Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature.

Histoplasmosis is a serious opportunistic infection in patients with AIDS, often representing the first manifestation of the syndrome. Most infections occurring within the endemic region are caused by exogenous exposure, while those occurring in nonendemic areas may represent endogenous reactivation of latent foci of infection or exogenous exposure to microfoci located within those nonendemic regions. However, prospective investigations are needed to prove the mode of acquisition. The infection usually begins in the lungs even though the chest roentgenogram may be normal. Clinical findings are nonspecific; most patients present with symptoms of fever and weight loss of at least 1 month's duration. When untreated, many cases eventually develop severe clinical manifestations resembling septicemia. Chest roentgenograms, when abnormal, show interstitial or reticulonodular infiltrates. Many cases have been initially misdiagnosed as disseminated mycobacterial infection or Pneumocystis carinii pneumonia. Patients are often concurrently infected with other opportunistic pathogens, supporting the need for a careful search for co-infections. Useful diagnostic tests include serologic tests for anti-H. capsulatum antibodies and HPA, silver stains of tissue sections or body fluids, and cultures using fungal media from blood, bone marrow, bronchoalveolar lavage fluid, and other tissues or body fluids suspected to be infected on clinical grounds. Treatment with amphotericin B is highly effective, reversing the clinical manifestations of infection in at least 80% of cases. However, nearly all patients relapse within 1 year after completing courses of amphotericin B of 35 mg/kg or more, supporting the use of maintenance treatment to prevent recurrence. Relapse rates are lower (9 to 19%) in patients receiving maintenance therapy with amphotericin B given at doses of about 50 mg weekly or biweekly than with ketoconazole (50-60%), but controlled trials comparing different maintenance regimens have not been conducted. Until results of such trials become available, our current approach is to administer an induction phase of 15 mg/kg of amphotericin B given over 4 to 6 weeks, followed by maintenance therapy with 50 to 100 mg of amphotericin B given once or twice weekly, or biweekly. If results of a prospective National Institutes of Allergy and Infectious Disease study of itraconazole maintenance therapy document its effectiveness, alternatives to amphotericin B may be reasonable.

Subcutaneous phaeohyphomycosis of the finger caused by Exophiala spinifera.

A patient with severe rheumatoid arthritis treated with prednisone had a painless soft tissue nodule develop on the dorsal aspect of the ring finger. She denied any history of hand trauma, animal exposure, or systemic symptoms such as fever or malaise. Fungal cultures performed on an aseptically obtained aspirate of this lesion demonstrated dark, olive-black creamy colonies on Sabouraud's agar. Slide cultures made from mold colonies produced slender conidial forms with annellations and spine-like conidiophores, features characteristic of Exophiala spinifera. The lesion was surgically excised, and the patient was successfully treated with a course of oral itraconazole. This nodular lesion has not recurred at the time of this writing. Exophiala species are difficult to differentiate, and E. spinifera may be confused with Exophiala jeanselmei. A literature review will consider Exophiala species and clinical manifestations produced by these dematiaceous fungi.

Single- and multiple-dose pharmacokinetics of moxalactam in normal subjects.

The pharmacokinetics of moxalactam were studied in 86 normal adult male volunteers who received single or multiple doses intravenously or intramuscularly. The short absorption half-times and lag times indicate that the intramuscular dose is rapidly absorbed. The mean plasma half-life was 1.85 +/- 0.24 h for intravenous doses and 2.24 +/- 0.44 h for intramuscular doses. The mean renal clearances for intravenous doses were 0.052 and 0.067 liters/kg per h for intramuscular doses. Although moxalactam is eliminated primarily by the kidney a chromatogram of the feces from volunteers who received multiple doses showed that it is also excreted as the parent compound in to the feces via the biliary tract. The pharmacokinetics parameters of moxalactam when administered intravenously or intramuscularly in single and multiple doses clearly show the kinetics of moxalactam are linear over the dosage ranges studied and are independent of dose.

Effect of probenecid on the pharmacokinetics of moxalactam.

The effects of probenecid on the pharmacokinetics of moxalactam were studied in normal volunteers administered a 2-min l-g intravenous infusion. The results showed that probenecid did not alter the plasma or urinary concentrations of moxalactam, its apparent volume of distribution, plasma elimination half-life, elimination rate constant, or plasma and renal clearances. Therefore, moxalactam appears to be eliminated primarily by the kidney via glomerular filtration.

Pharmacology of cinoxacin in humans.

Cinoxacin was almost completely absorbed when given orally and was found to be approximately 60 to 70% protein bound. Peak serum concentrations were reached within 2 h, and detectable serum concentrations persisted up to 12 h after administration of 0.25-, 0.5-, and 1-g multiple oral doses. Although food delayed the absorption and caused a 30% reduction in mean peak serum concentrations, the overall 24-h urinary recovery was not significantly altered. Approximately 50 to 55% of the drug was excreted in the urine as unchanged drug. At 12 h, urine concentrations were still above the minimal inhibitory concentration for most common gram-negative urinary pathogens. Cinoxacin was well tolerated when administered to 23 volunteers from 10 to 28 days. Resistance among fecal isolates initially susceptible to cinoxacin was not observed in nine volunteers who were administered 0.5 g every 12 h for 4 to 28 days.

Cinoxacin: pharmacokinetics and the effect of probenecid.

Cinoxacin is a new synthetic organic antibacterial compound which has a serum half-life of approximately 1 hour. Most of the drug is eliminated in man by the kidney, primarily as unchanged drug. The renal clearance of cinoxacin is slightly greater than the usually accepted value for the average glomerular filtration rate, which suggests that it is probably filtered and is also secreted by the tubule. Results after pretreatment with probenecid further suggest secretion of the drug.

Histoplasmosis in immunosuppressed patients.

Infection with Histoplasma capsulatum in 58 patients whose immune responses were suppressed (Immunosuppressed patients) (16 from the present series and 42 described previously) was analyzed. The most common underlying diseases were Hodgkin's disease (29 per cent), chronic lymphocytic leukemia (19 per cent) and acute lymphocytic leukemia (17 per cent). Sixty-three per cent of the patients had received cytotoxic drugs, and 57 per cent had taken corticosteroids. Widely disseminated infection occurred in 88 per cent of the patients, with predominant involvement of lungs and organs of the reticuloendothelial system. Localized pulmonary infection was present in the remaining patients. The most useful diagnostic method was bone marrow biopsy with microscopic examination for the intracellular yeast form of H. capsulatum. Biopsy of oral lesions, lung, liver and lymph node also proved diagnostically helpful. Growth of H. capsulatum in culture was frequently too slow to be beneficial in diagnosing histoplasmosis in ill patients. Serologic methods were of little diagnostic help in this population of immunosuppressed patients. The response to amphotericin B therapy was excellent (6.7 per cent mortality rate) in those patients in whom the diagnosis was established early and in whom a full course of antifungal therapy could be given. In contrast, the mortality rate in patients who received no antifungal therapy or less than 1 g of amphotericin B was 100 per cent.

Bactericidal and opsonic activity against Neisseria gonorrhoeae in sera from patients with disseminated gonococcal infection.

Bactericidal and opsonic activities in convalescent-phase sera from patients with disseminated gonococcal infection (DGI) were analyzed with use of the patients' infecting strains and other strains of Neisseria gonorrhoeae. Serum from a patients with C8 deficiency was opsonic for her first DGI isolate grown on solid medium or in chick embryos; with added complement the serum was bactericidal (at a dilution of 1:320). Her serum was not bactericidal for nine other isolates from patients with DGI. Only one of the other patients with DGI had detectable serum bactericidal activity (dilution, 1:2,5) against her own isolate; this patient's serum was also active against one other DGI isolate. Opsonization was detectable only in sera that were potentially bactericidal and could be distinguished from bactericidal activity only with C8-deficient serum. The isolates from patients with DGI were of an auxotype different from that of most other gonococci, and most of the isolates tested were not killed by sera from patients with uncomplicated gonorrhea, even though these wera killed other gonococci. Thus, isolates from patients with DGI appeared to be significantly different from other gonococcal isolates.

Aspects of the pharmacology and toxicology of tobramycin in animals and humans.

The pharmacology and toxicology of tobramycin in animals and humans are reviewed. After intramuscular and intravenous administration, tobramycin diffuses throughout most body tissues and tissue fluids. Therapeutic concentrations can be obtained by intravitreal or intradural injections. Dogs tolerate intracisternal doses of 0.2 mg/kg without adverse reaction. The half-life of tobramycin in cochlear fluid of guinea pigs and in renal tissues of rats is significantly longer than the serum half-life in these species and is reflected in the ototoxic and nephrotoxic potential of tobramycin and other aminoglycosides. In man, the serum half-life of tobramycin is 2 hr; renal clearance, apparent volume of distribution, and recovery from urine are similar to those parameters for gentamicin. The serum half-life in neonates in prolonged (4.5-8.7 hr). Concentrations of tobramycin in serum are effectively reduced by hemodialysis, but peritoneal dialysis is less efficient in elimination of the antibiotic. Tobramycin crosses the placenta and is concentrated in the kidney and urine of the fetus.

Neonatal and childhood gonococcal infections.

Maternal, fetal, and neonatal morbidity and mortality can be significantly decreased by selective screening of prenatal patients for gonorrhea, early treatment, and follow-up cultures after treatment for gonorrhea. Ophthalmia is the most significant neonatal gonococcal infection. Administration of silver nitrate at delivery is the best prophylaxis against gonococcal ophthalmia. Treatment of gonococcal ophthalmia, however, requires parenteral penicillin, conjunctival antimicrobial therapy, and hospitalization. Treatment of the gonococci-infected mother is also indicated. Childhood gonorrhea is most commonly manifested as vulvovaginitis in girls or urethritis in boys, usually without associated disseminated gonococcal infection. Transmission can occur by indirect contact with an infected parent or involuntary or voluntary sexual activity: in children over age 10 years transmission of gonococci most commonly involves voluntary sexual activity. Emphasis should be placed on early treatment of the infected child, follow-up cultures, and contact tracing. Diagnosis of gonococcal infection requires adequate specimens, gram stains, and cultures for N. gonorrhoeae. In disseminated neonatal gonococcal disease, gram strains and cultures of the conjunctiva, oropharynx, orogastric aspirates, anogenital area, umbilicus, and external ear canal frequently aid in the diagnosis. Frequently, a gram strain of the urethral discharge in boys is sufficient for diagnosis of gonorrhea; in girls cultures are necessary. Since the incidence of gonorrhea in children has increased, the importance of epidemiologic analysis and follow-up after treatment can not be overemphasized.