group (51 of 149 [34%]) developed mucosal candidiasis (P = 0.004). A total of 112 isolates were recovered from 56 of the 74 (76%) subjects with mucosal candidiasis assigned to the placebo group, compared to 97 isolates from 45 of the 51 (88%) subjects in the itraconazole group. C. albicans accounted for 98% of isolates in the placebo group and 89% of isolates in the itraconazole group. The itraconazole MIC at which 50% of the isolates tested were inhibited (MIC(50)) for last-episode isolates from the itraconazole group was 0.125 microg/ml compared to 0.015 microg/ml for the placebo group subjects, P = 0.0001. The MIC(50) of fluconazole for the last isolates from the itraconazole group was 1.5 microg/ml compared to 0.5 microg/ml for the placebo subjects (P = 0.005). A lower proportion of isolates recovered from subjects on itraconazole therapy were classified as susceptible to itraconazole (63%) compared to isolates from the placebo group (96%) (P = 0.001). Similarly, a lower proportion of C. albicans isolates from subjects on itraconazole therapy were susceptible to fluconazole (78%) compared to isolates from the placebo group (96%) (P = 0.01). Also, the proportion of isolates that were not fully susceptible to itraconazole or fluconazole was greater in patients assigned to the itraconazole group than the placebo group (itraconazole susceptibility, 37 and 4%, respectively (P = 0.001); fluconazole susceptibility, 23 and 4%, respectively (P = 0.01). In conclusion, long-term itraconazole prophylaxis in patients with AIDS is associated with reduction in susceptibility to itraconazole and cross-resistance to fluconazole.

Prospective multicenter surveillance study of funguria in hospitalized patients. The National Institute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group.

Although fungal urinary tract infections are an increasing nosocomial problem, the significance of funguria is still not clear. This multicenter prospective surveillance study of 861 patients was undertaken to define the epidemiology, management, and outcomes of funguria. Diabetes mellitus was present in 39% of patients, urinary tract abnormalities in 37.7%, and malignancy in 22.2%; only 10.9% had no underlying illnesses. Concomitant nonfungal infections were present in 85%, 90% had received antimicrobial agents, and 83.2% had urinary tract drainage devices. Candida albicans was found in 51.8% of patients and Candida glabrata in 15.6%. Microbiological and clinical outcomes were documented for 530 (61.6%) of the 861 patients. No specific therapy for funguria was given to 155 patients, and the yeast cleared from the urine of 117 (75.5%) of them. Of the 116 patients who had a catheter removed as the only treatment, the funguria cleared in 41 (35.3%). Antifungal therapy was given to 259 patients, eradicating funguria in 130 (50.2%). The rate of eradication with fluconazole was 45.5%, and with amphotericin B bladder irrigation it was 54.4%. Only 7 patients (1.3%) had documented candidemia. The mortality rate was 19.8%, reflecting the multiple serious underlying illnesses found in these patients with funguria.

Meningococcal pneumonia: characterization and review of cases seen over the past 25 years.

Fifty-eight cases of meningococcal pneumonia were included in this review. Fifty cases previously described in the literature from 1974 through 1998 and 8 new cases were included in this series. The median age of patients was 57.5 years, and pleuritic chest pain was described in 21 (53.9%) of 39 cases. Blood cultures were positive in 42 (79.3%) of 53 cases for which results were mentioned. Despite the presence of bacteremia, patients did not develop the syndrome of meningococcemia with its associated complications. Serogroup Y meningococci were most commonly recovered and accounted for 44.2% of identified isolates. Therapy has dramatically changed over the past 25 years; prior to 1991, penicillin antibiotics were most often used. Since 1991, 12 (80%) of 15 patients received cephalosporin antibiotics. Only 5 (8.62%) of 58 patients died. Secondary cases of meningococcal infections following exposure to patients with meningococcal pneumonia were noted in 2 instances.

Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. National Institute of Allergy and Infectious Diseases Mycoses Study Group.

In a prospective, randomized, double-blind trial, 149 patients with advanced human immunodeficiency virus (HIV) infection were randomized to receive itraconazole capsules (200 mg daily) and 146 to receive a matched placebo. Both groups were monitored for evidence of fungal infections. Baseline characteristics of the two groups were similar. Failure of prophylaxis occurred in 29 (19%) of the itraconazole recipients and 42 (29%) of the placebo recipients (P = .004; log-rank test). There were 6 invasive fungal infections in the itraconazole group (4, histoplasmosis; 1, cryptococcosis; 1, aspergillosis) and 19 in the placebo group (10, histoplasmosis; 8, cryptococcosis; 1, aspergillosis) (P = .0007; log-rank test). Itraconazole significantly delayed time to onset of histoplasmosis (P = .03; log-rank test) and cryptococcosis (P = .0005; log-rank test). Prophylaxis failure due to recurrent or refractory mucosal candidiasis occurred with similar frequency in the two groups (itraconazole, 15%; placebo, 16%). A survival benefit was not demonstrated. Itraconazole generally was well tolerated. Primary prophylaxis with itraconazole capsules prevents histoplasmosis and cryptococcosis in patients with HIV infection.

Histoplasmosis in AIDS: advances in management.

Histoplasmosis is one of the most common opportunistic infections in HIV-infected patients who reside in endemic areas, and "imported infections" also occur elsewhere. A recent decline in the incidence of histoplasmosis appears to correlate with advances in antiretroviral therapy. Histoplasmosis occurs due to either dissemination of newly acquired infection or reactivation of latent foci of infection. Major risk factors include a CD4 count < or = 150/microL, positive complement fixation serology for the Histoplasma capsulatum mycelial antigen, and a history of exposure to chicken coops; in addition, suboptimal antiretroviral therapy seems likely to be a risk factor. Although there are a variety of clinical manifestations, most patients present with a several-week history of fever, chills, weakness, and weight loss. Diagnosis is based on positive cultures of blood, bone marrow, or other sites; detection of antigen in serum or urine; or characteristic histopathologic findings in biopsy specimens. Induction therapy consists of amphotericin B for acutely ill patients or itraconazole for patients with mild to moderately severe disease. Subsequent lifelong maintenance therapy with itraconazole is recommended. In patients with CD4 counts of < or = 150/microL, itraconazole is effective primary prophylaxis.

Prospective study of histoplasmosis in patients infected with human immunodeficiency virus: incidence, risk factors, and pathophysiology.

Histoplasmosis is a common opportunistic infection in patients with human immunodeficiency virus (HIV) infection who reside in areas where Histoplasma capsulatum is endemic. We undertook a prospective study of a cohort of 304 HIV-Infected patients in Kansas City from October 1990 through March 1993 to define the incidence-specific risk factors, and pathophysiology of histoplasmosis. The annual incidence of histoplasmosis was 4.7%; 74% of the patients with histoplasmosis were symptomatic (all of whom had disseminated disease). A history of exposure to chicken coops, a positive baseline serology for complement-fixing antibodies to Histoplasma mycelium antigen, and a baseline CD4+ lymphocyte count of < 150/microL were associated with an increased risk for histoplasmosis. Histoplasmin reactivity and the presence of pulmonary calcifications were not useful markers for patients at high risk. Symptomatic infection occurred in 9.9% of patients with evidence of prior exposure to H. capsulatum, in 4.0% of patients without documented prior exposure, and in 3.0% of patients who were anergic; these findings suggest that the pathophysiology of histoplasmosis in patients with AIDS involves reactivation of latent infection in some cases and dissemination of exogenously acquired infection in other cases.

Fluconazole therapy for histoplasmosis. The National Institute of Allergy and Infectious Diseases Mycoses Study Group.

We assessed the efficacy of oral fluconazole (200-800 mg daily) in the treatment of non-life-threatening acute pulmonary histoplasmosis, chronic pulmonary histoplasmosis, or disseminated histoplasmosis in patients without human immunodeficiency virus infection. Of 27 evaluable patients, two had progressive acute pulmonary histoplasmosis, 11 had chronic pulmonary histoplasmosis, and 14 had disseminated histoplasmosis. Median durations of treatment in each of the three groups were 6 months, 7 months, and 11 months, respectively. Nineteen patients were treated with 400 mg of fluconazole daily (two of these patients received 800 mg daily for a portion of their treatment courses), seven were treated with 200 mg daily, and one was treated with 800 mg daily. Treatment was successful in 17 (63%) of 27 cases. Both of the patients with acute pulmonary infection responded to therapy, as did five (46%) of 11 patients with chronic pulmonary infection and 10 (71%) of 14 patients with disseminated infection. No substantial toxicity was observed. We conclude that fluconazole therapy for histoplasmosis is only moderately effective and should be reserved for patients who cannot take itraconazole.

The effect of a portable HEPA-filtered body exhaust system on airborne microbial contamination in a conventional operating room.

OBJECTIVE: To study the effect of a portable HEPA-filtered air exhaust system (Stackhouse Freedom Surgical Helmet System) on airborne microbial contamination in a modern conventional operating room. DESIGN AND SETTING: Microbial air sampling was done with a two-stage Anderson sampler at the wound site during 46 total joint replacements. All operations were performed by the same surgeon in the same operating room at a large community hospital. RESULTS: In 18 cases done without air exhaust hoods, the number of bacterial and fungal colony-forming units (CFU) ranged from 0.6 to 11.7 (mean, 3.6). Air sampling during 28 operations with the operating team in air exhaust hoods revealed a mean of 3.6 CFU (range, 0 to 11.4). Bacterial CFU averaged 3.4 without hoods and 3.2 with exhaust hoods. Coagulase-negative staphylococci were the most common isolates (48% of isolates with hood, 55% without hood). No infections occurred. CONCLUSION: We concluded that these air exhaust hoods did not lower airborne microbial contamination detectable with this air sampling method, as compared to standard head cover and mask, in a modern conventional operating room.

A prospective study of 2,092 "curbside" questions asked of two infectious disease consultants in private practice in the midwest.

We prospectively studied 2,092 consecutive informal (or "curbside") consultations (CCs) posed of two infectious disease (ID) consultants in private practice in different cities. The frequency of CCs was similar for the two physicians: 31 and 30 per month. The majority of CCs (69%) were initiated by staff physicians, of whom 47% were engaged in primary care. The average duration of CCs was 5.1 minutes overall and increased significantly from 3 minutes in 1990 to 7 minutes in 1994 for one consultant (P < .0001). Overall, 52% of questions asked by staff physicians were considered inappropriate (on the basis of their complexity); this rate increased from 40% in 1990 to 53% in 1994 for one physician (P = .005). Although a variety of subject matters were represented, questions concerning treatment of specific infections were the most common. We conclude that the demand for community-based ID physicians' informal advice remains significant. Any need-assessment for the practice of these specialists in the community should take into account their often unrecognized direct and indirect contribution to the care of many patients they never formally see.

Treatment of lymphocutaneous and visceral sporotrichosis with fluconazole.

Thirty patients with documented sporotrichosis were treated with 200-800 mg of fluconazole daily. Fourteen patients had lymphocutaneous infection; only five (36%) of these patients had any underlying illnesses. Sixteen patients had osteoarticular or visceral sporotrichosis; 12 (75%) of these patients had underlying diseases, mostly alcoholism, diabetes mellitus, and chronic obstructive pulmonary disease. Eleven of the 30 patients had relapsed after prior antifungal therapy. Most patients were treated with 400 mg of fluconazole; however, four received 200 mg of fluconazole daily for the entire course, and four received 800 mg of fluconazole daily for a portion of their therapy or for the entire course of therapy. Fluconazole therapy cured 10 (71%) of 14 patients with lymphocutaneous sporotrichosis. However, only five (31%) of 16 patients with osteoarticular or visceral sporotrichosis responded to therapy; the conditions of two of these five patients improved only, and there was no documented cure of their infections. With the exception of alopecia in five patients, toxic effects were minimal. Fluconazole is only modestly effective for treatment of sporotrichosis and should be considered second-line therapy for the occasional patient who is unable to take itraconazole.

Alopecia associated with fluconazole therapy.

OBJECTIVE: To describe the association between fluconazole and reversible alopecia. DESIGN: A retrospective survey of 1) patients enrolled in NIAID Mycoses Study Group (MSG) protocols involving the long-term use of fluconazole for treatment of endemic mycoses and 2) patients treated with fluconazole outside of a protocol setting but by the MSG investigators who were MSG members. SETTING: 26 MSG sites in the United States. PATIENTS: 33 patients with various deep and superficial mycoses who developed alopecia while receiving fluconazole. RESULTS: 11 of 26 investigators reported a total of 33 patients with substantial alopecia related to fluconazole therapy. Underlying mycoses included blastomycosis, sporotrichosis, histoplasmosis, cryptococcosis, coccidioidomycosis, and mucosal candidiasis. In separate MSG studies, 17 of 136 (12.5%) and 8 of 40 (20%) patients had substantial reversible alopecia associated with fluconazole therapy. Eight patients who were not in the protocol had similar adverse effects. Twenty-nine of 33 patients (88%) received at least 400 mg of fluconazole daily for a mean of 7.1 months. Alopecia developed a median of 3 months after initiation of fluconazole therapy and involved the scalp in all patients. Other sites were involved in about one third of patients. Three patients required wigs because of extensive hair loss. Alopecia resolved within 6 months of discontinuation of fluconazole therapy or reduction of the daily dose by at least 50%. CONCLUSIONS: Alopecia appears to be a common adverse event associated with higher-dose (400 mg/d) fluconazole given for 2 months or longer. This effect may be severe but is reversed by discontinuing fluconazole therapy or substantially reducing the daily dose.

Mycobacterium kansasii among patients infected with human immunodeficiency virus in Kansas City. Kansas City AIDS Research Consortium.

Previous reports of infection due to Mycobacterium kansasii among patients infected with human immunodeficiency virus (HIV) have conflicted with regard to the significance of the isolate; the clinical, radiographic, and laboratory features of the disease; and the response to therapy. To clarify the spectrum of M. kansasii infection in this population, we conducted a retrospective study of 35 patients. Twenty-eight of these patients were believed to have disease due to M. kansasii, while the remaining seven patients were probably colonized with the organism. All but two patients presented with advanced HIV infection; the median CD4 cell count was 12/microL. Most patients with pulmonary disease presented with fever, cough, and dyspnea, but only eight of these 22 patients had radiographic findings of either pulmonary cavitation or predominantly upper-lobe disease. Ten patients had M. kansasii isolated from blood or bone marrow. The majority of patients with pulmonary or disseminated disease responded to therapy. However, 11 patients died either before mycobacterial infection was diagnosed or early in the course of treatment, and two had a relapse of infection during therapy.

Histoplasmosis in Missouri: historical review and current clinical concepts.

Histoplasmosis is particularly common in Missouri, and many important clinical observations about the disease were made in this state in the 1950s and 1960s. When the AIDS epidemic spread to Missouri in the mid-1980s, histoplasmosis became recognized as a common and important opportunistic infection among Missourians with AIDS. Clinicians must maintain a high level of suspicion for histoplasmosis in any HIV-infected patient who presents with unexplained fever, particularly if the patient has evidence of hepatosplenomegaly, generalized lymphadenopathy, pancytopenia, abnormal liver function tests, or bilateral pulmonary infiltrates. The diagnosis of histoplasmosis can be established rapidly by observation of organisms on peripheral blood smear or bone marrow biopsy specimens or by Histoplasma Polysaccharide Antigen testing. The diagnosis can be confirmed by blood cultures in most cases. Histoplasmosis in AIDS is invariably fatal if not treated. Treatment consists of two phases: initial induction therapy and subsequent lifelong maintenance therapy. Amphotericin B and itraconazole are extremely effective for induction and maintenance therapy; fluconazole appears to be effective maintenance therapy. Strategies for the prevention of histoplasmosis in high risk patients are being evaluated currently.

Recurrent massive pleural effusion due to pleural, pericardial, and epicardial fibrosis in histoplasmosis.

Acute histoplasmosis is generally a benign, self-limited pulmonary infection. Although Histoplasma capsulatum pneumonitis is common, pleural effusions associated with histoplasmosis are quite rare, and massive pleural effusions have not been reported. There have been several reports of pericardial fibrosis secondary to histoplasmosis, but epicardial fibrosis has not been described. We report a biopsy-proven case of histoplasmosis initially associated with recurrent massive pleural effusions and excessive pleural fibrosis causing a trapped lung. The patient later developed constrictive pericarditis. Despite pericardiectomy, severe cor pulmonale occurred, and the patient died. Necropsy demonstrated fibrosis of the epicardium.

Detection of the source of recurrent Staphylococcus aureus bacteremia by ultrafast computerized tomography.

A patient with spina bifida secondary to an Arnold-Chiari deformity experienced seven episodes of sustained bacteremia due to Staphylococcus aureus over 2 years. Despite an extensive diagnostic evaluation the source of the recurrent bacteremia remained obscure. The patient's mother eventually recalled that a procedure for replacement of a ventriculoatrial shunt performed 16 years earlier had been complicated by retention of a shunt fragment in the bloodstream. Standard radiographic techniques failed to identify an intravascular foreign body; however, ultrafast computerized tomography of the heart demonstrated a density in the right atrium. Atriotomy was performed and a plastic catheter fragment was excised. Bacteremia has not recurred during a follow-up period of 24 months. Patients with recurrent unexplained bacteremia should be evaluated carefully for the presence of occult intravascular catheter fragments that may be retained after surgical procedures or intravascular instrumentation. Ultrafast computed tomographic scanning of the heart is a useful technique for detecting intracardiac catheter fragments.