Thomas M. Kerkering

The Evolution of Pulmonary Cryptococcosis: Clinical Implications from a Study of 41 Patients With and Without Compromising Host Factors

Over 14 years 41 patients were diagnosed as having pulmonary cryptococcosis. Cryptococcus neoformans remained localized to the lung in 12 cases and disseminated in the remaining 29. Thirty-four patients were compromised hosts. Disseminated disease developed in 28 of these 34, and four of these 28 patients with disseminated disease presented with concomitant pulmonary and meningeal infections. In all the remaining 24 central nervous system involvement developed 2 to 20 weeks after the finding of an abnormal chest roentgenogram. Seven patients were normal hosts, and in six of these cases disease remained localized to the lung. Four important conclusions were drawn from this study: pulmonary cryptococcosis is rarely considered in the differential diagnosis of an abnormal chest roentgenogram, thereby leading to missed diagnoses and therapeutic errors; the natural history of untreated pulmonary cryptococcosis in compromised hosts is extrapulmonic dissemination; compromised hosts with pulmonary cryptococcosis should receive antifungal therapy because of a high propensity for dissemination; and normal hosts in whom dissemination has been excluded generally do not need antifungal therapy.

Efficacy Testing of Recombinant Human Immunodeficiency Virus (HIV) gp160 as a Therapeutic Vaccine in Early-Stage HIV-1-Infected Volunteers

A phase II efficacy trial was conducted with recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein gp160 (rgp160) in 608 HIV-infected, asymptomatic volunteers with CD4+ cell counts >400 cells/mm3. During a 5-year study, volunteers received a 6-shot primary series of immunizations with either rgp160 or placebo over 6 months, followed by booster immunizations every 2 months. Repeated vaccination with rgp160 was safe and persistently immunogenic. Adequate follow-up and acquisition of endpoints allowed for definitive interpretation of the trial results. There was no evidence that rgp160 has efficacy as a therapeutic vaccine in early-stage HIV infection, as measured at primary endpoints (50% decline in CD4+ cell count or disease progression to Walter Reed stage 4, 5, or 6) or secondary endpoints. A transient improvement was seen in the secondary CD4 endpoint for the vaccination compared with the placebo arm, but this did not translate into improved clinical outcome.

Opportunistic zygomycotic infections

This is a literature review of 361 opportunistic fungal infections caused by the Zygomycetes. The clinical and laboratory diagnosis, pathogenesis, management, treatment, and outcome of infection are discussed. The Zygomycetes are a group of opportunistic fungi (orders Mucorales and Entomophthorales) which cause severe infections which may be fatal. Early clinical recognition, prompt diagnostic procedures, control of underlying disease and treatment with high doses of amphotericin B and aggressive surgery increases survival in an otherwise lethal infection.

Zygomycosis of the basal ganglia in intravenous drug users

Zygomycosis of the basal ganglia should be recognized as a syndrome in intravenous drug users associated with a culture-negative cellular CSF, fever, lethargy, and lesions apparent on contrast-enhanced CT scans of the head. The infection is most likely the result of intravenous inoculation of fungal spores. This entity is different from the rhinocerebral zygomycosis seen with diabetes mellitus and other diseases. In the rhinocerebral form, there are external signs of the disease with involvement of the orbit, paranasal sinuses, and palate. In these drug users, infection was directed to areas deep within the brain.

Early Clinical Observations in Prospectively Followed Patients With Fungal Meningitis Related to Contaminated Epidural Steroid Injections

UNLABELLED Chinese translation BACKGROUND Administration of epidural steroid injections (ESIs) with contaminated methylprednisolone resulted in an outbreak of fungal meningitis in many locations in the United States. OBJECTIVE To characterize early clinical findings and initial response to treatment. DESIGN Case series with standardized observation studied from 4 October to 31 October 2012. SETTING An 800-bed hospital in Virginia. PATIENTS 172 patients who presented to the hospital with exposure to contaminated ESI. INTERVENTION Standardized approach to screening, case definition, treatment, and data collection. MEASUREMENTS Clinical findings, cerebrospinal fluid (CSF) values, magnetic resonance imaging (MRI), serum and CSF voriconazole concentrations, and clinician assessment of response to therapy. RESULTS Of 172 patients presenting to the hospital who had had ESI, 131 had lumbar puncture because of symptoms or signs consistent with central nervous system disease. Twenty-five (19%) had neutrophilic meningitis. All were started on voriconazole therapy alone. Three patients developed stroke during treatment. Ten patients had arachnoiditis, another had an epidural abscess, and 9 had urine retention. Fifteen continued to receive voriconazole, and 10 were switched to amphotericin B. Cerebrospinal fluid leukocyte counts began to decrease by day 13 of treatment. Findings on MRI included ventriculitis, leptomeningeal enhancement, infarction, hemorrhage, and arachnoiditis. Serum voriconazole levels varied, and CSF concentrations of voriconazole were approximately 50% those of serum. Exserohilum rostratum and Cladosporium species have been cultured. LIMITATIONS This is an observational study of an evolving outbreak. Not all exposed patients presented for evaluation. Follow-up is too short to determine final outcomes. CONCLUSION Meningitis after receipt of contaminated ESI has been diagnosed in many exposed patients presenting to 1 hospital. Most patients have improved on receipt of empirical voriconazole therapy. The full natural history and long-term sequelae of this infection are currently unknown. PRIMARY FUNDING SOURCE None.

In-vitro studies with four new antifungal agents: BAY n 7133, bifonazole (BAY h 4502), ICI 153,066 and Ro 14-4767/002

Four new antifungal agents were compared in vitro with miconazole and ketoconazole. The agents were BAY n 7133 and ICI 153,066, two orally active triazoles, and bifonazole (BAY h 4502) and Ro 14-4767/002, both topical agents. While all four were found to be broad spectrum antifungal agents they also demonstrated certain gaps in their spectra. In general, Ro 14-4767/002 was the most active agent tested whereas bifonazole and BAY n 7133 were the least active. Noteworthy activities included that of Ro 14-4767/002 against Candida albicans, the dermatophytes and Sporothrix schenckii and that of ICI 153,066 against Torulopsis glabrata.

Cefmenoxime pharmacokinetics in patients with renal insufficiency.

The pharmacokinetics of cefmenoxime were determined after a 30-min intravenous infusion of 15 mg/kg of total body weight to 33 adult subjects with normal renal function (CLCR, greater than 80 ml/min per 1.73 m2, group I), mild renal insufficiency (CLCR, 40 to 79 ml/min per 1.73 m2, group II), moderate renal insufficiency (CLCR, 10 to 39 ml/min per 1.73 m2, group III), or severe renal impairment, (CLCR, less than 10 ml/min per 1.73 m2, group IV) or to patients between hemodialysis (CLCR, less than 10 ml/min per 1.73 m2, group V). Concentrations of cefmenoxime in serum and urine were determined by high-pressure liquid chromatography, and serum concentrations were fit to a two-compartment model. There was no significant relationship between creatinine clearance and either peak serum concentrations or volume of distribution at steady state. Patients in group I excreted 81% of the dose into the urine within 24 h; recovery decreased with worsening renal function. The mean terminal half-lives in groups I to V were 1.06, 1.50, 3.55, 4.60, and 11.4 h, respectively. There were good linear relationships between creatinine clearance, and the elimination rate and total body clearance of cefmenoxime. Dosage recommendations for subjects with renal insufficiency are proposed.

Cefmenoxime kinetics during continuous ambulatory peritoneal dialysis

SummaryThe kinetics of the aminothiazolyliminomethoxy cephalosporin, cefmenoxime, were determined after a 30 min intravenous infusion of 15 mg/kg body weight in 6 adult subjects undergoing continuous ambulatory peritoneal dialysis. Concentrations of cefmenoxime in serum, urine and dialysate were determined by high-pressure liquid chromatography. The mean peak serum concentration was 92.8±11.6 µg/ml and the harmonic mean for the elimination half-life was 5.46 h. The volume of distribution at steady-state was 14.60±3.01 l/kg. Total body clearance of the drug was 31±7.7 ml/min with 8±5% and 5.75±2.72% of the administered dose being eliminated by renal and peritoneal clearance, respectively. Peritoneal clearance for all exchanges (n=24) was 1.93±68 ml/min. These data suggest that peritoneal losses of this drug are minimal and doses conventionally employed in advanced renal failure can be utilized in the management of systemic infections.