Gerald Medoff

A Comparison of Amphotericin B Alone and Combined with Flucytosine in the Treatment of Cryptoccal Meningitis

We compared amphotericin B therapy for cryptococcal meningitis with a newer regimen containing both amphotericin B and flucytosine. In 50 patients with 51 courses of therapy adherent to the protocol, 27 courses were with amphotericin B and 24 with the combination. Even though the combination regimen was given for only six weeks and amphotericin B for 10 weeks, the combination cured or improved more patients (16 vs 11), produced fewer failures or relapses (three vs. 11), more rapid sterilization of the cerebrospinal fluid (P less than 0.001) and less nephrotoxicity (P less than 0.05) than did amphotericin B alone. The number of deaths was the same (five) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening. We conclude that combined flucytosine-amphoericin B therapy is the regimen of choice in cryptococcal meningitis.

Amphotericin B: current understanding of mechanisms of action.

This minireview describes the problems associated with the use of Amphotericin B and what is known about the mechanism(s) of its action. The efforts to design a more efficient vehicle for AmB are summarized in the following minireview (8)

Treatment of Cryptococcal Meningitis with Combination Amphotericin B and Flucytosine for Four as Compared with Six Weeks

One hundred ninety-four patients with cryptococcal meningitis were enrolled in a multicenter, prospective, randomized clinical trial to compare the efficacy and toxicity of four as compared with six weeks of combination amphotericin B and flucytosine therapy. Among 91 patients who met preestablished criteria for randomization, cure or improvement was noted in 75 percent of those treated for four weeks and in 85 percent of those treated for six weeks. The estimated relapse rate for the four-week regimen was higher--27 as compared with 16 percent--whereas the incidence of toxic effects for the two regimens was similar--44 as compared with 43 percent. Among 23 transplant recipients, 4 of 5 treated for four weeks relapsed, leading to the decision to treat the rest of the group for six weeks. Only 3 of the 18 treated for six weeks relapsed. In a third group of 80 patients, the protocol was not followed during the initial four weeks, and these patients were not randomized. Thirty-eight died or relapsed. Multifactorial analysis of pretreatment factors for all 194 patients identified three significant predictors (P less than 0.05) of a favorable response: headache as a symptom, normal mental status, and a cerebrospinal fluid white-cell count above 20 per cubic millimeter. These and other findings in this study are consistent with the view that the four-week regimen should be reserved for patients who have meningitis without neurologic complications, underlying disease, or immunosuppressive therapy; a pretreatment cerebrospinal fluid white-cell count above 20 per cubic millimeter and a serum cryptococcal antigen titer below 1:32; and at four weeks of therapy, a negative cerebrospinal fluid India ink preparation and serum and cerebrospinal fluid cryptococcal-antigen titers below 1:8. Patients who do not meet these criteria should receive at least six weeks of therapy.

Strategies in the Treatment of Systemic Fungal Infections

IN the past few years, there has been an increase in the number of systemic fungal infections seen in clinical practice. These infections have been of two types: those due to primary pathogens such...

Amphotericin B-resistant yeast infection in severely immunocompromised patients

Systemic yeast infections are a major cause of morbidity and mortality in severely immunocompromised patients. The in vitro susceptibility to amphotericin B of 29 yeasts causing fungemia was examined in 26 patients undergoing allogeneic or autologous bone marrow transplantation and/or myelosuppressive chemotherapy. The minimal inhibitory concentrations (MICs) of amphotericin B observed with blood isolates from these patients were significantly higher than those observed with blood, sputum, or skin isolates from non-immunocompromised patients (p less than 0.01). All episodes (10 of 10) of bloodstream infection in immunocompromised patients caused by isolates with MICs greater than 0.8 micrograms/ml were fatal, versus eight of 17 episodes of bloodstream infection caused by yeasts with MICs of 0.8 micrograms/ml or less (p = 0.04). Although 15 of 26 patients received empiric treatment with amphotericin B before laboratory evidence of fungemia developed, the amphotericin B susceptibilities of their isolates were not significantly different from those of patients who had not received empiric amphotericin B treatment. It is concluded that yeast fungemia in severely immunocompromised patients is often caused by organisms resistant to the usual concentrations of amphotericin B obtainable in vivo, and that this finding is clinically significant.

Antibiotic Synergism Against Listeria monocytogenes

The effectiveness of ampicillin, penicillin, streptomycin, and gentamicin against 20 strains of Listeria monocytogenes was studied in vitro. For all strains, the minimal bactericidal concentration (MBC) of both ampicillin and penicillin was much higher than the minimal inhibitory concentration (MIC). The MBC of both streptomycin and gentamicin was close to the MIC, but relatively high concentrations of these antibiotics were necessary to inhibit the growth of most of the strains of Listeria. The combination of penicillin plus streptomycin was synergistic against 19 of 20 strains and in the remaining strain produced enhanced killing (but of less magnitude than our criterion for synergism). Combinations of penicillin plus gentamicin, ampicillin plus streptomycin, and ampicillin plus gentamicin produced enhanced killing against all strains tested. No antagonism was observed when ampicillin or penicillin was combined with streptomycin or gentamicin.

Antibiotic cost savings from formulary restrictions and physician monitoring in a medical-school-affiliated hospital

Strictly enforced formulary restrictions for aminoglycosides, cephalosporins, and a vancomycin group generated combined savings of

Treatment of Systemic Mycoses with Ketoconazole: Emphasis on Toxicity and Clinical Response in 52 Patients: National Institute of Allergy and Infectious Diseases Collaborative Antifungal Study

2.61 (p less than 0.0046) per antibiotic day and

Antimicrobial misuse in patients with positive blood cultures

34,597 (p less than 0.0003) per month. Even after some cost increases (not significant) in new and other antibiotics, the program saved

Classification of Polyene Antibiotics According to Chemical Structure and Biological Effects

1.33 (p less than 0.0175) per antibiotic day and