David S. Feingold

Hospital-Acquired Infections

THE major infectious disease problems in most hospitals today are those that occur in the hospital — so-called nosocomial infections. In this discussion I shall define briefly the scope of the prob...

Aerosol polymyxin and pneumonia in seriously ill patients.

Pneumonia caused by Pseudomonas aeruginosa occurs frequently in critically ill patients and is associated with a mortality rate of 70 per cent. An aerosol of polymyxin B was administered (2.5 mg per kilogram per day) to the upper airways of 292 patients in a respiratory-surgical intensive-care unit during a seven-month period, in an attempt to prevent Ps. aeruginosa pneumonia. Although only one of the patients studied acquired pneumonia due to Ps. aeruginosa, 10 others acquired pneumonia caused by a polymysinx-resistant organism. Seven pneumonias were caused by organisms not frequently pathogenic to man (flavobacteria, serratia and Streptococcus faecalis). The mortality rate for acquired pneumonia in this study, 64 per cent, is greater than that in previous studies in which either no polymyxin or cyclic polymyxin therapy was used. Continuous use of polymyxin B aerosol appears to be a dangerous form of therapy.

Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the fingernail.

BACKGROUND Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens of onychomycosis, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of superficial fungal infections. OBJECTIVE The purpose of this study was to compare the efficacy and safety of three different doses of fluconazole (150, 300, and 450 mg) given orally once weekly to that of placebo in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. METHODS In this multicenter, double-blind study, 362 patients with mycologically confirmed onychomycosis were randomized to treatment with fluconazole, 150, 300, or 450 mg once weekly, or placebo once weekly for a maximum of 12 months. To enter the study, patients were required to have at least 25% involvement of the target nail with at least 2 mm of healthy nail from the nail fold to the proximal onychomycotic border. Patients who were clinically cured or improved at the end of treatment were further evaluated over a 6 month follow-up period. At both the end of therapy and the end of follow-up, clinical success of the target nail was defined as reduction of the affected area to less than 25% or cure. RESULTS At the end of therapy, 86% to 89% of patients in the fluconazole treatment groups were judged clinical successes as defined above compared with 8% of placebo-treated patients. Clinical cure (completely healthy nail) was achieved in 28% to 36% of fluconazole-treated patients compared with 3% of placebo-treated patients. Fluconazole demonstrated mycologic eradication rates of 47% to 62% at the end of therapy compared with 14% for placebo. The rates at the end of follow-up were very similar, indicating that eradication of the dermatophyte was maintained over the 6-month period. All efficacy measures for the fluconazole groups were significantly superior to placebo (p=0.0001); there were no significant differences between the fluconazole groups on these efficacy measures. The clinical relapse rate among cured patients over 6 months of follow-up was low at 4%. Fluconazole was well tolerated at all doses over the 12-month treatment period, with the incidence and severity of adverse events being similar between the fluconazole and placebo treatment groups. Mean time to clinical success in the fluconazole treatment groups was 6 to 7 months. This time frame may be used as a guideline for fluconazole treatment duration. CONCLUSION The results of this study support the use of fluconazole in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. Doses between 150 to 450 mg weekly for 6 months were clinically and mycologically effective as well as safe and well tolerated.

Polyene antibiotic action on lecithin liposomes: effect of cholesterol and fatty acyl chains.

Abstract The effect of cholesterol incorporation upon amphotericin B and nystatin susceptibility of lecithin liposome systems containing various fatty acids has been studied. Cholesterol was shown to: 1) confer sensitivity to low concentrations of amphotericin B in liposomes derived from egg lecithin, and 2) suppress the amphotericin B and nystatin-induced response in liposomes derived from dipalmitoyl or distearoyl lecithins. This clear cut difference cannot be explained by mechanisms of drug action so far presented. They are discussed in connection with the possibility that susceptibility to these polyene antibiotics is related to the over-all state of the membrane organization, in particular to the over-all conformation of membrane components.

Extrarespiratory streptococcal infections. Importance of the various serologic groups.

IN the 1940s Rantz1 and Foley2 reported on the frequent isolation from clinical specimens of streptococci belonging to serologic groups other than A. During the last two decades, however, the atte...

BASIS FOR THE SELECTIVITY OF ACTION OF THE POLYMYXIN ANTIBIOTICS ON CELL MEMBRANES

Polypeptide antibiotics are among the most important agents that exert their antibiotic action on cell membranes. Of the several polypeptide antimembrane compounds that have been studied, only the polymyxins have the requisite selective toxicity to be used parenterally to treat infections in humans. Although the polymyxins are in this unique position, little knowledge has been gained on the molecular mechanism of action of these agents since the studies of Newton1 and of Few in the mid 1950s that defined the cytoplasmic membrane as the locus of cytotoxicity. In this paper, the spectrum of activity that the polymyxins exhibit against both naturally occurring and model membranes is detailed. Some observations on the relationship of binding of polymyxin and on the activity on model membranes are described. Data on the effect of pH on polymyxin-induced membrane damage are also presented, From these data and the observations of others, a mechanism by which the antibiotics may act has been suggested.

The action of amphotericin B on Mycoplasma laidlawii

Abstract M. laidlawii grown in cholesterol-free medium are resistant to amphotericin B; when grown in the presence of cholesterol they are sensitive to the drug. Incubation of the resistant organisms in the presence of cholesterol results in a rapid conversion to sensitivity by a temperature-dependent process involving incorporation of sterol into the cells. Similarly, amphotericin B-sensitive M. laidlawii are rendered resistant by incubation in a cholesterol-free medium, and this change is associated with loss of some of the radioactivity previously incorporated from labeled cholesterol.

Selective Membrane Toxicity of the Polyene Antibiotics: Studies on Natural Membranes

The effect of polyene antibiotics on Candida albicans, human erythrocytes, and Acholeplasma laidlawii was studied. The results sustain the observations made with lecithin-sterol liposomes. The distribution of double bonds in the membrane sterol nucleus appears to be of major importance in conferring polyene susceptibility; those sterols with the ergosterol nucleus are far more effective than those with a nucleus similar to cholesterol. Different polyenes vary in their membrane selectivity. The clinical implications of these observations are discussed.

Antimicrobial Chemotherapeutic Agents: The Nature of Their Action and Selective Toxicity

Agents Affecting Protein Synthesis General Comments In bacteria ribosomes are the sites of protein synthesis. These subcellular organelles constitute the workbenches on which amino acids are ordere...

Selective Membrane Toxicity of the Polyene Antibiotics: Studies on Lecithin Membrane Models (Liposomes)

In the absence of sterol, amphotericin B at 5 × 10−6 M caused maximum marker release from the saturated dipalmitoyl lecithin liposomes, minimum release from the unsaturated dioleoyl lecithin liposomes, and an in-between response from egg lecithin liposomes. Nystatin at 2.5 to 4.0 × 10−5 M induced appreciable marker release from all three types of sterol-free liposomes. The amphotericin B- and nystatin-induced permeability changes in dipalmitoyl lecithin liposomes were drastically suppressed by the incorporation of cholesterol or stigmasterol (with identical Δ5 sterol nuclei), but were unaffected by the incorporation of ergosterol or 5,7-cholestadien-3β-ol (with identical Δ5,7 sterol nuclei). The nystatin sensitivity of dioleoyl lecithin liposomes remained low after the incorporation of cholesterol or stigmasterol, but was greatly enhanced by the incorporation of ergosterol or 5,7-cholestadien-3β-ol. Digitonin, a compound known to interact specifically with membrane sterol, induced marker release from liposomes in proportion to the amount of either cholesterol or ergosterol incorporated; epicholesterol did not sensitize to digitonin. These results lead to the following conclusions: (i) polyene-induced permeability alteration in model membrane systems is effected by the composition of membrane phospholipid fatty acyl chains; (ii) the distribution of double bonds in the sterol nucleus is related to the selective toxicity of the polyenes toward natural sterol-containing membranes; and (iii) polyenes differ in membrane selectivity.