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The objective of this survey was to determine physicians' opinions of the importance of drug costs, sources of drug cost information used, preferences for mechanisms to lower drug costs, and to assess knowledge of the relative cost of common drugs. A questionnaire containing opinion statements and five categories of drugs to be ranked from least to most expensive was sent to 598 physicians at our tertiary-care, university-affiliated teaching hospital. In all, 398 (66.6%) surveys were completed. Survey results indicate that physicians are interested in lowering the cost of drug therapy, and that they are knowledgeable of relative drug costs but would like more cost information to make more informed prescribing decisions. Most believe that a readily available drug cost index is the most beneficial mechanism to decrease drug expenditures.

Nine percent of 2,721 hospital employees, previously tuberculin negative, were PPD positive when tested with 5 TU of PPD (Aplisol, Parke-Davis). Seventy percent of the positive reactions were found to be erroneous on retesting with Tubersol (Connaught). The excessive potency of Aplisol led to excessive expenditures of time and money investigating a nonexistent outbreak.

This article discusses empiric therapy for several serious infections in surgical patients. The accepted antibiotic treatment for purulent peritonitis, the empiric treatment of postsurgical wound infection, and the empiric treatment of postsurgical pneumonia are discussed. The cost of the various regimens is listed. Recommendation of the various regimens is based on the seriousness of the infection, peculiarities of the hospital flora, effectiveness of the regimens, and cost.

In a multicenter, randomized, open, comparative trial, patients with uncomplicated gonorrhea were treated with 400 mg of oral fleroxacin or 250 mg of intramuscular ceftriaxone. A total of 458 men and 447 women were enrolled. Of these, 312 men (68%) and 245 women (55%) were evaluable for efficacy. The treatment groups were demographically similar. Among evaluable men, fleroxacin eradicated 154 of 155 (99%; 95% confidence interval [CI]: 98.1-100%) urethral and 2 of 2 pharyngeal infections, while ceftriaxone eradicated 156 of 156 (95% CI: 99.4-100%) urethral and 5 of 5 pharyngeal infections. Among evaluable women, fleroxacin eradicated 127 of 128 (99%; 95% CI: 97.7-100%) cervical, 20 of 20 anorectal, 16 of 16 urethral, and 7 of 7 pharyngeal infections, while ceftriaxone eradicated 108 of 108 (95% CI: 99.1-100%) cervical, 24 of 24 anorectal, 25 of 25 urethral, and 9 of 9 pharyngeal infections. Adverse events were reported by 68 (16%) of 426 subjects in the fleroxacin group and 20 (5%) of 380 in the ceftriaxone group (p < 0.0001). The most common adverse events reported by the patients who received fleroxacin were nausea (5%), headache (3%), and vaginitis (3%). One patient had severe vomiting, 19 participants had adverse reactions classified as moderate, and 48 patients had mild adverse reactions. Fleroxacin was highly effective in the treatment of uncomplicated gonorrhea and represents an oral alternative to ceftriaxone. Adverse events were more common with fleroxacin than with ceftriaxone.

The use of vancomycin as part of the initial antibiotic therapy of febrile neutropenic patients has become a controversial issue. Some studies support its incorporation in the initial regimen, and others suggest that vancomycin can be added later. We examined this issue in a prospective, randomized trial. We randomized 127 febrile neutropenic patients to receive either ceftazidime alone or ceftazidime plus vancomycin as the initial empiric antibiotic treatment. We added vancomycin to the ceftazidime arm of the study when fever persisted after 96 h of monotherapy, when new fever occurred after this time, or when a moderately ceftazidime-resistant gram-positive bacterium was isolated. Each of these regimens had similar initial response rates, similar durations of initial fever, similar frequencies of new fever during therapy, similar microbiological cure rates, similar superinfection rates, and similar survival rates. We observed more renal and cutaneous toxicities in patients receiving vancomycin and ceftazidime as initial therapy. We conclude that ceftazidime is appropriate as initial therapy for febrile neutropenic patients and that the addition of vancomycin is appropriate when fever persists after 4 days of monotherapy or when fever recurs following an initial response.

Adverse effects are common in patients with acquired immunodeficiency syndrome (AIDS) who receive trimethoprim-sulfamethoxazole (TMP-SMX). Two patients experienced a rare anaphylactoid syndrome. Within hours of receiving a double-strength TMP-SMX tablet, a 28-year-old human immunodeficiency virus (HIV)-positive man developed fever, hypotension, and bilateral pulmonary infiltrates. Broad-spectrum antimicrobial therapy was begun but discontinued 2 days later when signs and symptoms resolved and specimens for Pneumocystis carinii were negative. A 38-year-old man developed rash, fever, hypotension, hyperbilirubinemia, renal dysfunction, and bilateral pulmonary infiltrates after taking two doses of oral TMP-SMX. Several antimicrobial agents, including parenteral pentamidine, were administered despite lack of evidence for P. carinii or other infection. four case reports of similar reactions in patients with AIDS have been published. Notable differences exist between the syndrome described and anaphylaxis. The TMP-SMX anaphylactoid reactions in patients with AIDS mimic sepsis or opportunistic infection, thus making diagnosis difficult.

Ceftazidime was compared with a combination of cephalothin, carbenicillin and gentamicin as empirical therapy for fever in granulocytopenic patients. Forty-eight patients were studied in this randomized trial. In the 44 evaluable cases, favourable clinical responses were seen in 9/21 ceftazidime-treated cases and 13/23 patients treated with the combination. Four of 5 bacteraemias were cured with ceftazidime and 3 of 4 with triple therapy. Comparable numbers of patients developed new fevers while on therapy. Five ceftazidime-treated patients developed documented superinfection compared to 6 patients in the other group. Five patients treated with ceftazidime died from the initial infection or a superinfection compared with 3 on the combination. The overall results appear to be similar at this time. However, remarkable differences were observed between the types of superinfecting organisms with the two regimens. If all 48 patients are considered the isolates were as follows: ceftazidime treatment--5 clostridia, 3 enterococci, 1 Staphylococcus epidermidis and 1 Citrobacter; cephalothin-carbenicillin-gentamicin treatment--4 Pseudomonas, 1 Escherichia coli, 1 Bacteroides fragilis and 2 Candida spp. These results suggest that Gram-positive coverage should be added to ceftazidime in the empirical treatment of febrile granulocytopenic patients.

Events associated with endotoxin-induced mitogenesis in murine spleen cells were investigated. Commitment to deoxyribonucleic acid (DNA) synthesis, the onset of DNA synthesis, and phases of cell cycle were timed. Increased levels of DNA synthesis in murine spleen cells stimulated with endotoxin were observed 12 to 16 h after the addition of the mitogen. The total cell cycle time of stimulated B-cells was 11 to 14 h. The S-phase was 8 h. The G2-phase was 1 h, and the combined M-plus G1-phase of cycling cells was 2 to 5 h. A 1- to 4-h exposure to lipopolysaccharide elicited a significant increase in DNA synthesis. Progressively longer exposures to lipopolysaccharide, up to 24 h, produced further increases in first-cycle DNA synthesis. Polymyxin B, when added with endotoxin to cultures from the outset, inhibited first-cycle DNA synthesis. However, if addition of the antibiotic was delayed, progressive increases in first-cycle dna synthesis were observed. These data indicate a heterogeneity among B-cells in their responsiveness to endotoxin.

A patient with Legionnaires' disease developed consolidated pneumonia with severe hypoxemia and mental confusion; his condition improved with therapy with positive end-expiratory pressure, steroids, and chloramphenicol. The retrospective diagnosis was made by a fourfold rise in indirect fluorescent antibody titers. The chest x-ray films showed bilateral alveolar infiltrates and air bronchograms.

LPS stimulation of mouse spleen cells in the presence of Hu resulted in almost total suppression of [3H]thymidine incorporation without affecting the percentage of cells induced to produce IgM. Utilizing a method which permitted the simultaneous measurement of IgM production and [3H]thymidine incorporation in individual cells, it was demonstrated directly that LPS stimulation of IgM production can occur in the absence of DNA synthesis.

The percentage of mouse spleen cells rosetted by bacteria-antibody-complement complexes (BAC) was found to be temperature dependent. Maximal rosetting was observed when BAC and spleen cells were incubated in ice (0.5 degrees C), whereas less rosetting resulted from 37 degrees C incubations. When rosetted cells were incubated at 37 degrees C, cap formation was found to occur, and indirect evidence suggested that the capped bacteria were subsequently shed from the lymphocyte surface. Neither capping nor shedding occurred at 0.5 degrees C, suggesting that these phenomena were responsible for the decreased percentage of rosetted cells found after incubation at 37 degrees C. An incidental observation indicated that a second factor potentially contributing to the loss of rosetted cells at 37 degrees C was the removal of BAC from the surface of cells by phagocytes.

The comparative efficacy of 2 g of piperacillin and 4.8 X 10(6) U of penicillin G in the treatment of uncomplicated gonococcal urethritis was assessed in a randomized prospective study. Sixty-five evaluable patients received piperacillin, and 55 received penicillin G. All patients received either therapy were cured of gonorrhea. We conclude that piperacillin is as efficacious as aqueous procaine penicillin G in the therapy of uncomplicated gonococcal urethritis.

This paper reports studies showing the effects of serum antibody upon influenza infection at two different sites: the trachea and lung. Tracheal desquamation, pulmonary consolidation, death, and virus shedding were examined after infection of mice with a lethal A/Port Chalmers/1/73 (H3N2) influenza virus. Immune serum administered intraperitoneally before infection prevented death and pulmonary consolidation and also significantly lowered lung virus shedding as compared with controls receiving normal serum. However, this protection did not extend to the ciliated epithelium of the trachea because serum antibody did not prevent desquamation of the trachea or significantly decrease viral yield from the trachea. These results indicate that serum antibody is protective against severe pulmonary parenchymal disease but not for disease of the ciliated epithelium.

The responsiveness of murine lymphocytes and human peripheral blood lymphocytes to phytohemagglutinin, concanavalin A, pokeweed mitogen, and endotoxin was tested in vitro at 32, 35, and 37 degrees C. The responses at 32 degrees C were delayed and often depressed. Mouse cells responded equally well at 35 and 37 degrees C. Human lymphocytes often responded more rapidly at 37 than at 35 degrees C. Since skin temperature, particularly that of the distal extremities, is usually 32 degrees C or less, a relative deficiency in cell-mediated immunity may exist in these sites. This may be part of the reason for the usual localization of certain infections, such as sporotrichosis, to these coller areas.

Five cases of pyoderma gangrenosum occurring in a kindred are presented. Three of the cases occurred after abdominal surgery and tended to be confused with postoperative wound infections. Two cases occurred after superficial injury to the leg and were also thought to represent a peculiar form of cellulitis. None of the patients are known to have any of the underlying diseases usually associated with pyoderma gangrenosum. The cases are presented to alert the physician to this entity and to document the unusual familial occurrence.

Four cases of chronic granulomatous skin infections (two due to Sporothrix schenckii and two to Mycobacterium marinum) were treated primarily by the intermittent application of local hyperthermia. This treatment was initiated either because of intolerance to conventional iodide therapy for sporotrichosis or as interim therapy while awaiting diagnosis of the mycobacterial infections. The response indicated that the application of heat is a useful adjunct to the therapy of these infections. Our experience, and that of others, suggests that in some cases heat alone may be curative.

A unilateral neck mass is an unusual clinical presentation for histoplasmosis. A patient with a large, unilateral neck mass caused by Histoplasma capsulatum is presented to alert readers to such a possibility and to illustrate some of the difficulties in diagnosing and managing the disease.

Acute pyogenic meningitis occurred in a 46-year-old woman receiving long-term steroid therapy. Cultures for bacteria and fungi were negative, and the meningitis failed to respond to broad spectrum antibiotics. Abundant Strongyloides stercoralis larvae were found in the patient's feces a sputum, and a filariform larva was found in a hanging drop preparation from centrifuged cerebrospinal fluid. Therapy with thiabendazole eradicated the Strongyloides from feces and sputum. The abnormal CSF values returned toward normal, and the patient has had no recurrence of illness.

Adherence of Pseudomonas aeruginosa to normal, injured, and regenerating tracheal mucosa was examined by scanning electron microscopy. Uninfected and influenza-infected murine tracheas were exposed to six strains of P. aeruginosa isolated from human sources and one strain of platn origin. All of the strains tested adhered to desquamating cells of the infected tracheas, but not to normal mucosa, the basal cell layer, or the regenerating epithelium. Adherence increased when the incubation time of the bacteria with the trachea was prolonged. Strains isolated from human tracheas appeared to adhere better than strains derived from the urinary tract. After endotracheal intubation of ferrets, P. aeruginosa adhered only to the injured cells and to areas of exposed basement membrane. We call this phenomenon "opportunistic adherence" and propose that alteration of the cell surfaces or cell injury facilitates the adherence of this bacterium and that adherence to injured cells may be a key to the pathogenesis of opportunistic Pseudomonas infections.

Murine exudate macrophages elicited by different stimuli and bone marrow-derived macrophages were studied for their capacity to synthesize factor VII and tissue factor in a basal state and on stimulation with endotoxin (LPS). Cells elicited by different stimuli varied in their production of both factors. Thioglycollate-elicited cells generally made more, but not significantly more, tissue factor in response to endotoxin than cells elicited with periodate or streptococci. Cells elicited with proteose-peptone, fetal calf serum (FCS), or LPS produced less or very little tissue factor. Thioglycollate-elicited cells and cells elicited with streptococci or proteose-peptone consistently made more factor VII than cells elicited with periodate, FCS, and LPS. Bone marrow-derived macrophages were responsive to LPS by the production of tissue factor by the fifth day of culture, and this rose to a maximum by day 10. The maximal production of factor VII occurred on day 5 of culture and declined with longer cultivation. Factor VII production was not enhanced by LPS, and prolonged cultivation in the presence of LPS turned off the synthesis of both tissue factor and factor VII. We conclude that exudate cells are heterogeneous in the production of coagulant factors and that the production of these factors varies with the maturity of the cells. In addition, the production of the tissue factor and the factor VII were not necessarily expressed in a coordinate fashion.

The percentage of endotoxin-stimulated lymphoblasts possessing C3 receptors (CR) decreases during a 72-hr period of in vitro cultivation. In studies reported here we attempted to determine whether the drop in the percentage of CR+ blast cells resulted from receptor loss by transformed cells or whether it resulted from the proliferation of additional blast cell types which lacked the CR. Using methods which permitted simultaneous detection of cytoplasmic IgM, the presence of the CR, and 3H-thymidine uptake we found that: a) LPS stimulation resulted in a progressive increase in the number of IgM+ blasts, b) these constituted approximately 30% of the total cell population at 72 hr after LPS stimulation, c) of the IgM+ blasts 72 to 84% were CR+ and 16 to 28% were CR- at 72 hr, d) from 48 to 72 hr there was no decrease in the percentage of IgM+ blasts possessing the CR, and e) an additional blast cell type was observed which incorporated 3H-thymidine but which was IgM- and lacked the CR. These cells constituted from 11 to 27% of total 3H-thymidine+ cells at 72 hr after LPS stimulation. We conclude that the decrease in the percentage of CR+ blasts in LPS-stimulated spleen cell cultures is not due to receptor loss from IgM+ blasts cells but apparently is partly due to the stimulation and proliferation of other cell type(s) which lack(s) the CR. This cell(s), although its functional identity is unknown, does not appear to be of thymic origin. The heterogeneity of the markers on LPS-stimulated blast cells suggests that a heterogeneous population of cells responds to LPS.

Monocytes and macrophages can be induced to produce tissue factor. Recent data suggest that macrophages make other products involved in the extrinsic coagulation pathway. These include vitamin K-dependent factors, factor X activators and a prothrombinase.

The lipopolysaccharide (LPS) was isolated from three strains of Salmonella typhimurium, a "smooth" strain, STM 7, the Ra mutant, TV 119, and the Re mutant, SL 1102. The effect of depletion of divalent cations on structure and the effect of deoxycholate on hydrodynamic behavior were studied. The results confirmed previous work by others that divalent cations and hydrophobic forces are important factors influencing LPS size and morphology. The binding of deoxycholate to LPS was measured. When the weight average molecular weights of the deoxycholate-dissociated LPS were determined by sedimentation equilibrium and corrected for bound deoxycholate, the values 5,555, 10,607, and 15,592, respectively, for Re, Ra, and "smooth" LPS were in good agreement with calculated formula weights. Although others have suggested that the basic LPS subunit is a trimer, our results suggest that it exists in the dimeric form.

The putative requirement for lymphocytes as instructor cells in the induction of macrophage procoagulant (PCA) by endotoxin (LPS) was tested on elicited mouse peritoneal macrophages and on bone marrow-derived macrophages. Percoll purification of thioglycollate macrophages to at least 99.8 percent failed to diminish PCA induction by LPS. Bone marrow macrophages synthesized most PCA in response to LPS when they constituted more than 95 percent of the cells. In addition, PCA synthesis by these cells was not enhanced by the addition of splenic lymphocytes in a ratio of four to one. Exudate macrophages from endotoxin unresponsive C3H/HeJ mice failed to increase PCA synthesis in the presence of LPS. The addition of responsive C3H/HeN splenic lymphocytes to non-responsive HeJ macrophages did not permit LPS to induce the synthesis of PCA, suggesting the absence of unidirectional lymphocyte-instructed pathway. These data provide no evidence for lymphocyte collaboration in the LPS induction of murine macrophage PCA. LPS appears to induce PCA by acting directly on the macrophage.

Monocytes and macrophages from a variety of animal species produce procoagulants upon stimulation with endotoxin in vitro. While C3H/HeJ mice and their cells have exhibited refractoriness to known effects of phenol-water extracted endotoxin, two recent reports indicate that the cells of these mice produce procoagulants in a normal manner in response to endotoxin. This study compares the responsiveness of cells of C3H/HeJ and C3H/HeN mice to phenol-water extracted endotoxin and to disrupted gram-negative cell walls. Phenol-water extracted endotoxin had no mitogenic effect on spleen cells and failed to elicit procoagulant synthesis in exudate macrophages from C3H/HeJ mice. In contrast it was an effective stimulant for spleen cells and exudate macrophages of C3H/HeN mice. Gram-negative cell walls were an effective stimulant for spleen cells and macrophages from both mouse strains. I conclude that exudate macrophages of C3H/HeJ mice do not respond to endotoxin by producing procoagulant.

The murine model of influenza virus infection is generally a lethal pneumonitis produced by a highly mouse-adapted virus. However, we infected mice with a less adapted virus and produced a nonlethal disease that involved the airways without producing gross pneumonitis. Changes that occurred in the tracheal epithelium were studied by scanning and transmission electron microscopy. Complete desquamation of the epithelium occurred within 3 days after infection, regeneration began within 5 days, and repair was complete within 2 wk after infection. This model is proposed as an alternative to the lethal pneumonitis for the study of murine influenza and also as a model for the study of repair of the respiratory ciliated epithelium.

Purulent pericarditis is typically an acute and often catastrophic illness. The case presented herein has unusual manifestations of pericarditis caused by Staphylococcus aureus. The clinical course was indolent and prolonged, and unlike the usual case, no primary source could be found.

The in vitro effect of endotoxin (LPS) on unfractionated mouse peritoneal cells and cells fractionated into glass adherent and nonadherent populations was studied. LPS caused blast transformation and deoxyribonucleic acid synthesis in the nonadherent, nonphagocytic cells. There was no evidence of a mitogenic effect on macrophages. Instead, a cytotoxic effect was noted. When incubated with unfractionated peritoneal cells, LPS was still cytotoxic for macrophages, but the mitogenic effect for nonadherent cells was decreased or ablated. The intraperitoneal administration of LPS to mice resulted in an acute inflammatory response with a transient depletion of mononuclear cells. There was no stimulation of division of macrophages. Data were obtained which indicated that local cell division is an important factor in the normal turnover of peritoneal macrophages.

The mechanism of the hypoglycemic activity of endotoxin in hyperreactive BCG mice was investigated. The mechanism was found to be an inhibition of the synthesis of glucose from noncarbohydrate sources. The possibilities of an induced hypermetabolic state and an induced release of insulin in response to endotoxin as causes for the hypoglycemic response were essentially ruled out. In addition, no clear-cut evidence of an insulin-like action by endotoxin was found in the in vivo setting.

In agreement with previous observations, mice dying of salmonellosis were found to have a relatively constant number of Salmonella cells in their carcasses (ca. 5 x 10(9)). This number was not the result of bacterial overgrowth in moribund animals and therefore appears to be related to lethality. Similar numbers of salmonellae were recovered from the carcasses of infected mice which had previously been rendered hyperreactive to endotoxin either by infection with M. tuberculosis BCG or by adrenalectomy. In BCG mice, desensitization to endotoxin did not occur during the infection and, therefore, at death these mice contained a number of bacteria which would be equivalent to 1,000 ld(50) of endotoxin. Although the number of bacteria recovered from normal mice is roughly equivalent to a lethal quantity of endotoxin, this is obviously not the case in hyperreactive mice. Therefore, the relationship between lethality and 5 x 10(9) salmonellae cannot be explained by their endotoxin content. Nevertheless, when hyperreactive BCG mice are challenged parenterally with Salmonella, the endotoxin content of the inoculum may markedly influence the course of the infection.

The in vitro mitogenic effects of endotoxin (LPS), phytohemagglutinin (PHA), pokeweed mitogen (PWM) and staphylococcal enterotoxin B (SEB) on mouse spleen cells were studied by light and electron microscopy. By light microscopy, LPS was found to "transform" a culture largely composed of small lymphocytes into "large lymphocytes" which did not synthesize DNA and into blast cells which did synthesize DNA. The blast cells were morphologically similar to those transformed by PHA, PWM and SEB. By electron microscopy, a large percentage of the endotoxin-transformed cells developed extensive dilated rough ER. Their appearance was similar to that reported by others for cells stimulated by PWM, but in our hands the development of rough ER was more conspicuous in LPS-stimulated cells. In contrast, PHA and SEB produced few blast cells which contained significant rough ER. The morphologic observations are consistent with the hypothesis that the mitogenic effect of endotoxin is on bone-marrow-derived lymphocytes. This effect may relate to the known adjuvant effect of endotoxin in vivo.

The interaction of various lipopolysaccharides (LPS) with sheep erythrocytes was studied. When subjected to mild alkaline hydrolysis, the affinity of LPS for the red cell surface was greatly increased, as others have reported. In addition, excessive quantities of alkali-treated LPS (but not parent or heated products) were found to cause hemolysis of red cells. Experiments indicated that the hemolysis was caused by the LPS particles themselves and not by liberated free fatty acids.

Systemic infection of mice with Mycobacterium BCG leads to focal liver damage by producing many granulomas. By undefined mechanisms, this infection markedly enhances the animal's susceptibility to the lethal effect of endotoxin. Small doses of endotoxin given to BCG-infected mice were found to cause acute hepatic damage, as demonstrated by elevated activities of liver enzymes in serum and by morphologic alterations documented by light and electron microscopy and by histochemical technics. The morphologic alterations caused by endotoxin included glycogen depletion, mitochondrial swelling, disruption of the continuity of sinusoidal endothelium and focal injury characterized by marked vacuolization of hepatocytes and distension and fragmentation of rough endoplasmic reticulum. Histochemical studies revealed the apparent release of acid phosphatase from granules in the central portions of granulomas, and the release of beta-glucuronidase from the cytoplasm of hepatocytes.