Cefepime plasma concentrations and clinical toxicity: a retrospective cohort study.

OBJECTIVES: Cefepime remains an important antibiotic for severe bacterial infections, yet some meta-analyses have shown elevated mortality among patients randomized to it. Therapeutic drug monitoring (TDM) of ß-lactam antibiotics is increasing, but optimal plasma concentrations remain unknown. We examined clinical outcomes of patients undergoing cefepime TDM in an initial effort to define the drug's toxicity threshold. METHODS: In this single-centre retrospective cohort study, we enrolled all adult hospitalized patients receiving cefepime and undergoing TDM from January 2013 through July 2016. The primary outcome was the incidence of clinical toxicity; a secondary outcome was clinical failure. Plasma samples were analysed via high-performance liquid chromatography with ultraviolet detection. RESULTS: A total of 161 cefepime concentrations were drawn from 93 patients. Roughly half (82/161, 51%) and one-third (49/161, 30%) were trough and steady-state levels from patients receiving intermittent and continuous infusions, respectively; median concentrations were 17.6 mg/L (IQR 9.7-35.2) and 29.2 mg/L (IQR 18.9-45.9). Ten patients (11%) experienced a neurologic event considered at least possibly related to cefepime; neurotoxicity was associated with poorer renal function (median creatinine clearance 54 (IQR 39-97) vs. 75 mL/min/1.732 (IQR 44-104)) and longer cefepime durations (mean 8.3 (SD±6.7) vs. 13.3 days (± 14.2), p = 0.071). Patients with trough levels >20 mg/L had a fivefold higher risk for neurologic events (OR 5.05, 95% CI 1.3-19.8). CONCLUSIONS: Neurotoxicity potentially related to cefepime occurred at plasma concentrations >35 mg/L. For those receiving intermittent infusions, trough concentrations >20 mg/L should be avoided until further information is available from prospective studies.

'Tubular' epithelioid cell nevus: a new variant of Spitz's nevus.

The term Spitz's nevus refers to a large spectrum of nevi composed of spindle and/or epithelioid cells. We report on a hitherto undescribed tubular variant of a dermal epithelioid nevus, characterized by aggregates composed exclusively of cuboidal cells with the prominent feature of tubular or microcystic structures. Immunohistochemically, the epithelioid cells expressed melanocytic markers (S-100, NKI/C3) lacking markers for cytokeratin or carcinoembryonic antigen. The three-dimensional analysis of the lesions by confocal laser scanning microscopy revealed the structural configuration of tubular or microcystic empty spaces bordered by cuboidal nevus cells. This rare variant of epithelioid nevus is another example for the remarkable diversity of Spitz's nevi.

[Latex allergy--an increasing problem in clinical practice]. / Latexallergie--ein zunehmendes Problem in der Praxis.

In the last few years the allergenic potential of rubber has been receiving more and more attention. Its widespread application in medical devices and everyday objects has increased exposure to this allergen. The central role of rubber in the prevention of HIV infection has certainly played a part in this development. Latex allergy manifests itself as immediate type allergy (type I), delayed type allergy (type IV) or as a combination of both types of hypersensitivity. In this review the different types of latex allergy are illustrated by means of selected case reports. Immediate type allergy to latex leads to contact urticaria, but it may also cause generalized urticaria, bronchial asthma or even anaphylactic reactions (contact urticaria syndrome). Hence, not only dermatologists and allergologists are confronted with latex allergy. Immediate type hypersensitivity can be proven by skin prick test and RAST (radio allergosorbent test). Contact dermatitis in patients using rubber gloves is generally due to delayed type hypersensitivity to rubber additives. However, a recently observed case suggests the possibility of isolated delayed type hypersensitivity to natural latex.

A case of fallow deer allergy. Cross-reactivity between fallow deer and horse allergy.

We report the case of a 25-year-old housewife, a native of Mexico City, with rhinitis and asthma induced by exposure to fallow deer in an animal park close to her home. In the literature, we could find only one previous case. The patient presented a polyvalent IgE sensitization in prick skin tests and RAST to several animals' dander and epithelia, but RAST inhibition experiments showed a cross-reactivity only between fallow deer and horse allergen extracts.

[Allergic and pseudo-allergic reactions in the perioperative period]. / Allergische und pseudoallergische Reaktionen in der perioperativen Phase.

Most drugs or infusions are potent inducers of allergic or pseudoallergic reactions. During the perioperative period the patient is usually on multiple medication. Thus, life-threatening reactions can be expected. In this publication these adverse reactions are considered from an allergological point of view. A review of the literature is given. Four case reports point out the variety of possible allergens, the difficulties in definite causal identification and the necessity of referring the patient to an allergological work-up.

Variant of hyper-IgE syndrome: the differentiation from atopic dermatitis is important because of treatment and prognosis.

The hyper-IgE syndrome is characterized clinically by recurrent staphylococcal abscesses of the skin, lungs and other sites from infancy. Affected patients also have a pruritic dermatitis that differs in character and distribution from lesions of atopic dermatitis. Most lack other signs of atopic disease, develop persistent pneumatoceles and have osteopenia. Laboratory abnormalities include the consistent presence of marked hyperimmunoglobulinemia E and eosinophilia of blood, sputum and tissues. They may have other inconsistent abnormalities of humoral and cellular immune responses and sometimes of phagocytic cell chemotactic responsiveness. Other clinical problems reported in such patients have included lymphomas, cryptococcal meningitis and cutaneous fungal disease. An 18-year-old male patient with a variant of the hyper-IgE syndrome, which he had acquired after a measles attack at the age of 5 years, suffered from recurrent ulcerative dermatitis and lymph node abscesses. Immunological investigation revealed an excessively elevated total serum IgE level (46,850 IU/ml), the presence of specific IgE to staphylococci, and quantitative and functional deficiency of IgG2. Skin and serological (radioallergosorbent) tests to inhalant and nutritive allergens were negative. Differentiation from atopic dermatitis should be made, because a long-term antistaphylococcal regime not only improves skin lesions but hinders the occurrence of lung abscesses and pneumatoceles.

[Comparative study of 2 in vitro screening tests for the diagnosis of allergy]. / Vergleichende Untersuchung von zwei In-vitro-Screeningtests zur Atopiediagnose.

In 108 patients with inhalant disorders, atopy screening was performed with two in-vitro tests; Phadiatop (Pharmacia) and inhalant screening (IHS 1 and 2 discs) (Kallestad). Both tests are accurate and useful tools in differentiating atopics from non-atopics. In contrast to the Phadiatop the allergens on the IHS discs are known, and thus if the results are positive single RAST detection is possible.

[Angioedema caused by enalapril (Reniten)]. / Enalapril-(Reniten-) assoziierte Angioödeme.

Two cases of enalapril(Reniten)-induced angioedema are described. In both patients the time lag between the first manifestation of angio-edema and diagnosis was more than one year, during which several bouts of edema occurred. One patient developed life-threatening swelling of the tongue and the larynx followed by asystole and apnea. The second patient had recurrent edema of the tongue and dyspnea. In general, enalapril-induced edema is not thought to be based on immunological mechanisms. However, in both patients we found elevated titres of antinuclear antibodies, which were reversible upon cessation of enalapril medication. The possible pathomechanisms are discussed.

[Asthma due to disulfites]. / Das Disulfit-Asthma.

Sulfites are recognized as food and drug additives responsible for anaphylactoid adverse reactions, especially in asthmatics. We report on 7 patients (6 females and one male) aged between 24 and 70 years, with preexistent asthma and/or rhinitis of the "intrinsic" type, who experienced severe, life-threatening asthmatic and urticarial reactions after ingestion of wine, salads and other food containing sulfites as preservatives or antioxidants. In a 70-year-old female anaphylactoid shock occurred after injection of a parenteral preparation of doxycycline containing disulfite and benzoic acid as preservative. The diagnosis was established by oral blind challenge tests with increasing doses of natrium disulfite, which provoked a 30% to 57% decrease in FEV1 at a 5 to 50 mg dose. Bronchospasm mainly occurred 15-30 minutes later and in one case one hour after oral disulfite intake. In two patients a severe, life-threatening asthmatic reaction occurred. In one patient with a positive scratch test of the immediate type to powdered natrium disulfite, the oral challenge was not done. Three other patients reacted one + positive. Only in one case was aspirin (ASS) intolerance also present, while the other 6 patients tolerated ASS in the oral provocation test. The pathogenetic mechanisms of sulfite sensitivity are not fully understood, but recent reports and our four cases with positive skin tests suggest an IgE-mediated hypersensitivity reaction in some patients. Food containing sulfites in Switzerland are listed. 5% of drug formulations, and 15% of injectables most frequently prescribed in Switzerland contain sulfites.(ABSTRACT TRUNCATED AT 250 WORDS)

[Experiences with podophyllotoxin in the treatment of condylomata acuminata]. / Erfahrungen mit Podophyllotoxin bei der Behandlung spitzer Kondylome.

We treated 26 patients with condylomata acuminata with a 0.5% solution of podophyllotoxin (Condyline). Twelve of these patients were unsuccessfully pretreated with a common podophyllin 20% solution - some of them up to three months. In 22 patients (84.5%) we observed complete healing of lesions within 30 (6 bis 175) days with podophyllotoxin. Prompt response, minor side-effects, and the possibility for the patients to carry out the treatment themselves are the advantages of this podophyllotoxin preparation.

[Lichen ruber ulcerosus plantae]. / Lichen ruber ulcerosus plantae.

A 66-year-old patient suffering from painful ulcerative lichen planus of the feet is presented. Various treatments (topical and oral corticosteroids, irradiation and a 6-month therapy with acitretin) were tried without success. Skin grafting in the affected areas was helpful and resulted with an acceptable and painless state.

Effect of cations and cation channel blockers on human natural killer cells.

We studied the influence of various extracellular Ca++ and Mg++ concentrations on human natural killer (NK) cells and found that NK cell-mediated target cell lysis requires the presence of both divalent cations. The calcium channel blocker verapamil and the local anaesthetics procaine and lidocaine inhibited NK cell-mediated killing of K 562 target cells, whereas the selective K+ channel blocker tetraethylammonium and the selective Na+ channel blocker tetrodotoxin had no effect on NK activity. Our results demonstrate an important role of extracellular Ca++ and Mg++ for NK cell-mediated killing and suggest that a free transmembrane Ca++ passage is required for target cell lysis.

Effect of ascorbic acid on human natural killer cells.

Ascorbic acid (vitamin C) was found to inhibit human natural killer cell (NK cell) activity in a dose-dependent manner. Neither effector/target cell binding nor interferon (IFN)- or interleukin-2 (IL-2)-induced increases of NK activity were affected by vitamin C. Lymphocytes incubated for 1 h at 4 degrees C with vitamin C showed a normal NK activity, whereas lymphocytes incubated for 1 h at 37 degrees C with vitamin C exhibited low NK activity. Our findings suggest that vitamin C influences NK cells, probably by acting as a radical scavenger which inactivates killing factors of NK cells.

Correlation of natural killer cell function with Leu 7 reactivity in patients with humoral immunodeficiency.

We studied the surface markers Leu 7, Leu 1, Leu 2a and Leu 3a on lymphocytes of 54 healthy blood donors and 19 patients with humoral immunodeficiencies and compared the relative numbers of positive cells with the natural killer cell (NK) activity. In controls, and in 12 out of 19 patients (group A) the percentage of the Leu 7+ cells was positively correlated with NK activity. Seven of 19 patients had increased relative numbers of Leu 7+ cells and low NK activity (group B). In controls and group A patients about 40% of the Leu 7+ cells simultaneously expressed the cell markers Leu 1 and Leu 2a. In group B patients approximately 70% of the Leu 7+ cells carried T cell antigens. Furthermore, a distinct suppressor T cell predominance was noticed and the large granular lymphocytes of these patients showed morphological abnormalities.

Stimulation of nigrostriatal dopamine neurones by nicotine.

In rats anaesthetized with urethane, firing of neurones of the substantia nigra zona compacta was accelerated after subcutaneous or iontophoretic administration of nicotine or after iontophoretic application of acetylcholine. The excitation was prevented by iontophoretic application of dihydro-beta-erythroidine, but not by atropine. The units were identified by antidromic stimulation as neurones of the nigrostriatal system; their activity was depressed by iontophoretically applied dopamine (DA). Under the same conditions of anaesthesia, a subcutaneous injection of nicotine produced an increase in DA turnover and in homovanillic acid levels in the striatum. The effect of nicotine on striatal DA turnover was comparable to that of electrical stimulation of the nigrostriatal pathway at the average frequency seen in the firing of zona compacta neurones after systemic administration of nicotine. These observations corroborate the idea that nicotine exerts an excitatory action at the level of nigral DA nerve cells. Observations made after electrical stimulation or haloperidol under urethane anaesthesia and after nicotine in unanaesthetized rats suggest that the relatively modest effect of nicotine on striatal DA turnover is due mainly to the short duration of drug action rather than to effects of the anaesthetic on DA metabolism.