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background Benign familial pemphigus (BFP) is a chronic blistering disease with significant morbidity. Surgical methods are often needed to control flares in difficult cases. objective To describe the response of BFP to vaporization with a pulsed carbon dioxide (CO2) laser. methods A 38-year-old woman with chest and axillary involvement unresponsive to conventional therapy was treated with the UltraPulse 5000 Laser (Coherent Medical Group, Palo Alto, CA). After active sites of BFP showed good response to treatment, we treated uninvolved skin of the left axilla to assess the efficacy of prophylactic therapy. results Treatment of affected areas, except biopsy sites, resulted in clearing of active lesions after 1–2 weeks. We noted striking sparing of the treated areas from developing subsequent disease. The region that was later treated prophylactically has shown minor, asymptomatic recurrence of BFP in less than 5% of the area treated over an 18-month follow-up period. conclusion The pulsed carbon dioxide laser is a useful modality in treatment of BFP. In our patient, prophylactic treatment led to near complete eradication of disease in the treated area. A controlled, larger study is needed to confirm our results, and to determine optimal laser parameters. Long-term effects and duration of remission remain to be determined.

Background: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. Objective: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. Methods: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. Results: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steady-state concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. Conclusion: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global outcomes. (J Am Acad Dermatol 1998;38:S110-6.)

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.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.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.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.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.

Background: Preliminary clinical data suggest that fluconazole is effective in the treatment of patients with onychomycosis. To design optimum dosage regimens, a better understanding of fluconazole's distribution into and elimination from nails is needed. Objective: The purpose of this study was to determine plasma and toenail concentrations of fluconazole. Methods: In this multicenter, randomized, double-blind investigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maximum of 12 months to patients with onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail clippings from both affected and healthy nails were obtained for fluconazole concentration determinations at baseline, at the 2-week visit, at each monthly visit until the end of treatment, and then at 2, 4, and 6 months (nail samples only at the latter two) after fluconazole was discontinued. Results: Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median time to reach steady-state fluconazole concentrations in healthy nails was 4 to 5 months in the three fluconazole dose groups. In affected nails, steady-state fluconazole concentrations were achieved more slowly, with a median time of 6 to 7 months. At the 8-month assessment, affected toenail fluconazole concentrations were higher than corresponding plasma fluconazole concentrations, with ratios of 1.31 to 1.50 in the three active treatment groups. Toenail concentrations of fluconazole declined slowly after treatment was discontinued, with elimination half-lives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, respectively. Measurable fluconazole concentrations were still present in toenails at 6 months after treatment in most subjects. Conclusion: Fluconazole penetrates healthy and diseased nails rapidly, yielding detectable concentrations after two weekly doses. Once it penetrates nail, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic characteristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis. (J Am Acad Dermatol 1998;38:S103-9.)

Dr. Walter F. Lever, former Professor and Chairman of the Department of Dermatology at the New England Medical Center and Tufts University School of Medicine from 1961 until his retirement in 1976, died in Germany on Dec. 13,1992. He was a pioneer in the fieldofdermatopathology and made seminal contributions to the understanding and treatment of bullous diseases. Dr. Lever was born in Erfurt, Germany, on Dec. 13, 1909. He studied in Heidelberg and obtained his MD degree in 1934 from Leipzig. His father, Alexander Lever, was head of dermatology at the City Hospital of Erfurt. It was not surprising that Walter and his twin brother Kurt both became dermatologists. From the beginning, Dr. Lever was interested in an academic career. He and his father decided that dermatopathology was a worthy subject for academic study, so he set off for the United States in 1936 with Alexander's going-away present of two treasured volumes of Gans' Histologie der H autkrankheiten. Lever arrived at the Massachusetts General Hospital and Harvard Medical School for his dermatology residency in 1936, and stayed for more than 20 years, developing his skills in dermatopathology and pursuing research on pemphigus vulgaris. In 1959he became chief of dermatology at the New England Medical Center. Two years later he was appointed Professor and Chairman of the Dermatology Department at Tufts University School of Medicine and chief of the dermatology service of the Boston City Hospital. With the help of National Institutes of Health training grants and research grants, Lever built strong skin research groups and continued his prolific writing. In 1971 Dr. Gundula Schaumburg joined Lever's department and began to participate in his research and writing efforts. Soon she entered

THE WORLD of pathogenic microorganisms and infectious diseases has been enlarged during the past several decades by the emergence and discovery of newly recognized human pathogens, 1-3 by the reemergence of older diseases and new syndromes caused by historically familiar bacteria and viruses, 3,4 and by major changes in antimicrobial susceptibility requiring new therapeutic strategies. 5-8 That these observations are of great concern is evidenced by the number of recent publications. Examples include multiple communications in the weekly publication of the Centers for Disease Control and Prevention 9,10 ; increasing scrutiny by the Institute of Medicine 2 ; the 1995 initiation of a new journal, Emerging Infectious Diseases 11 ; and countless other communications, articles, and conferences on the subject. 12,13 These revelations give eloquent testimony to the resourcefulness and adaptability of microbes. Many other factors may also be responsible for the new emerging infections. Host factors, including immune status, nutrition, and stress

Background: All physicians, including dermatologists, are at risk for prescribing drugs that interact in a harmful way. Although prescribing a harmful drug combination may have serious consequences, no review has examined the drug-drug combinations that are of greatest concern for dermatologists. Our goal is to review the pharmacologic mechanisms of adverse drug interactions, the risky drugs, and the patients who are most vulnerable. In so doing, we hope to provide guidance through a potential minefield of adverse interactions. Observations: Although there are only sparse epidemiologic data regarding the prevalence or cost of adverse drug interactions in dermatology, the consequences may range from a minor loss of therapeutic effect of an admin- istered agent to a life-threatening toxic reaction. We will review methotrexate, cyclosporin A, antifungal agents, antibiotics, retinoids, and antihistamine interactions with each other and with other systemic medications. Conclusions: An organized reporting system needs to be developed so that statistically meaningful epidemiologic data can be obtained for adverse drug interactions, such as the Medwatch program recently proposed by the Food and Drug Administration. Such a system will provide valuable data regarding drug combinations that may be dangerous and determine the scope of the problem as a public health issue. (Arch Dermatol. 1995;131:468-473)

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.

A dangerous and little-discussed group of soft tissue (skin, subcutaneous tissue, fascia, and skeletal muscle) infections are characterized by the presence of extensive gangrene and/or discernible tissue gas. The identifying characteristics of these infections, as well as diagnostic measures and therapy, are reviewed.

Kinetic data on potassium release from and killing of Candida albicans by the four polyene antibiotics amphotericin B, amphotericin B methyl ester hydrochloride, nystatin, and nystatin methyl ester hydrochloride are presented. The nystatins were relatively more effective than the amphotericins in causing potassium release rather than killing. These data suggest that the aqueous channels or pores formed by the polyene antibiotics are not central to the lethal action of the drugs.

Clindamycin has become a highly popular drug for the topical therapy of acne; however, the extent to which it is systemically absorbed from the skin has has not been established. We measured the serum level and urinary excretion of clindamycin on the third day and the twenty-seventh day of therapy in thirteen patients who were applying 1% clindamycin hydrochloride topically for acne. There was no detectable antibiotic in the serum of any subject (less than 0.4 microgram/ml); in contrast, clindamycin was found in the urine of ten of the thirteen patients. There was marked intersubject variation in the urinary excretion of the drug, ranging from less than 10 to 500 micrograms/day. However, there was a highly significant correlation (p less than 0.0001) for a given subject between excretion values on days 3 and 27. There was no correlation between urinary excretion of clindamycin and either racial pigmentation or severity of acne in this relatively small group of patients. After topical application of 1% clindamycin hydrochloride, an average of 4% to 5% of clindamycin appears to be absorbed systemically, but greater amounts are absorbed in some individuals.

The three imidazole antimycotics clotrimazole, miconazole, and ketoconazole all inhibit the demethylation of lanosterol to ergosterol, resulting in inhibition of growth of Saccharomyces cerevisiae; this is a fungistatic action. At higher concentrations clotrimazole and miconazole are fungicidal, whereas ketoconazole is not. The fungicidal action reflects direct membrane damage by the imidazoles. Evidence for this is that ketoconazole is markedly less active than the other imidazoles in its ability to allow methylene blue entry into cells and to disrupt liposome model membranes. The possible clinical significance of these findings is discussed.

A method for the detection of 3-hydroxy dodecanoic acid at low picogram levels is described. The procedure involves preparation of a heptafluorobutryl derivative of the butyl ester of the fatty acid and its detection by gas-liquid chromatography using an electron capture detector. The method was adapted for use with biological specimens. Potential of the method for screening for gonococcal infection is discussed. Limitations of the method are that about 10 5 Neisseria gonorrhoeae cells are required for detection and that interfering substances are a major problem working at maximum sensitivity of the electron capture detector necessitating complex purification procedures. The method eliminates the need to maintain the viability of cells in specimens, thus. facilitating collection and transport of specimens.

In Staphylococcus aureus, using the imidazoles miconazole and ketoconazole, detailed studies of minimal inhibitory concentrations, kinetics of growth, viability, and release of intracellular K+ confirm that the two imidazoles work differently in this bacterium. Miconazole is bactericidal at low concentrations and causes release of cellular K+. Ketoconazole has no bactericidal effect at any tested concentration and has little effect on K+ permeability of S. aureus; it slows growth at high concentration. This is reflected in a low minimal inhibitory concentration for miconazole and a high one for ketoconazole. The probable mechanisms of the bacteriostatic and bactericidal effects of the imidazoles are discussed in light of these results and the previously described antifungal mechanisms of the drugs. alpha-Tocopherol blocks the action of both imidazoles.

Uncouplers of oxidative phosphorylation such as cyanide carbonyl m-chlorophenylhydrazone (CCCP) foster proton (H(+)) permeability of bacterial and other membranes; counter cation movement is required for the effect of the uncoupler on proton permeability to be manifested maximally. Treatment ofEscherichia coli with colicin E 1 had little effect on the proton impermeability of the bacteria after challenge with an acid load; however, the subsequent addition of CCCP revealed that colicin E 1-treated cells became much more permeable to protons than control cells. Thus the colicin caused specific rather than generalized alterations in the membrane permeability properties, allowing the movement of some cations but not H(+). This cation permeability was confirmed directly with studies of(42)K leakage on treatment with colicin E 1. N,N'-dicyclohexylcarbodiimide blocked the fall in ATP levels usually associated with colicin E 1 action, but did not block the K(+) leakage, the inhibition of protein and nucleic acid synthesis, or the lethal effect of the colicin, suggesting that reduced availability of ATP is not the cause of these colicin E 1-induced effects. The possible primary action of the colicin E 1 molecule is discussed in relation to these data.

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.

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.

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 problem, explore some of the causes of the unacceptably high prevalence of hospital-acquired infections, evaluate some of the current preventive measures, and speculate on developments that may improve prevention and therapy. I shall focus on bacterial infections, although in certain classes of patients other organisms at times may be etiologic. The Problem Prevalence In 1959, Rogers1 presented data from an autopsy study confirming that the types of infection causing . . .

A prospective study used polymyxin B by aerosol to reduce colonization of the upper respiratory tract with nosocomial gram-negative bacilli. 58 high-risk patients from the Respiratory-Surgical Intensive Care Unit entered the trial. 33 were randomly selected to receive 2.5 mg/kg/day of polymyxin B by hand atomizer into the pharynx, and tracheal tube if present. 17 of 25 control patients became colonized with gram-negative bacilli as compared with 7 of 33 polymyxin-treated patients (p < 0.01). Control patients became colonized with a total of 33 gram-negative bacilli: 3 were Pseudomonas aeruginosa, 21 were species of Enterobacteriaceae. The polymyxin-treated patients became colonized with a total of 11 gram-negative bacilli: no P. aeruginosa and only 3 species of Enterobacteriaceae were recovered. Colonization increased with duration in Respiratory-Surgical Intensive Care Unit and with time of required controlled ventilation. Polymyxin most effectively prevented the increase in colonization in treated patients who stayed in the Respiratory-Surgical Intensive Care Unit for longer than 1 wk and who required controlled ventilation for at least 72 h.

Presentation of Case A nineteen-year-old girl entered the hospital because of fever and a heart murmur. She had been well until nineteen days previously, when she began to experience myalgia, malai...

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.

Summary The serum bactericidal reaction was studied using the rough E. coli 200P and a system of serum reagents made selectively deficient in various complement components. In replacement experiments functionally pure individual components were added and requirements for C1, C4 and C2, and C9 as well as antibody were shown. Cellular intermediates BAC1 and BAC142 were demonstrated. The results suggest that the entire complement system is required to kill bacteria. Note Added in Proof. Inoue et al. (Inoue, K., Yonemasu, K., Takamizawa, A. and Amano, T. Biken J., 11: 203, 1968) have recently reported that BAC142 cells, C3, 5, 6, 7, 8, 9 and lysozyme were required for immune bacteriolysis of a rough strain of E. coli. The complement components used were purified from guinea pig serum. Results were based on observations of spheroplast formation: with the complete system about 25% of the rod-shaped bacteria were converted to spheroplasts.

ANTIMICROBIAL agents encompass both synthetic compounds and natural products or antibiotics. The vast majority of antimicrobial drugs synthesized or isolated do not possess the requisite selectivity to be useful in the treatment of infectious diseases — that is, they affect the host organisms as well as the parasites. In this review discussion will be limited primarily to agents that have been found to show acceptable selective toxicity toward microorganisms and, hence, clinical usefulness. Attention will be focused on both the mechanism of action of these antimicrobial drugs and the nature of the selective toxicity that they exhibit. Sweeping advances toward . . .

The bactericidal effect of polymyxin B upon two Pseudomonas aeruginosa strains and two Escherichia coli strains was studied as a function of the concentration of the divalent cations Ca 2+ and Mg 2+ . Lipid spherules in aqueous suspension (liposomes) were prepared from the bacterial phospholipids and were examined for the release of trapped glucose induced by polymyxin B under similar conditions of divalent cation concentration. In contrast to the bacteria, which were protected markedly from the bactericidal action of polymyxin B by Ca 2+ or Mg 2+ at concentrations of 2 × 10 −3 m or less, neither cation had any protective effect on bacterial liposomes at concentrations up to 2 × 10 −2 m . These observations suggest that divalent cations antagonize the bactericidal effect of polymyxin B indirectly through interaction with the cell wall rather than at the primary membrane locus of action. The interaction of the divalent cations with the cell wall prevents access of the antibiotic to the cytoplasmic membrane by mechanisms that remain unclear.

It has been previously demonstrated (1) that particulate preparations from Phase&s uureus (mung bean) seedlings are capable of catalyzing the formation of uridine diphosphate-ngalacturonic acid1 and a mixture of UDP-n-xylose and UDP-Larabinose from UDP-n-glucuronic acid. The results indicated that the preparations contained UDP-uranic acid 4-epimerase and UDP-uranic acid decarboxylase activities. However, the individual reactions involved were not investigated. The work reported in this paper shows that three enzyme systems are operative in the conversions: a UDP-n-galacturonic acid-4-epimerase, a UDP-n-glucuronic acid decarboxylase, and a UDP-L-arabinose-4-epimerase. The enzyme systems catalyzing these reactions have been partially separated and the equilibrium constants have been determined for the two epimerization reactions.

Among the Enterobacteriaceae only members of the genus Proteus and Serratia marcescens are regularly resistant to the action of the polymyxins. In 1959, a synergistic action of sulfonamides and polymyxins against Proteus was first noted [1]; subsequently, the majority of isolates of Proteus from clinical specimens was found to exhibit this interesting susceptibility to the combined action of the drugs [2]. In some institutions, S. marcescens is a major cause of nosocomial infections due to gram-negative organisms [3, 4]. Since the organisms are often resistant to many antibiotics, including the polymyxins, we examined the effect of sulfadiazine and polymyxin B on clinical isolates of Serratia, with a view toward evaluating this antimicrobial combination for therapy of infections with gram-negative bacilli.

The mechanism of the lethal action of human serum on a rough strain of Escherichia coli was investigated by use of serum with and without lysozyme, in medium of low and high osmotic pressure, with cells radioactively labeled in the peptidoglycan polymer, and by electron microscopy. The results suggested that there are two separate components in the bacterial cell wall that afford structural support for the cell. Lysozyme attacked one of these, the peptidoglycan polymer. Serum damaged the other, which is probably the peripherally located lipopolysaccharide-phospholipid complex. The cell wall damage caused by lysozyme-free serum promptly resulted in cell death under usual conditions. In plasmolyzed cells, however, the wall damage was not lethal, presumably because the membrane of the plasmolyzed cell was protected from secondary lethal changes which otherwise occur.

Endogenous serum l-xylulose concentration exceeds 1 mg. per 100 ml. in pontosuric patients, and the level rises several-fold following administration of glucuronolaetone. L-xylulose is not detectable in the serum of most nonpentosuric subjects before administration of glucuronolactone, but appears following ingestion of this compound. The increase in both serum and urine pentose levels after glucuronolactone is greater in patients with pentosuria trait than in control subjects. A comparison of serum and urine levels suggests that both pentosuric and nonpentosuric subjects excrete most of the l-xylulose which is presented to the renal tubules. TPN-xylitol (l-xylulose) dehydrogenase, the enzyme believed to be defective in subjects with pentosuria, can be demonstrated in normal human liver and in rat and guinea-pig liver and kidney.

IN the 1940's 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 attention of physicians has focused on the streptococci primarily of Groups A and D as the cause of disease in man. Except for occasional case reports citing a single or a small collection of infections due to other groups3 4 5 and the recent emphasis that infections due to Group B streptococci are not infrequent,5 6 7 the literature on streptococcal infection during this period has dealt principally with various aspects of the nonsuppurative . . .

Several 14-α-aminomethyl-substituted lanosterol derivatives have been synthesized involving a complete Δ7,8to Δ8,9isomerization; these compounds are inhibitors of fungal ergosterol biosynthesis and are active against intact Candida and dermatophyte strains.

The effect of combination of ketoconazole with other sterol synthesis inhibitors on fungal growth was tested against a variety of fungi selected for resistance to ketoconazole. All of the sterol inhibitors, at concentrations lower than their MICs, caused an increase greater than fourfold in the ketoconazole susceptibility of some fungi. Some of the sterol synthesis inhibitors showed this effect with ketoconazole at levels that may be achieved clinically.

Monitoring of pseudomonas pyocine types from 640 patients and their environment was undertaken in a respiratory/surgical intensive-therapy unit (R.S.I.T.U.) during a nineteen-month period. Forty of fifty-six sputum or throat isolates of pseudomonas were clearly hospital acquired and at least 10 of the 16 patients who had Pseudomonas œruginosa on first culture were suspected of having hospital-acquired organisms. Pyocine types 1 and 10 were the "resident" strains; type-10 outbreaks occurred in clusters. Both types were regularly cultured from only one environmental source (the sinks), even during one to two week intervals during which no patients in the R.S.I.T.U. were colonised with pseudomonas. It is suggested that the sinks provide reservoirs of pseudomonas infection and that the hands of personnel are the vehicles of transmission.

Of 420 Staphylococcus aureus isolates, 3.1% were methicillin resistant. Most of the 13 isolates were from the flora of hospitalized patients. The organisms were also resistant to nafcillin and cephalothin. They shared many of the properties with methicillin-resistant staphylococci accumulated from other sources except for the lack of lysozyme-like activity.

causingmorphological changes inthecell surface (4, 9)andinactivation ofthebiological activity of endotoxin (1, 5). Proteus mirabilis isresistant tothelethal action ofhighconcentrations ofpolymyxin B butisusually susceptible tothepenicillins. Several studies suggest thatpolymyxin Bresistance inthese organisms results fromacell wallwhich blocks access oftheantibiotic tothecytoplasmic membrane (3, 7,8). Teuber, using aP.mirabilis strain unusually susceptible toL-form generationbypenicillin, showed thattheL-forms are 400times moresusceptible topolymyxin Bthan intact organisms (8). Thelikely interpretation of this experiment isthatdamaged, orabsent, cell wallallows polymyxin Baccess tothepolymyxin B-susceptible cytoplasmic membrane. Inthe studies presented herein, wehavedemonstrated another typeofinteraction between polymyxin B andpenicillin onP.mirabilis. Atlow, but lethal, concentrations ofpenicillin there isantagonism between theantibiotics. Polymyxin B protects theorganisms fromlethal penicillin damage. FourP.mirabilis strains usedwereisolates

The lipid composition of Prototheca wickerhamii ATCC 16529 is presented and discussed in relation to the unique susceptibility of the organism to drugs of three membrane-active antimicrobial classes: the polyenes, the polymyxins, and the imidazoles. The presence of ergosterol in the neutral lipid fraction of the membrane is likely responsible for the exquisite susceptibility to amphotericin B. The presence of a large quantity of free fatty acids in the membrane appears responsible for imidazole susceptibility. The membrane determinants of polymyxin B susceptibility are less well defined.

STUDIES reported during the past 15 years have led to the widely accepted conclusion that polyene antibiotics function by binding with the sterol molecules in susceptible cells to cause permeability change and eventual death of the cell1–3. In recent reports4–6 based on liposomal model membrane studies, it has been suggested that susceptibility to polyene antibiotics is determined by organisation rather than by a single component of the membrane, namely sterol. Here, through study of polyene-resistant mutants, we further propose that, at least in some cases, permeability alteration may not be the specific critical event in the fungicidal action of polyene antibiotics.