Cryptococcal meningitis: diagnostic value of cryptococcal antigen in cerebrospinal fluid.

In three previously reported cases of cryptococcal meningitis, the only laboratory evidence for this diagnosis was the presence of cryptococcal antigen in the cerebrospinal fluid (CSF). Three additional patients had chronic meningitis and repeatedly negative CSF cultures and had cryptococcal antigen demonstrated in the CSF. In our patients, the diagnosis was further supported by the complete recovery after amphotericin B therapy in two and the demonstration of Cryptococcus neoformans in the meninges at autopsy in the third. In certain patients with chronic meningitis, the detection of cryptococcal antigen in the CSF may be the only means of establishing a diagnosis during life. In such patients, if cryptococcal antigen is present in the CSF in a titer of larger than or equal to 1:8, antifungal therapy should be initiated, pending results of other diagnostic studies.

Posttraumatic Aeromonas hydrophila osteomyelitis.

Aeromonas hydrophila is a gram-negative organism that is the causative agent in several clinical infections. Although it has been reported to cause osteomyelitis in immunocompromised patients, it has not been reported to cause this in the normal host. We describe two patients in whom acute osteomyelitis developed following trauma in freshwater lakes. Cultures yielded A hydrophila, and both patients responded to a two-week course of parenteral antibiotics followed by oral tetracycline hydrochloride in the outpatient setting. Since A hydrophila is a common inhabitant of freshwater lakes, it should be suspected in infections occurring in this epidemiologic setting.

Failure of sulfonamides and trimethoprim in the treatment of nocardiosis.

An immunocompromised patient with Nocardia brasiliensis pneumonia and empyema acquired disseminated disease due to Nocardia asteroides and died. The treatment of choice for pulmonary or disseminated nocardiosis is 6 to 12 g/day of sulfisoxazole (or adjusted dosage to achieve a serum level of 100 to 150 mg/L) continued for six to 18 months. Combination therapy may be beneficial in selected patients; if trimethoprim therapy is used with sulfonamides, higher than usual doses of trimethoprim may be required to achieve optimal antinocardial activity. When the condition of a patient with nocardiosis falls to improve on sulfonamide therapy, patient compliance should be questioned, serum sulfonamide levels should be measured, cultures and susceptibility studies should be repeated, and a search for sequestered pus should be made.

Failure of colchicine in the treatment of Mollaret's meningitis.

A 32-year-old man was hospitalized 23 times in 11 years because of attacks of Mollaret's meningitis. Colchicine (0.6 mg twice daily) was administered for 15 months but failed to decrease the severity or the frequency of attacks. The prophylactic efficacy of drugs in Mollaret's meningitis is difficult to assess because episodes are unpredictable and remissions occur spontaneously. There remains no established therapy for Mollaret's meningitis.

High-dose ketoconazole therapy and adrenal and testicular function in humans.

Ketoconazole, an oral antifungal, when given in conventional doses, transiently blocks testosterone synthesis and adrenal response to corticotropin. Higher therapeutic doses (ie, 800 to 1,200 mg/day), even once daily, caused more prolonged blockade. In some men, the serum testosterone concentrations were always subnormal. Bound and free testosterone values were equally diminished. Oligospermia and azospermia after prolonged therapy were noted. Impotence and decreased libido were found. Gynecomastia appeared more common than with lower doses. Depressed response to corticotropin was pronounced. Urine cortisol excretion was depressed. The blockade appeared related to the serum ketoconazole concentration. Instances of normal hormone levels or responsiveness were associated with low ketoconazole concentrations. The hormonal effects were generally unrelated to duration of therapy, although there may have been partial reversal with continued therapy. These effects appeared reversible with discontinuation of therapy. Patients receiving ketoconazole should be considered potentially unable to mount an adrenal stress response and may require testosterone supplementation.

Disseminated histoplasmosis in patients with the acquired immune deficiency syndrome.

The ongoing epidemic of acquired immune deficiency syndrome (AIDS) has affected homosexual men, intravenous (IV) drug abusers, Haitians, hemophiliacs, and others. Defects in cell-mediated immunity place these patients at risk for opportunistic infections. We recently saw three men from Alabama with disseminated infection due to Histoplasma capsulatum. Two of these men were homosexual and the other was an IV drug abuser. These three patients had evidence of depressed cellular immunity consistent with a diagnosis of AIDS. Infection caused by organisms indigenous to certain geographic areas of the United States may become more common in patients with AIDS as the epidemic continues.

Spontaneous bacterial peritonitis. A review of pathogenesis, diagnosis, and treatment.

Spontaneous bacterial peritonitis (SBP) is an increasingly recognized complication of cirrhosis with ascites. However, the presence of ascites from any cause appears to be a risk factor for this infection. The etiology of SBP is multifactorial, including derangements in the reticuloendothelial system, abnormalities of both the serum and ascitic fluid humoral immune systems, and systemic bacteremia. Gram-negative enteric pathogens are the etiologic agents in 70% of the cases; anaerobes are an uncommon cause. Fever and abdominal pain are the most common presenting symptoms. However, asymptomatic patients are being increasingly recognized. When SBP is suspected, paracentesis is indicated. An absolute polymorphonuclear leukocyte count greater than 500/mm3 is highly suggestive of SBP. Ascitic fluid lactate and pH may offer additional diagnostic assistance when the PMN count is ambiguous. Appropriate antibiotic therapy should be initially based on the centrifuged Gram stain of ascites as well as the patient's renal function. Mortality is substantial and appears to be related to the severity of the underlying liver disease.

Catastrophic visual loss due to Cryptococcus neoformans meningitis.

We have reviewed our experience with 17 of our own patients with cryptococcal meningitis and 32 cases from the literature. Although this complication is an uncommon event, patients with cryptococcal meningitis may develop visual loss in the absence of other ocular lesions (endophthalmitis or cryptococcomas in the visual pathway) that could explain the visual symptoms. There are 2 distinct patterns of visual loss: rapid visual loss and slow visual loss. Rapid visual loss is characterized by onset of profound visual loss over a period as short as 12 hours before or early in the course of therapy and a clinical syndrome that is strongly suggestive of optic neuritis. Direct invasion of the optic nerve by C. neoformans is demonstrated by cases in this and other reports. Slow visual loss is characterized by slow but progressive visual loss which typically begins later during therapy and may be due to the effects of increased intracranial pressure. While the initial deficit may be mild, patients with slow visual loss can progress to severe visual loss over weeks to months. The only factors that appear to predict either pattern of visual loss are the presence of papilledema, an elevated CSF opening pressure, and a positive CSF India ink preparation. In the 25 visual loss patients for whom data were available for all 3 items, 10 (40%) were positive for all 3, as opposed to only 4 of 114 (3.5%) from a reference group of cryptococcal meningitis patients without visual loss (p < 0.00001). The only therapeutic measures with any degree of consistent success were those directed at reducing intracranial pressure. When begun early and used aggressively, such therapy halted and sometimes even reversed the course of visual loss, particularly in the slow visual loss group. Corticosteroids did not appear to be of value in the small number of patients who received them.

Blastomycosis in immunocompromised patients.

Among the endemic mycoses, blastomycosis has been least often associated with disorders of immune function, but the data presented herein suggest that blastomycosis may occur more commonly in immunocompromised patients than was previously recognized. We have observed a marked increased in the number of immunocompromised patients with blastomycosis over the last 15 years, increasing from about 3% of patients seen between 1956 and 1977 to almost 24% patients seen between 1978 and 1991. The disease appears to be much more aggressive in immunocompromised than in normal hosts. Almost 30% of the patients in our series died secondary to blastomycosis, with most deaths occurring within 5 weeks following the diagnosis. Furthermore, almost one third of those patients who died of other causes had evidence of persistent blastomycosis at death. Multiple organ and central nervous system involvement were relatively common in this series. For these reasons, early and aggressive therapy with amphotericin B is indicated for most immunocompromised patients with blastomycosis. Oral therapy with an azole compound should probably be reserved for patients who have responded to a primary course of amphotericin B but who require additional or long-term suppressive therapy. Until more data are available, the newer azoles should be used with caution as primary therapy in immunocompromised patients with blastomycosis, and considered only in patients with limited disease and a stable underlying condition. Caring for the immunocompromised patient poses many diagnostic and therapeutic challenges to the clinician, and among those patients who have been exposed to areas endemic for blastomycosis, B. dermatitidis must be regarded as a potentially important opportunistic pathogen.

Itraconazole treatment of coccidioidomycosis. NAIAD Mycoses Study Group.

PURPOSE: The purpose of this study was to assess the tolerance and efficacy of itraconazole in the treatment of coccidioidomycosis. PATIENTS AND METHODS: Fifty-one patients with nonmeningeal coccidioidomycosis were considered for treatment with intraconazole. Forty-nine patients who met study criteria were treated with itraconazole given orally in doses of 100 to 400 mg/day for periods up to 39 months. Of these patients, 12 had osteoarticular disease, 23 had chronic pulmonary disease, and 14 had skin or soft tissue disease. Clinical response was evaluated using a scoring system accounting for lesion number and size, symptoms, culture, and serologic titer. Remission was defined as reduction of the pretreatment score by 50% or more. RESULTS: Patients with osteoarticular, chronic pulmonary, and soft tissue disease improved at similar rates. Because two patients had no scoring assessment for efficacy, they were considered inassessable for efficacy. Forty-seven patients are evaluable. Of these patients, 44 have completed therapy, and three are still receiving itraconazole. Of the 44 patients no longer receiving therapy, 25 (57%) achieved remission. Of the 25 patients achieving remission, four later experienced a relapse. Therapy failed in 19 patients (43%). Of these cases, 16 (36%) were clinical failures and three (7%) developed drug intolerance that precluded continuation of treatment. Evaluation of culture conversions was of limited value in the osteoarticular patients, fewer than half of whom had follow-up biopsies. However, culture conversions were a useful index of response in patients with chronic pulmonary disease. During the course of treatment, serologic titers declined in the two groups with extrapulmonary disease, but not in patients with pulmonary coccidioidomycosis. Possible toxicities were generally mild. CONCLUSION: Itraconazole appears efficacious and very well tolerated in patients with coccidioidomycosis.

Ketoconazole therapy of progressive coccidioidomycosis. Comparison of 400- and 800-mg doses and observations at higher doses.

One hundred and twelve patients with progressive pulmonary, skeletal, or soft tissue infections caused by Coccidioides immitis were randomly assigned to treatment with 400 or 800 mg per day dosages of ketoconazole. During therapy, if response was unsatisfactory, the protocol provided for treatment with higher doses. With 400 mg, ketoconazole resulted in 23.2 percent successes, which was similar to 32.1 percent successes with 800-mg treatments (p = 0.29). An additional six of 23 patients in whom initial therapy failed and who later received 1,200 or 1,600 mg per day of ketoconazole also showed improvement. However, among patients completing successful courses of therapy, relapses were more frequent in those requiring higher than 400-mg dosages for their success. From these studies, it is concluded that ketoconazole in doses above those currently recommended offer little or no benefit for most patients with non-meningeal forms of coccidioidomycosis.

Late prosthetic valve endocarditis: clinical features influencing therapy.

To assess the clinical features which might influence therapy, we studied 43 patients with late prosthetic valve endocarditis (LPVE). Twenty patients (47 per cent) survived. Of patients with streptococcal LPVE 61 per cent (11 of 18) survived compared to 36 per cent (nine of 25) of the patients with nonstreptococcal LPVE (p less than 0.10). Among patients with new regurgitant murmurs 33 per cent (nine of 27) survived versus 69 per cent (11 of 16) with such murmurs (p less than 0.03). Of patients with moderate to severe congestive heart failure (CHF) 16 per cent (three of 19) survived compared to 71 per cent (17 of 24) with mild or no CHF (p less than 0.001). The concurrence of two of these three features, i.e., nonstreptococcal etiology, a new regurgitant murmur or moderate to severe CHF, was associated with a mortality rate of 50 to 90 per cent. Persistent fever during therapy, a regurgitant murmur, atrioventricular conduction disturbances and relapse frequently reflected myocardial invasion. In view of the poor outcome with medical therapy and late reoperation, early surgical intervention should be considered when two of the three features noted are present or when myocardial invasion is suspected.

Treatment of sporotrichosis with itraconazole. NIAID Mycoses Study Group.

PURPOSE: To describe the clinical presentation and outcomes of treatment with itraconazole in patients with sporotrichosis. METHODS: A culture for Sporothrix schenckii or compatible histopathology was required for inclusion in the study. Patients with both cutaneous and systemic sporotrichosis were treated. Patients received from 100 to 600 mg of itraconazole daily for 3 to 18 months. Patients were classified as responders or nonresponders. Responders were further classified as remaining on treatment, relapsed, or free of disease. Nonresponders included patients who failed to respond or progressed during treatment with itraconazole. RESULTS: Twenty-seven patients (mean age: 53 years) were treated with 30 courses of itraconazole. Diabetes mellitus and alcoholism were present in eight and seven patients, respectively. Sites of involvement included lymphocutaneous alone in 9 patients, articular/osseous in 15 (multifocal in 3), and lung in 3. Prior therapy was unsuccessful in 11 patients. Among the 30 courses, there were 25 responders and 5 nonresponders. All 5 nonresponders received at least 200 mg daily of itraconazole for durations that ranged from 6 to 18 months. Of the 25 responders, 7 relapsed 1 to 7 months after treatment durations of 6 to 18 months. Of the 7 who relapsed, 2 are responding to a second course. One responder was lost to follow-up after 10 months of treatment with itraconazole. Of the remaining 17 responders, 3 remain on treatment, and 14 are free of disease over follow-up durations of 6 to 42 months (mean: 17.6 months). Itraconazole was well tolerated with few side effects noted. CONCLUSIONS: These results document the efficacy of itraconazole in the treatment of cutaneous and systemic sporotrichosis.

Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis.

A multicenter prospective randomized trial of four versus six weeks of amphotericin B, 0.3 mg/kg per day, plus flucytosine, 150 mg/kg per day, was performed with 194 patients with cryptococcal meningitis. One or more toxic drug reactions developed in 103 patients: azotemia (51), renal tubular acidosis (two), leukopenia (30), thrombocytopenia (22), diarrhea (26), nausea/vomiting (10), and hepatitis (13). The four- and six-week regimens were complicated by toxicity in 44 percent and 43 percent of cases, respectively. Toxicity appeared during the first two weeks of therapy in 56 percent and during the first four weeks in 87 percent. Azotemia did not occur more frequently in renal transplant recipients or diabetic patients. Cytopenias did not appear more often in patients with hematologic malignancies or those receiving immunosuppressive therapies. Toxic reactions that contributed to death developed in five patients (two with azotemia, one with pancytopenia, one with hepatitis, one with ileus). Amphotericin B-induced azotemia was not a significant risk factor for the subsequent development of bone marrow, gastrointestinal, or hepatic toxicity attributable to flucytosine. Flucytosine toxicity was associated with peak serum flucytosine levels of 100 micrograms/ml or more during two or more weeks of therapy (p = 0.005). Peak 5-fluorouracil levels were not predictive of toxicity. An initial dose of flucytosine is recommended based on the creatinine clearance: 150 mg/kg per day at a creatinine clearance above 50 ml/minute, 75 mg/kg per day at a creatinine clearance of 26 to 50 ml/minute, and 37 mg/kg per day at a creatinine clearance of 13 to 25 ml/minute. The serum creatinine level should be monitored twice weekly and the creatinine clearance weekly during therapy in order to anticipate changes in serum flucytosine concentration. In addition, it is recommended that the serum flucytosine level be determined two hours after an oral dose once a week, and that the dose be adjusted to maintain a level of 50 to 100 micrograms/ml.

Itraconazole therapy for blastomycosis and histoplasmosis. NIAID Mycoses Study Group.

OBJECTIVE: To assess the efficacy and toxicity of orally administered itraconazole in the treatment of nonmeningeal, nonlife-threatening forms of blastomycosis and histoplasmosis. DESIGN: Prospective, nonrandomized, open trial. SETTING: Multicenter trial at 14 university referral centers. PATIENTS: Eighty-five patients with culture or histopathologic evidence of blastomycosis (48 patients) or histoplasmosis (37 patients). Patients receiving other systemic antifungal therapy were excluded. INTERVENTIONS: Itraconazole was administered orally at doses of 200 to 400 mg/d. Patients in whom treatment was considered a success were treated for a median duration of 6.2 months (blastomycosis) and 9.0 months (histoplasmosis). Disease activity was assessed at baseline; drug efficacy and toxicity were evaluated at monthly intervals during therapy, and efficacy was evaluated at regular follow-up visits after completion of therapy. The median duration of posttreatment evaluation for successfully treated patients was 11.9 months (blastomycosis) and 12.1 months (histoplasmosis). MEASUREMENTS AND MAIN RESULTS: Among the 48 patients with blastomycosis, success was documented in 43 (90%). The success rate for patients treated for more than 2 months was 95% (38 of 40). Among the 37 patients with histoplasmosis, success was documented in 30 (81%). The success rate for patients treated for more than 2 months was 86% (30 of 35). All patients with histoplasmosis in whom treatment failed had chronic cavitary pulmonary disease. Toxicity was minor; only 25 (29%) patients experienced any side effects, and itraconazole toxicity necessitated stopping therapy in only 1 patient. CONCLUSIONS: Itraconazole is a highly effective therapy for nonmeningeal, nonlife-threatening blastomycosis and histoplasmosis. The drug is associated with minimal toxicity.

Treatment of histoplasmosis and blastomycosis.

Prior to the development of ketoconazole, the treatment of systemic histoplasmosis and blastomycosis was limited to AMB. The convenience of oral dosing, combined with avoidance of the significant toxicities associated with AMB, make ketoconazole an attractive alternative for the treatment of selected forms of histoplasmosis and blastomycosis. Although high-dose (800 mg/day) ketoconazole is generally more effective than low-dose (400 mg/day), therapy should be initiated at the lower dose due to significantly more adverse effects at higher doses; the daily dose should be increased in patients with progressive disease. Caution should be exercised when ketoconazole is used to treat patients with GU tract disease and in patients with naturally occurring or pharmacologically induced achlorhydria. Thus, AMB remains the drug of choice for difficult to treat cases of histoplasmosis and blastomycosis; however, recent studies have established ketoconazole as the drug of choice in immunocompetent patients with non-life-threatening, non-meningeal H capsulatum and B dermatitidis disease.

Evolution of reactive lymphadenopathy into lymphoma over a nine-year period. A clinicopathologic study.

Reported is a case of lymphoma which was preceded for nine years by an apparently reactive lymphadenopathy. Original slides of the multiple lymphoid tissue samples are reviewed, with emphasis on the gradually increasing numbers of mitoses, atypical histiocytes, and eosinophils, suggestive of malignant transformation. The scarcity of such cases in the literature prompts this report.

Ketoconazole treatment of coccidioidal meningitis.

Fifteen patients with coccidioidal meningitis were treated with high doses of ketoconazole for up to 4 years. Five patients were treated with ketoconazole alone. One clinically failed, one developed hepatotoxicity, and three achieved remission of meningitis. One patient received intrathecal AMB in addition to ketoconazole for only 2 weeks before continuing on ketoconazole alone. He improved, but discontinued ketoconazole because of nausea and vomiting, and suffered a lethal relapse. Nine patients received ketoconazole in combination with prolonged courses of intrathecal AMB. Two patients were failures from nausea and vomiting, and the remaining seven either improved or experienced remission. The clinical responses appeared to be similar in patients receiving high-dose ketoconazole, either alone or combined with AMB, suggesting that there is no clinically significant antagonism of the drugs. Nausea and vomiting are significant limitations of high-dose ketoconazole. Ketoconazole alone is effective in some patients with coccidioidomycotic meningitis.

Biochemical serogrouping of clinical isolates of Cryptococcus neoformans.

Three hundred twenty-three clinical isolates of Cryptococcus neoformans of diverse geographic origins were biochemically serogrouped using glycine-cycloheximide-phenol red agar (GCP), the same medium less cycloheximide (GOP), and glycine-L-canavanine bromothymol blue agar (CGB). Twenty isolates gave positive reactions on all three media typical of the B and C serotypes. Three were from the Peoples' Republic of China; three each were from Michigan (two patients) and Louisiana; two each were from California, Georgia, and Virginia; and one each was from Alabama, Florida, North Carolina, Oklahoma, and Tennessee. Two hundred seventy-six isolates were identified as belonging to the A/D serogroup; 272 were of American origin and four were from China. Twenty-seven isolates were biochemically ungroupable. Evaluations of the reactions on all three media were open to subjective interpretations. Utilization of glycine was the most frequent atypical variable; 36 of 276 (13%) A/D isolates utilized glycine while being inhibited by either GCP or CGB or both. Significant differences between A/D and B/C serogroups in terms of susceptibility to 5-fluorocytosine but not to amphotericin B were observed; B/C serogroup isolates appeared to be less susceptible to 5-fluorocytosine in vitro than were the A/D serogroup isolates. These results provided new evidence on the distribution of B/C serogroup isolates of C. neoformans in America and demonstrate the difficulties of using biochemical tests for serotyping purposes. They also offer a possible explanation for the apparent more refractory therapeutic responses of infections caused by B and C serotypes to conventional antifungal chemotherapy.

Citrobacter diversus endocarditis.

Citrobacter species are motile Gram-negative bacilli that cause disease in humans, such as urinary tract infection, pneumonia, superficial and deep wound infections, gastroenteritis, meningitis, bacteremia, and rarely endocarditis. In those cases of endocarditis, intravenous drug use has been associated with Citrobacter species. Gram-negative organisms are present in less than 10% of cases of endocarditis in intravenous drug users. We present a case of tricuspid valve endocarditis in an intravenous drug user caused by Citrobacter diversus alone.