Ann Otol Rhinol Laryngol, 1996 Aug, 105(8), 624 - 7 Microbiology of tracheal granulation tissue associated with silicone airway prostheses; Brown MT et al.; Granulation tissue formation and contraction is inevitable during the healing of open wounds . The presence of infection and a foreign body, such as a silicone airway prosthesis or other tracheotomy tube, magnifies this response . In airway reconstruction, wound contraction secondary to chronic inflammation is a liability . Cultures of granulation tissue were taken from 12 patients with silicone cannulas of T-Tubes . Polymicrobial colonization predominated, with variable combinations of gram-positive, gram-negative, and anaerobic organisms being present . On the basis of sensitivity data, amoxicillin-clavulanate potassium and ciprofloxacin hydrochloride were chosen as empirical antimicrobials . Anecdotally, impressive decreases in the quantity of granulation tissue were seen . We recommend a prospective trial to more accurately define the role of antibiotics in this setting. Laryngoscope, 1996 Aug, 106(8), 966 - 71 Microsporidian sinusitis in patients with the acquired immunodeficiency syndrome; Rossi RM et al.; Sinusitis in patients with human immunodeficiency virus (HIV) infection usually arises from the same organisms that are infective in the nonimmunosuppressed population . The authors of this article report that optimal antimicrobial treatment and functional endoscopic sinus surgery failed to eradicate sinonasal disease in three of five patients with acquired immunodeficiency syndrome (AIDS) and refractory sinusitis . The sinonasal disease was manifested by congested, edematous, and polypoid mucosa, often with a superimposed bacterial infection from ostial obstruction . After tissue was sent for electron microscopy (EM), the patients were eventually diagnosed with microsporidiosis of the sinonasal cavities . Microsporidia are obligate intracellular protozoans that have been seen in AIDS patients with diarrhea . These protozoans have only recently been identified in sinonasal tissue . Microsporidia are often missed on routine histopathology . The authors present case reports on their five AIDS patients with refractory sinusitis . The management of refractory sinusitis in the HIV-infected population, including mandatory EM of sinonasal tissue, is also discussed. Pediatr Clin North Am, 1996 Aug, 43(4), 933 - 47 Pediatric bone and joint infections . Diagnosis and antimicrobial management; Sonnen GM et al.; Bone and joint infections in children provide unique clinical challenges . When evaluating children with suspected bone and joint infection, the differential diagnosis is broad . Consideration must be given to possible neoplastic and traumatic causes . Appropriate imaging and diagnostic techniques should be initiated without delay . Orthopedic consultation for surgical evaluation should be made early . Prolonged use of antibiotics is often warranted . Treatment often is continued in the outpatient setting, requiring frequent follow-up with appropriate serial laboratory studies to monitor side effects of antimicrobial agents. Gastroenterology, 1996 Aug, 111(2), 358 - 67 Effect of omeprazole on the distribution of metronidazole, amoxicillin, and clarithromycin in human gastric juice; Goddard AF et al.; BACKGROUND & AIMS: The mechanism by which antimicrobial therapy against Helicobacter pylori is enhanced by acid suppression is unknown . The aim of this study was to investigate the effect of omeprazole on gastric juice, plasma, and saliva concentrations of metronidazole, amoxicillin, and clarithromycin . METHODS: Single doses of antibiotic were administered intravenously to 24 healthy men (each antibiotic to 8 subjects) while taking placebo or omeprazole . Antibiotic concentrations were measured in gastric juice, plasma, and saliva . The pharmacokinetic parameters gastric clearance and gastric transfer fraction were calculated for each antibiotic . RESULTS: In the omeprazole group compared with the placebo group, mean maximum antibiotic gastric juice concentrations (in milligram per liter) of metronidazole decreased from 33.6 to 8.3 (P = 0.0001), whereas those of clarithromycin were unchanged, and those of amoxicillin increased from 0.13 to 0.68 (P = 0.02) . Omeprazole increased salivary concentrations of metronidazole (P = 0.02) but had no effect on clarithromycin concentrations (no amoxicillin was detectable in saliva) . CONCLUSIONS: Omeprazole decreases the intragastric concentrations of metronidazole by reducing acid secretion and increases intragastric concentrations of amoxicillin partly by reducing gastric juice volume . Novel pharmacokinetic parameters have been described that provide an insight into the mechanisms underlying drug transfer across the blood-stomach barrier. N Engl J Med, 1996 Aug 1, 335(5), 311 - 5 Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha; Fekade D et al.; BACKGROUND: In patients with louse-borne relapsing fever (Borrelia recurrentis infection), antimicrobial treatment is often followed by sudden fever, rigors, and persistent hypotension (Jarisch-Herxheimer reactions) that are associated with increases in plasma concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6, and interleukin-8 . We attempted to determine whether sheep polyclonal Fab antibody fragments against TNF-alpha (anti-TNF-alpha Fab) could suppress the Jarisch-Herxheimer reaction . METHODS: We conducted a randomized, double-blind, placebo-controlled trial in 49 patients with proven louse-borne relapsing fever . Immediately before the intramuscular injection of penicillin, the patients received an intravenous infusion of either anti-TNF-alpha Fab or a control solution . RESULTS: Ten of the 20 patients given anti-TNF-alpha Fab had Jarisch-Herxheimer reactions with rigors, as compared with 26 of the 29 control patients (P = 0.006) . The controls had significantly greater mean maximal increases in temperature (1.5 vs . 0.8 degrees C, P < 0.001), pulse rate (31 vs . 13 per minute, P < 0.001), and systolic blood pressure (25 vs . 15 mm Hg, P < 0.003), as well as higher mean peak plasma concentrations of interleukin-6 (50 vs . 17 micrograms per liter) and interleukin-8 (2000 vs 205 ng per liter) (P < 0.001 for both comparisons) . Levels of TNF-alpha were undetectable after treatment with anti-TNF-alpha Fab . CONCLUSIONS: Pretreatment with sheep anti-TNF-alpha Fab suppresses Jarisch-Herxheimer reactions that occur after penicillin treatment for louse-borne relapsing fever, reduces the associated increases in plasma concentrations of interleukin-6 and interleukin-8, and may be useful in other forms of sepsis. J Biol Chem, 1996 Jul 26, 271(30), 17650 - 5 Defensin modulates tissue-type plasminogen activator and plasminogen binding to fibrin and endothelial cells; Higazi AA et al.; Defensins are naturally occurring antimicrobial peptides that may participate in host defense against microorganisms . We previously reported that the amino acid sequence of leukocyte defensins resembles the lysine-binding site in the kringles of plasminogen and that defensin inhibits fibrinolysis mediated by tissue-type plasminogen activator (tPA) and plasminogen . In the present paper we analyze the mechanisms of this inhibition . Defensin binds specifically to cultured human umbilical vein endothelial cells (HUVEC) (half-maximal binding = 3 microM) as well as to fibrin . At saturating concentrations (5-10 microM), defensin stimulates the maximum binding of plasminogen to HUVEC and to fibrin approximately 10-fold . However, defensin inhibits plasminogen binding to both surfaces at concentrations >10 microM . Defensin also inhibits tPA and plasminogen-mediated fibrinolysis in a dose-dependent manner at all concentrations tested . Fibrinolysis is almost totally inhibited by 6 microM defensin, a concentration that stimulates the binding of plasminogen to fibrin . Discordance between the enhancement of plasminogen binding and its activation cannot be explained by an inhibitory effect of defensin on tPA binding nor by inhibition of plasmin activity, each of which occur only at higher concentrations . Rather, these results suggest that plasminogen bound to fibrin in the presence of defensin is less susceptible to activation by tPA. Cancer Res, 1996 Jul 15, 56(14), 3238 - 43 Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants; Mannick EE et al.; Helicobacter pylori infection is a known risk factor for gastric cancer . We hypothesized that H . pylori infection would lead to the sustained production of the reactive nitrogen species nitric oxide and peroxynitrite as part of the host immune response . We further hypothesized that H . pylori infection would lead to increased apoptosis of gastric epithelial cells, possibly in response to free radical-mediated DNA damage . Using immunohistochemistry, we stained and scored gastric antral biopsies from 84 Colombian patients with nonatrophic gastritis before and after treatment for H . pylori infection . We examined expression of inducible nitric oxide synthase (iNOS); nitrotyrosine, a marker for peroxynitrite; and DNA fragmentation, a marker for apoptosis . Patients were treated with triple therapy (amoxicillin, 500 mg three times a day for 2 weeks; metronidazole, 400 mg three times a day for 2 weeks; and bismuth subsalicylate, 262 mg four times a day for 2 weeks, followed by 262 mg every day for 4-12 months) . Eradication of H . pylori infection resulted in a significant reduction in iNOS and nitrotyrosine staining and a marginally significant reduction in apoptosis . Dietary supplementation with beta-carotene (30 mg every day for 4-12 months) resulted in a significant decrease in iNOS staining . Supplementation with ascorbic acid (1 g twice a day for 4-12 months) led to a significant reduction in nitrotyrosine staining . In patients supplemented with either ascorbic acid or beta-carotene, there was a trend toward a reduction in apoptosis, but this was not statistically significant . We conclude that H . pylori infection is accompanied by the formation of endogenous reactive nitrogen intermediates, which may contribute to DNA damage and apoptosis . In addition to antimicrobial therapy, dietary supplementation with beta-carotene and ascorbic acid may prevent the formation of these potential carcinogens. Lancet, 1996 Jul 13, 348(9020), 86 - 9 Scrub typhus infections poorly responsive to antibiotics in northern Thailand; Watt G et al.; BACKGROUND: Rickettsia tsutsugamushi, the aetiological agent of scrub typhus, is common in Asia and readily infects visitors to areas where disease transmission occurs . Rapid defervescence after antibiotic treatment is so characteristic that it is used as a diagnostic test for R tsutsugamushi infection . Reports from local physicians that patients with scrub typhus in Chiangrai, northern Thailand responded badly to appropriate antibiotic therapy prompted us to do a prospective clinical evaluation and antibiotic susceptibility testing of human rickettsial isolates . METHODS: The clinical response to doxycycline treatment in patients with early, mild scrub typhus in northern Thailand was compared with the results of treatment in Mae Sod, western Thailand . Prototype and naturally occurring strains of R tsutsugamushi were tested for susceptibility to chloramphenicol and doxycycline in mice and in cell culture . FINDINGS: By the third day of treatment, fever had cleared in all seven patients from Mae Sod, but in only five of the 12 (40%) from Chiangrai (p < 0.01) . Median fever clearance time in Chiangrai (80 h; range 15-190) was significantly longer than in Mae Sod (30 h; range 4-58; p < 0.005) . Conjunctival suffusion resolved significantly more slowly in Chiangrai (p < 0.05) . Antibiotics prevented death in mice infected by Chiangrai strains of R tsutsugamushi less often than after infection by the prototype strain (p < 0.05) . Only one of three Chiangrai strains tested in cell culture was fully susceptible to doxycycline . INTERPRETATION: Chloramphenicol-resistant and doxycycline-resistant strains of R tsutsugamushi occur in Chiangrai, Thailand . This is the first evidence of naturally occurring antimicrobial resistance in the genus Rickettsia. Biochem Pharmacol, 1996 Jul 12, 52(1), 105 - 11 The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline analogues as measured by a novel microtiter assay for inhibitors; Paemen L et al.; A quantitative nonisotopic solution assay for gelatinases and inhibitors was developed using biotinylated gelatin as enzyme substrate . In this assay, residual biotinylated substrate is sandwiched between avidin-coated plates and streptavidin-peroxidase and is quantified by the peroxidase reaction . This assay was useful for measuring gelatinase activities and defining the activities of gelatinase inhibitors . When 23 tetracycline analogues were compared, significant differences in gelatinase B inhibition were found between various compounds . 4-epioxytetracycline base, 4-epichlortetracycline, meclocyclinesulfosalicylate, and unmodified metacycline and minocycline proved to be the most potent gelatinase B (EC 3.4.24.35) inhibitors . The gelatinase B inhibitory activity of tetracyclines was clearly dissociated from their antimicrobial activity . The effect of high-molecular-weight inhibitors, such as monoclonal antibodies, was also demonstrable in the microtiter plate assay . In view of the pathophysiological function of gelatinases, the definition of gelatinase inhibitors with known efficacy, safety, and side effects is crucial for the treatment of diseases such as rheumatoid arthritis and multiple sclerosis . Particular tetracyclines fulfil these criteria and the described assay is useful for defining other gelatinase-inhibiting lead compounds. Cancer Lett, 1996 Jul 12, 104(2), 145 - 52 Interphase and M-phase oral KB carcinoma cells are targetted in staurosporine-induced apoptosis; Swe M et al.; The effect of staurosporine, an antimicrobial agent and inhibitor of protein kinase C (PKC) on programmed cell death/apoptosis (PCD) was investigated in the human oral cavity epidermoid carcinoma KB cell line . Staurosporine-treated oral KB carcinoma cells exhibited morphological features characteristic of apoptosis such as (a) cell shrinkage and increased nuclear fluorescence (quantitated by image analysis with laser scanning confocal microscopy), (b) nuclear condensation and fragmentation observed under fluorescence microscopy with propidium-iodide-DNA staining and (c) chromatin condensation seen under transmission electron microscopy . Specific terminal deoxynucleotidyl transferase (TdT)-mediated labeling of 3'OH ends of DNA breaks in staurosporine-treated cells confirmed DNA fragmentation . In addition, we show the concomitant existence of M-phase PCD with interphase PCD in staurosporine-treated KB cells . It would appear that staurosporine induces apoptosis regardless of the cell cycle phase and that mitosis and apoptosis are not necessarily mutually exclusive events. Exp Cell Res, 1996 Jul 10, 226(1), 80 - 9 Differentiation-associated antimicrobial functions in human colon adenocarcinoma cell lines; Bernet-Camard MF et al.; We report that the enterocytic cells of the HT-29 glc-/+ cell subpopulation strongly expressed two antimicrobial enzymes: the lysozyme and alpha1-antitrypsin . Moreover, we found that 20 to 30% of these cells expressed positive immunoreactivity using the mAbs directed against the gut porcine PR-39 and cecropin P1 antimicrobial peptides, but did not express immunreactivity against the human antimicrobial polymorphonucleated neutrophil-associated HNP 1-3 defensin and the Xenopus skin magainin . The HT-29 glc-/+ cell subpopulation develops bacteriolytic activity against the enterovirulent diffusely adhering C1845 Escherichia coli characterized by dramatic alterations of the bacterial cell, suggesting lysis, and bacterial death . In contrast, no expression of immunoreactivity against the antimicrobial peptides and no C1845 bacterial alteration were found in the cultured human embryonic undifferentiated INT407 cells and the colon adenocarcinoma T84 crypt cells . The development of the bacterial alteration and the expression of the antimicrobial components were examined as a function of the cell differentiation using the Caco-2 cell line which spontaneously differentiates in culture . We found that the bacterial alteration and the expression of the PR-39 immunoreactivity are differentiation-associated events . Altogether, our results suggest that in the intestine the enterocytes could develop antimicrobial defenses participating in the protection of the gut epithelium against enterovirulent microorganisms. J Ethnopharmacol, 1996 Jul 5, 52(3), 175 - 7 Antimicrobial activity of extracts of three major plants from the Chihuahuan desert; Verastegui MA et al.; Dilution methods were employed to determine the effect of ethanolic extracts of Agave lecheguilla Torr . (Agavaceae), Baccharis glutinosa Pers . (Compositae) and Larrea tridentata (DC.) Cov . (Zygophyllaceae) on growth of yeasts, molds and bacteria . The three extracts analyzed showed good antimicrobial activity against more than one organism . The minimal inhibitory concentration of the extracts was also determined. Roum Arch Microbiol Immunol, 1996 Jul-Sep, 55(3), 241 - 51 Study of the sensitivity to antimicrobial drugs of some S . pneumoniae strains isolated from different pathological states; Ungureanu V et al.; 76 Str.pneumoniae strains isolated from different clinical disease forms were studied for the sensitivity to antimicrobial drugs using the diffusimetric method and the dilution in agar method (MIC to penicillin) . The results revealed that 44.74% of pneumococci were sensitive to penicillin, the remaining pneumococci being resistant; 18.42% showed a high resistance (MIC > or = 2 micrograms/ml) . A close relationship was seen between sensitivity to penicillin on the one hand and the Pneumococcus origin and serotype on the other . As concerning the multiresistance to antimicrobial drugs, 47.4% of the strains presented resistance to > or = antibiotics belonging to different classes, the most frequent resistance pattern being P, E, Te, SxT . The most active antimicrobial drugs were vancomycin, amoxiclave, rifampicin, followed by ceftriaxone and amoxicillin. Sante, 1996 Jul-Aug, 6(4), 249 - 53 {Recent results on the pharmacodynamics of Strychnos malgaches alkaloids}; Rasoanaivo P et al.; Investigation of Strychnos (Loganiaceae) shrubs and trees was initiated by their traditional uses of their inherent poisons on arrows: this led to the discovery of strychnine and curare alkaloids . Subsequently, phytochemical investigation of several Strychnos species has shown great structural diversity of the alkaloid constituent which also display various biological effects, i.e . convulsive and relaxant effects on muscles, and antimicrobial, antitumor and antihypertensive properties . Ethnobotanical field work conducted in different regions of Madagascar revealed that infusion of three Strychnos species, S . mostueoides, S . myrtoides and S . diplotricha, is used in association with subcurative doses of chloroquine to treat chronic malaria . Bioassayfractionation led to the isolation of two major bioactive components, strychnobrasiline and malagashanine . Whereas strychnobrasiline is a previously known chemical compound, malagashanine is the first in a series of a new subtype of Strychnos alkaloids . These two alkaloids are devoid of intrinsic antimalarial effects, both in vitro (IC50 = 73.0 micrograms/ml for strychnobrasiline and 69.1 micrograms/ml for malagashanine) and in vivo (10 mg/kg conferred a 5% suppression of parasitemia) . When these alkaloids are combined with chloroquine at doses much lower than required for antiplasmodial effects, they greatly enhance the chloroquine action in a dose dependent manner as seen by the isobologram method . Several minor alkaloids structurally related to malagashanine were also isolated from Madagascan Strychnos . They all enhance, to greater or lesser degrees, the chloroquine effectiveness . Interestingly, there is a positive correlation between the ethnomedical use of the three Strychnos species as chloroquine adjuvants and the chloroquine-potentiating effects of malagashanine and strychnobrasiline isolated from them . After preliminary toxicological studies, infusion of stem barks of S . myrtoides in association with chloroquine was successfully evaluated in a clinical setting . Additional chemical, pharmacological and toxicological work is being conducted on these alkaloids with the aim of developing purified and standardized extracts for clinical trials . These trials will be carried out in the chloroquine-resistant regions of Madagascar which are in need of inexpensive and efficient drugs for the treatment of chloroquine-resistant malaria. Dtsch Tierarztl Wochenschr, 1996 Jul, 103(7), 278 - 80 {Health and environmental risks after the use of anti-infective agents and antiparasitic agents in domestic animal husbandry--avoidance strategies and ways out}; Blaha T; At the beginning, the field of controversy is described, in which the usage of antimicrobials and antiparasitics are discussed, and the areas of their every day application are analysed . Based on the evaluation of the individual kinds of application of antimicrobial substances, conclusions for their usage are drawn, with their total avoidance not being the ultimate goal, but the scientifically founded use of these valuable substances according the the principle: 1 . tailored to the correct diagnosis and 2 . as little as possible, but always the amount that is needed. Z Naturforsch {C}, 1996 Jul-Aug, 51(7-8), 527 - 33 Uptake and exudation of phenolic compounds by wheat and antimicrobial components of the root exudate; Kobayashi A et al.; In the course of our study, it was found that phenyl propenoic acid derivatives were readily taken up by wheat . Leaf leachate components were chosen for the feeding experiments and p-coumaric acid, ferulic acid and caffeic acid were found to be quickly taken up into the plants via the roots . The analytical study revealed that the exudate contained potent antimicrobial compounds together with amino acids and sugars . Besides the primary metabolites, 4-hydroxystyrene, 3-methoxy-4-hydroxystyrene and 3-methoxy-4-acetoxystyrene were identified as exudate components from wheat roots in sterile hydroponic culture . This indicates that these antimicrobial components may play a significant role in the defense system as allelochemicals for the rhizosphere. Mikrobiol Z, 1996 Jul-Aug, 58(4), 55 - 8 {The antimicrobial activity of thio-, thioxo- and oxo- derivatives of acridine}; Novosad NV; Antimicrobial activity of thio-, thioxo- and oxo- derivatives of acridine has been studied . It was shown, that the majority of compounds possesses the moderate antimicrobial activity . It was established, that acetic acid (6-nitroacridinil-9-thio), piperidine salt (2-ethoxi-6-nitroacridinil-9-thio) and ethyl ether (acridinil-9-thio) of acetic acid show the expressed anti-bacterial activity with respect to gram-positive bacteria . The ethyl ether (acridinil-9-thio) of acetic acid also actively suppresses the growth of similar yeast fungus. Therapie, 1996 Jul-Aug, 51(4), 410 - 3 How safe are bioequivalence studies in healthy volunteers? Huic M, Vrhovac B, Macolic-Sarinic V, Francetic I, Bakran I, Giljanovic S. Between 1981 and 1994, 58 bioequivalence studies (b.s.) were performed in 885 healthy volunteers . 93.1 per cent were single-dose, mainly of two way cross-over design . According to ATC groups, 13 were of cardiovascular drugs(C), 11 musculoskeletal (M), nine alimentary (A), seven urogenital (G), seven antimicrobial (J), six haematological (B), three nervous (N) and two respiratory (R) . 97.2 per cent of volunteers finished the studies . Out of 25 withdrawals, 14 did it by their own will, seven were excluded because of lack of compliance with the protocol, one because of an adverse drug reaction (ADR) (preputial oedema), one because of intercurrent illness, and two for other objective reasons . In 35 studies the probants have been males, in 23 both sexes . Subjects were between 18 and 40 years . 209 adverse events were reported in 18 studies (31 per cent) . From 885 volunteers that came to first session at the time, 115 (13 per cent) had ADRs . The association of the drug and ADRs was defined as probable in 91 ADRs (45.9 per cent), definite in 66 (33.4 per cent) and possible in 41 (20.7 per cent) . 73 (63.5 per cent) volunteers had one ADR, 22 (19.1 per cent) had two and 20 (17.4 per cent) more than two ADRs . The majority -117 (56 per cent)-of ADRs were mild, 78 (37.3 per cent) moderate and 14 (6.7 per cent) severe . The most frequent ADR was headache (22.9 per cent), followed by nasal congestion (12.9 per cent), sweating (12.4 per cent), nausea (6.7 per cent), restlessness (6.7 per cent), deafness and tinnitus (6.2 per cent), change of biochemical or haematological parameters (5.3 per cent) and other . An unusual and rare ADR was impotence and preputial oedema (two volunteers on frusemide) . All studies of G group (7-100 per cent) had ADRs, followed by C group (5-38 per cent) and A (3-33 per cent) . Glipizide (5 mg) had highest number of ADRs (64-30.6 per cent), bromocriptine (10 mg) had 31 (14.8 per cent) and frusemide (500 mg) 22 (10.6 per cent) . The largest number of subjects with ADRs were on frusemide (13-72 per cent), glipizide (17-68 per cent) and bromocriptine (15-52 per cent) . At a time when generic drugs are of increasing importance, the safety of b.s . is of considerable interest . Our data confirm their safety and indicate that the majority of ADRs are mild. Emerg Infect Dis, 1996 Jul-Sep, 2(3), 200 - 8 Antibody-based therapies for emerging infectious diseases; Casadevall A; In the 19th century, it was discovered that immune sera were useful in treating infectious diseases . Serum therapy was largely abandoned in the 1940s because of the toxicity associated with the administration of heterologous sera and the introduction of effective antimicrobial chemotherapy . Recent advances in the technology of monoclonal antibody production provide the means to generate human antibody reagents and reintroduce antibody therapies, while avoiding the toxicities associated with serum therapy . Because of the versatility of antibodies, antibody-based therapies could, in theory, be developed against any existing pathogen . The advantages of antibody-based therapies include versatility, low toxicity, pathogen specificity, enhancement of immune function, and favorable pharmacokinetics; the disadvantages include high cost, limited usefulness against mixed infections, and the need for early and precise microbiologic diagnosis . The potential of antibodies as antiinfective agents has not been fully tapped . Antibody-based therapies constitute a potentially useful option against newly emergent pathogens. J Foot Ankle Surg, 1996 Jul-Aug, 35(4), 344 - 9 Antibiotic prophylaxis and tourniquet application in podiatric surgery; Deacon JS et al.; The use of prophylactic antibiosis in podiatric surgery is common, especially in patients undergoing endoprosthetic procedures, major arthrodeses, lengthy procedures, or in immunocompromised patients . The goal of prophylaxis is to prevent infection . For this to occur, there must be an adequate concentration of the antimicrobial agent in the tissue at the time of the incision . Historically, prophylaxis has consisted of intravenous administration of 1 gm . of cefazolin, 30 to 60 minutes prior to surgery . Cefazolin concentrations in the medial eminence of the first metatarsal were measured in patients undergoing bunionectomy procedures where pneumatic ankle tourniquets were used for hemostasis . The goal of this study was to determine if the current standards of prophylactic antibiotic administration provide adequate bone levels of cefazolin to effectively inhibit potential infection-causing pathogens. Drug Saf, 1996 Jul, 15(1), 30 - 52 A risk-benefit assessment of drugs used in the eradication of Helicobacter pylori infection; Hackelsberger A et al.; Helicobacter pylori is the cause of chronic active gastritis and predisposes to peptic ulcer disease (PUD) . Furthermore, H . pylori is linked to the pathogenesis of gastric lymphoma and gastric cancer . However, treatment of this infection has proven difficult . In the last decade, many antimicrobial compounds have been studied extensively as monotherapy as well as in combination with bismuth or acid-suppressive drugs . The individual drugs and the most important eradication regimens are discussed with special regard to their risks . In the past, highly complex multidrug regimens, fear of adverse effects and frequent eradication failures have hampered the broad acceptance of H . pylori-eradication therapies . Recently, new 1-week, low-dose combination regimens of 2 antibacterials with a proton pump inhibitor have consistently achieved eradication rates of 90% and more with an acceptably low rate of adverse effects . One week's standard triple therapy {tripotassium dicitrato bismuthate (or bismuth salicylate plus metronidazole plus tetracycline or amoxicillin) has been shown to be highly effective and tolerated better in combination with a proton pump inhibitor . This regimen is, however, more complex and has more adverse effects . Therefore, it is not recommended as first-line therapy . Equipped with these therapies physicians can now be strongly encouraged to use H . pylori eradication as the therapy of choice for patients with PUD and even extend this treatment to other H . pylori-associated disease conditions. Eur J Gastroenterol Hepatol, 1996 Jul, 8(7), 709 - 16 How to treat Helicobacter pylori infection--should treatment strategies be based on testing bacterial susceptibility? A personal viewpoint; de Boer WA et al.; Peptic ulcer disease is an infectious disease . Only antibiotic regimens that achieve a 90% cure should be used to treat this infection . Antimicrobial susceptibility is the main determinant in the success of therapy; cure rates are usually lower in resistant strains . As in any other infectious disease it is essential in treatment studies to stratify results according to pretreatment bacterial susceptibility . Cure-rates have to be reported separately for sensitive and resistant strains . It must be realized that a study achieving a high cure rate with a certain regimen can either have included few patients with resistant strains or, alternatively, the regimen tested can have a high efficacy in resistant strains . This issue is fundamental and only if that information is available, do we know whether or not we can reproduce the results reported in that particular study in a different population . We have reviewed all Helicobacter studies that tested pretreatment bacterial susceptibility . The results achieved with dual therapy, bismuth triple therapy, proton pump inhibitor triple therapy and quadruple therapy in sensitive and resistant strains are discussed . Based on these data, treatment recommendations are made for empirical treatment in areas with low resistance rates and those with high resistance rates . If treatment is individualized and based on the antibiogram then easier, shorter and cheaper regimens seem possible. Gastroenterol Nurs, 1996 Jul-Aug, 19(4), 128 - 36 Recent advances in peptic ulcer disease: Helicobacter pylori infection and its treatment; Podolski JL; The identification of the gastric bacterium Helicobacter pylori was a significant advancement in the treatment of peptic ulcer disease . H . pylori infects the gastric mucosa and its eradication is associated with the prevention of ulcer recurrence . The significance of this finding is that bacterial infections can be treated and cured, offering hope to individuals with peptic ulcers . Characteristics of H . pylori and its putative role in ulcer formation are discussed . The recent challenge has been to identify a drug regimen that will effectively eradicate this organism inexpensively and conveniently, while not causing significant side effects . Current diagnostic methods and antimicrobial therapies for H . pylori are also presented . A look to future directions in therapies includes a hoped-for vaccine to prevent gastric infections with H . pylori. J Investig Allergol Clin Immunol, 1996 Jul-Aug, 6(4), 222 - 31 Action of cyclosporin A on mononuclear phagocytes; Losa Garcia JE et al.; Classically, cyclosporin A has been reported to exert its immunomodulatory action through its effect on T lymphocytes by inhibiting the synthesis of interleukin 2 . However, the inhibition of T-lymphocyte activation does not suitably account for all the effects observed following cyclosporin A administration . It is possible that some of them could be due to the action of cyclosporin A on other cells, among which are mononuclear phagocytes . This article offers a detailed review of the consequences of the interaction of cyclosporin A on the capacities (surface antigen expression and production of inflammatory mediators), functions (chemotaxis, phagocytosis, intracellular destruction and cytotoxicity) and actions (antimicrobial defense, antitumor defense and immune cooperation) of these cells . The general conclusion is that the capacities, functions and actions of the macrophages related to non-specific defense are more resistant to cyclosporin A than those related to immunoregulation. J Infect, 1996 Jul, 33(1), 39 - 42 Clinical audit of ciprofloxacin use in adults admitted to hospital with gastroenteritis; Fox R et al.; We audited the use of ciprofloxacin, before and after the introduction of simple clinical guidelines, in adults admitted to a regional infectious diseases unit with presumed gastroenteritis . The case notes of 128 consecutive adult admissions over 6 months in 1993 were reviewed and a comparable group of 125 adults in 1994 were prospectively followed . The discharge diagnosis was infective gastroenteritis in 73% of the 1993 admissions and 75% of the 1994 admissions, of whom 42% and 51% had confirmed bacterial enteropathogens . The 1994 cohort appeared to be more ill, with longer duration of symptoms prior to admission, more patients with profuse diarrhoea prior to admission, and longer mean duration of hospital stay . The proportion of patients with a discharge diagnosis of gastroenteritis who received ciprofloxacin did not change (64% in 1993, 67% in 1994) but the proportion of these patients who were subsequently found to be culture-positive rose from 54% to 68% . The proportion of patients receiving intravenous ciprofloxacin fell from 20% to 10% and the total number of doses (intravenous and oral) fell from 1027 in 1993 to 768 in 1994, with cost savings of pound 1465 over 6 months . The benefits and drawbacks of empirical use of ciprofloxacin are discussed . Our audit suggests that simple clinical guidelines can assist in identifying suitable patients for empirical antimicrobial therapy, and result in substantial cost savings. J Emerg Med, 1996 Jul-Aug, 14(4), 483 - 96 Antibiotic use in the emergency department . III . The quinolones, new beta lactams, beta lactam combination agents, and miscellaneous antibiotics; Schmidt J et al.; This article reviews several new, relatively broad-spectrum antibiotics that have utility in the emergency department (ED) . The quinolones have excellent activity against gram-negative organisms, including gonococcus, and are characterized by very high bioavailability after oral administration . The new beta-lactams aztreonam and imipenem have broad spectra but limited usefulness to the emergency physician, and should be reserved for judicious use in severe infections, particularly those involving Pseudomonas . Clavulanate, sulbactam, and tazobactam are themselves antimicrobials that have been combined with beta-lactams such as ampicillin and ticarcillin to produce agents with significant potential utility in the ED; these are typically not first-line agents, however, and their use should be governed by both clinical and cost concerns . Finally, three older antibiotics--vancomycin, metronidazole, and clindamycin--are reviewed with respect to updated indications for their use in the ED. Pharm Res, 1996 Jul, 13(7), 1065 - 8 Kinetics of quinolone antibiotics in rats: efflux from cerebrospinal fluid to the circulation; Ooie T et al.; PURPOSE: An active transport system, which pumps quinolone antimicrobial agents (quinolones) from cerebrospinal fluid (CSF) to systemic blood, exists at the choroid plexus, an epithelial tissue that forms the blood-CSF barrier (BCSFB) . The present study was carried out to clarify the contribution of this transport system to the disposition of quinolones in the central nervous system . METHOD: Six quinolones were administered intracerebroventricularly to rats and their elimination from the CSF was examined . The inhibitory effect of probenecid and quinolones on the efflux of fleroxacin from the CSF was also examined . Probenecid or two types of quinolone (AM-1155, pefloxacin) were co-administered intracerebroventricularly with fleroxacin . RESULTS: The elimination clearance from the CSF for norfloxacin, AM-1155, fleroxacin, ofloxacin, sparfloxacin and pefloxacin was 14, 22, 21, 20, 47 and 35 microliters/min/rat, respectively . An approximately 3.5-fold difference was thus observed between norfloxacin and sparfloxacin . These values were 4- to 14-fold larger than the {14C}mannitol clearance . Furthermore, the elimination clearance of quinolones from the CSF was 7- to 60-fold larger than the active efflux clearance at the BCSFB estimated from our previous in vitro data . Co-administration of AM-1155, pefloxacin and probenecid did not inhibit the elimination of fleroxacin from the CSF . CONCLUSIONS: The active transport system at the BCSFB plays only a small part in the elimination of quinolones from the CSF . Passive diffusion via the BCSFB and diffusion across the ependymal surface into brain extracellular fluid, followed by efflux across the blood-brain barrier, may be the predominant pathway for quinolone elimination from the CSF. Zentralbl Bakteriol, 1996 Jul, 284(2-3), 402 - 38 The immunomodulatory effects of antibiotics: in vitro and ex vivo investigations of 21 substances by means of the lymphocyte transformation test; Schubert S et al.; Besides their antimicrobial activity antibiotics can modulate immune response . The paper provides original data about in vitro and in vivo influence of antibiotics on lymphocyte transformation test (LTT) and gives a comprehensive overview of literature data . In the study presented here the influence of several antimicrobial substances on unstimulated and PHA-stimulated lymphocyte transformation was investigated . The proliferative response was measured as (3H) thymidine uptake by lymphocytes . For initial screening the lymphocyte transformation test was performed on murine lymphocytes in vitro . As a whole 21 antimicrobial substances were tested including representative substances of the most important main groups . As a second step experiments were done with selected substances on human lymphocytes that had shown a distinct influence on murine cells in vitro . At therapeutic concentrations a pronounced stimulation of murine lymphocyte transformation was caused by carbapenems, aminothiazole cephalosporins and imidazoles . Purine analogs had only suppressive effects . However, the increased (3H) thymidine uptake in murine cells could not be regularly reproduced in human lymphocytes and in ex vivo experiments. Dent Clin North Am, 1996 Jul, 40(3), 665 - 83 Pharmacologic considerations in the dental management of the patient with disorders of the renal system; Naylor GD et al.; As reviewed in this article, the patient with ESRD presents a number of unique management challenges . A rapidly increasing number of patients are receiving renal transplants and undergoing dialysis, making it necessary for the dental practitioner to have a thorough understanding of the special treatment considerations that arise . Conservative medical management is designed to slow the progression of the disease and ameliorate the clinical consequences . Dialysis and transplantation provide renal replacement to sustain life and allow for the medical and social rehabilitation of the patient . When considering transplantation, oral examination is an essential part of the preoperative evaluation . Elimination of pathologic entities and restoring patient function are essential before the transplant and the immunosuppressive drug regimen . Any oral symptom or sign of infection must be examined immediately and treated aggressively in an immunosuppressed transplant recipient . Patients receiving hemodialysis and those with transplants should be considered for antimicrobial prophylaxis before dental treatment that induces bleeding to protect the function and patency of the vascular access site and the transplant . Drug therapy may need to be adjusted, depending on the degree of chronic renal failure, the patient's dialysis schedule, or the presence of a transplant . Therefore, the dentist must be familiar with the complexity of this interesting patient population and pay particular attention when prescribing and using various medications. Ann Pharmacother, 1996 Jul-Aug, 30(7-8), 819 - 30 Nontuberculous mycobacterial infections; Guay DR; OBJECTIVE: To review the epidemiology, clinical manifestations, diagnosis, and treatment of nontuberculous mycobacterial infections other than Mycobacterium avium complex (MAC) . DATA SOURCES: A MEDLINE search of English-language literature pertaining to nontuberculous mycobacteria other than MAC was performed . Additional literature was obtained from reference lists of pertinent articles identified through the search . STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in the review . Information judged by the author to be pertinent was selected for discussion . DATA SYNTHESIS: Mycobacterial infections, including those caused by nontuberculous mycobacteria other than MAC, have assumed greater importance over the past decade, due in part to the changing spectrum of immunosuppression as manifested by organ transplantation and HIV infection . Many pathogenic nontuberculous mycobacteria have been identified that are associated with a wide variety of localized, organ-specific, and systemic infections . Of concern, these organisms exhibit variable, species-specific susceptibility to traditional antimycobacterial drugs and other antimicrobials . In addition, long treatment courses and adjunctive surgical therapy are often required to effect cure . Important antimicrobials for the management of these infections include cefoxitin, imipenem/cilastatin, aminoglycosides (other than streptomycin), tetracyclines, macrolides, and trimethoprim/sulfamethoxazole, as well as traditional antimycobacterials . CONCLUSIONS: Nontuberculous mycobacteria have assumed an increasing role in disease etiology in both nonimmunocompromised and immunocompromised individuals . Advent of rapid diagnostic techniques and susceptibility testing has allowed the clinician to identify these organisms and initiate effective treatment on a more timely basis with an improved chance for cure . Few therapeutic agents are available for treatment of these infections, many of which are not considered classic antimycobacterials. Pediatr Infect Dis J, 1996 Jul, 15(7), 610 - 5 Childhood brucellosis in Israel; Gottesman G et al.; BACKGROUND: Brucellosis has become a major medical problem in Israel particularly in the Muslim Arab population . METHODS: Eighty-eight children with acute brucellosis are described . Sixty-seven were studied retrospectively during 1987 through 1988, and 21 children were studied prospectively during 1989 through 1992 . Epidemiologic, clinical and laboratory features were evaluated, and the outcome of 4 antimicrobial regimens are compared . RESULTS: Although the clinical manifestation varied, the classical triad of fever (91%), arthralgia or arthritis (83%) and hepato- and/or splenomegaly (63%) characterized most patients . Sixty-one percent of the children had elevated liver enzymes . Brucella melitensis was isolated from 61% of blood cultures . The relapse rate in patients who were treated with monotherapy (doxycycline) was 43% compared with 14% with regimens of combined therapy with rifampin and doxycycline, streptomycin and doxycycline or rifampin and trimethoprim-sulfamethoxazole (P < 0.049) . Eleven children (33%) who were treated for 3 weeks had relapse compared with 1 patient (3.5%) treated for 4 weeks or longer . The total relapse or reinfection rate was 20% . All patients with relapse recovered after a second course of antibiotic therapy . During the 2 years of follow-up one child progressed to chronic osteomyelitis . CONCLUSIONS: Combination therapy and extending treatment for 4 weeks or longer gave significantly better results than monotherapy or shorter courses of therapy and resulted in fewer relapses. Pediatr Infect Dis J, 1996 Jul, 15(7), 576 - 9 The ten-day mark as a practical diagnostic approach for acute paranasal sinusitis in children; Ueda D et al.; BACKGROUND: Sinusitis is one of the diseases most frequently overlooked by the primary practitioner . METHODS: We suspected the diagnosis of sinusitis in children with respiratory symptoms that persisted for > 10 days: the 10-day mark . A radiographic projection of maxillary sinuses (Water's view) was indicated, and patients with abnormal radiographs were diagnosed as having sinusitis . After antimicrobial treatment for 2 weeks, we evaluated clinical outcome and follow-up radiographs . RESULTS: The 10-day mark culled 146 suspected children from 2013 outpatients with respiratory complaints . Water's view radiographs revealed sinusitis in 135 patients (92.5% of the suspected children) . They included 35 patients with allergy . After treatment only 4 patients in the allergy group (11%) improved completely . In contrast 61 nonallergic patients (61%) were completely improved . CONCLUSIONS: The 10-day mark is a simple and practical diagnostic basis for acute paranasal sinusitis . The associated allergic respiratory diseases respond infrequently to antimicrobial treatment. J Vet Intern Med, 1996 Jul-Aug, 10(4), 258 - 64 Case control and historical cohort study of diarrhea associated with administration of trimethoprim-potentiated sulphonamides to horses and ponies; Wilson DA et al.; Trimethoprim-potentiated sulphonamides (TPS) are among the most frequently administered antimicrobials in equine medicine . Anecdotally, TPS has been implicated as a cause of mild to moderate diarrhea in horses . The purpose of this study was to document the prevalence of diarrhea in horses receiving TPS, to characterize the severity of the diarrhea, and to identify any other factors associated with the development of diarrhea . A 2-part study was designed to identify the prevalence of diarrhea associated with TPS in our clinic population . Part I was a case-control retrospective study of 135 records over a 10.5-year period from January 1, 1980 through June 30, 1990 . Part II was a historical cohort study of 784 records over a 37-month period from July 1, 1990 through July 31, 1993 . There was no significant difference in the occurrence of diarrhea associated with TPS therapy in either study . The occurrence of diarrhea was 21% and 3% in parts I and II, respectively . Significant factors identified in association with diarrhea in part I were duration of hospital stay, and antibiotic therapy other than TPS or penicillin . Significant factors identified in part II included other antibiotic therapy, penicillin therapy, and combined penicillin and TPS therapy . Diarrhea does occur after the administration of antibiotics, most likely because of the alteration of the patient's normal intestinal flora . Diarrhea was noted in association with administration of TPS in this study; however, its prevalence was not significantly different than that in horses receiving other antibiotics, such as penicillin and its derivatives. J Anim Sci, 1996 Jul, 74(7), 1541 - 7 Serum insulin-like growth factor I (IGF-I) concentrations are increased in pigs fed antimicrobials; Hathaway MR et al.; The effect of antimicrobial supplementation on the sera concentrations of IGF-I was determined in crossbred weanling pigs . Pigs were allotted by weight, litter, and sex to either a control diet or a diet supplemented with ASP-250 (22.7 ppm of chlortetracycline, 22.7 ppm of sulfamethazine, and 11.4 ppm of penicillin) for 5 wk . The diets contained 21.8% crude protein and 1.15% lysine . Growth performance data were collected weekly . Insulin-like growth factor I and insulin-like growth factor binding protein (IGFBP) analyses were performed on blood samples that were drawn during the final week of the trial . Feeding ASP-250 to young pigs increased their sera IGF-I concentrations by 24.8% (P < .001) . A 59% increase in sera IGFBP-3 levels also was observed . The pigs fed ASP-250 had a 26% increase in average daily gain (P < .01), a 6.7% improvement in gain:feed ratio (P < .05), and a 18.5% increase in feed consumption (P < .01) compared with pigs fed the control diet . Increased serum IGF-I concentrations with antimicrobial feeding may be involved in the enhanced growth performance observed. Z Naturforsch {C}, 1996 Jul-Aug, 51(7-8), 500 - 12 Lachnellins A, B, C, D, and naphthalene-1,3,8-triol, biologically active compounds from a Lachnellula species (ascomycetes); Semar M et al.; In the course of our search for new biologically active metabolites, lachnellin A (1), a metabolite with high cytotoxic and antimicrobial activities, the structurally related lachnellins B, C and D (3, 4, 7), and naphthalene-1,3,8-triol (8), an inhibitor of malate synthase (EC 4.1.3.2), were isolated from submerged cultures of the ascomycete Lachnellula sp . A 32-89 . The antimicrobial, cytotoxic and phytotoxic activities of lachnellin A depended on its reactivity and could be abolished by the addition of cysteine . The enzyme inhibiting activity of (8) was due to reactive intermediates during melanization and was no longer observed in the presence of serum albumin . In addition, rac-scytalone (9), (+)-trans-3,4-dihydro-3,4,8-trihydroxy-1 (2H)-naphthalenone (10), 2,5-dihydroxytoluene (11), and (R)-(-)-5-methylmellein (12) were obtained from the same source and biologically characterized. Chem Biol, 1996 Jul, 3(7), 543 - 50 Solution structure of protegrin-1, a broad-spectrum antimicrobial peptide from porcine leukocytes; Fahrner RL et al.; BACKGROUND: The protegrins are a family of arginine- and cysteine-rich cationic peptides found in porcine leukocytes that exhibit a broad range of antimicrobial and antiviral activities . They are composed of 16-18 amino-acid residues including four cysteines, which form two disulfide linkages . To begin to understand the mechanism of action of these peptides, we set out to determine the structure of protegrin-1 (PG-1) . RESULTS: We used two-dimensional homonuclear nuclear magnetic resonance spectroscopy to study the conformation of both natural and synthetic PG-1 under several conditions . A refined three-dimensional structure of synthetic PG-1 is presented . CONCLUSIONS: Both synthetic and natural protegrin-1 form a well-defined structure in solution composed primarily of a two-stranded antiparallel beta sheet, with strands connected by a beta turn . The structure of PG-1 suggests ways in which the peptide may interact with itself or other molecules to form the membrane pores and the large membrane-associated assemblages observed in protegrin-treated, gram-negative bacteria. Antimicrob Agents Chemother, 1996 Jul, 40(7), 1754 - 6 Isoniazid induces expression of the antigen 85 complex in Mycobacterium tuberculosis; Garbe TR et al.; Exposure to isoniazid induced the expression of several secreted proteins in Mycobacterium tuberculosis H37Rv . Two-dimensional gel electrophoresis and immunoblot analyses indicated that two of the prominent isonicotinic acid hydrazide-inducible polypeptides were members of the antigen 85 complex, recently demonstrated to have mycolyltransferase activity . We postulate the existence of an intermediate, whose production is inhibited by isonicotinic acid hydrazide, which plays a negative feedback regulatory role in the metabolism of mycolic acids are revealed by the overexpression of the antigen 85 complex . The approach described here relies on analyses of differential gene expression following exposure to inhibitors and may become a more general tool in dissecting the effects of antimicrobial agents. Am J Vet Res, 1996 Jul, 57(7), 1040 - 3 Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after intravenous and intramuscular administrations in sheep; Mengozzi G et al.; OBJECTIVE: To evaluate the pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after administrations of enrofloxacin in sheep . DESIGN: Crossover study performed by i.v . and i.m . administrations of 2.5 mg of enrofloxacin/kg of body weight to 2 groups of 3 sheep . After a 15-day resting period, the drug administration was repeated, using the alternative route . ANIMALS: 6 clinically normal Massese sheep of either sex . PROCEDURE: Blood samples were collected at suitable intervals over a 24-hour period, and plasma concentrations of enrofloxacin and its main metabolite ciprofloxacin were determined by a high-performance liquid chromatography method . Pharmacokinetic variables for both substances after i.v . and i.m . enrofloxacin administrations were calculated by use of statistical moments and were analyzed, using a crossover ANOVA . RESULTS: After i.v . administration of enrofloxacin, a rapid distribution phase was followed by a slower elimination phase . When the same dose was administered IM, enrofloxacin was rapidly and almost completely absorbed, with bioavailability of 85% . After 24 hours, the mean plasma concentration of ciprofloxacin was similar to that of the parent drug . CONCLUSIONS: The large volume of distribution indicates that enrofloxacin is widely distributed in the body of sheep . The fraction of enrofloxacin metabolized to ciprofloxacin (35 and 55% for i.v . and i.m . administrations, respectively) suggests that, in this species, the antimicrobial activity of enrofloxacin could be attributable, at least in part, to its main metabolite ciprofloxacin . CLINICAL RELEVANCE: i.v . or i.m . administration of 2.5 mg of enrofloxacin/kg provides plasma concentrations higher than mean inhibitory concentration for most pathogens in sheep. Chemotherapy, 1996 Jul-Aug, 42(4), 280 - 5 Fleroxacin enhancement of superoxide production by polymorphonuclear leukocytes: the role of protein kinases; Matsumoto T et al.; New quinolone (NQ) antimicrobials may influence the functions of polymorphonuclear leukocyes (PMNs) . Fleroxacin (FLRX), one of the newer NQs which has a long half-life in blood and a strong bactericidal effect, was examined for its influence on superoxide production by PMNs . Augmentation of superoxide production by PMNs when stimulated with phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (fMLP) was observed following the addition of 25, 50, 100 and 200 micrograms/ml of FLRX . In addition, the effects of staurosporine and H-7, inhibitors of protein kinase C (PKC), and of genistein, a tyrosine kinase (TK) inhibitor, on FLRX-enhanced superoxide production were examined . Superoxide production augmented by FLRX was diminished by the addition of staurosporine and H-7, when PMNs were stimulated with PMA, and by the addition of genistein, when PMNs were stimulated with fMLP . These results suggest that FLRX augments superoxide production by PMNs through enhancing the activities of phosphorylation by PKC or TK within the signal transduction pathway in PMNs. Br J Ophthalmol, 1996 Jul, 80(7), 588 - 91 Control of microbial contamination in unpreserved eyedrops; Oldham GB et al.; AIMS/BACKGROUND: Preservatives are added to multidose eyedrop containers to ensure that the eyedrops do not become heavily contaminated during patient use . This enables eyedrops to be used for up to 1 month after opening . However, patients are frequently required to use unpreserved eyedrops as their eyes are unable to tolerate these preservatives . Some commercial unpreserved unit dose eyedrops are available, but the range is limited, and they cannot be used in all cases . Twenty one different unpreserved eyedrop formulations in multidose bottles were tested to establish their inherent efficacy in antimicrobial preservation, and to help determine a suitable in use storage life . METHODS: The eyedrops were inoculated with a known quantity of four different micro-organisms according to the method of the European Pharmacopoeia 'Test for the efficacy of antimicrobial preservation' . After set periods of time, samples were taken to determine the number of viable organisms remaining . RESULTS: Antibiotics and alkaloids were generally shown to have higher kill rates than other eyedrops such as artificial tears and steroids . CONCLUSIONS: In general, once opened by individual patients in a domiciliary situation, a 7 day in use storage life is confirmed for eyedrops containing alkaloids or antibiotics, if they are stored in the refrigerator after opening. J Antibiot (Tokyo), 1996 Jul, 49(7), 631 - 4 Chlovalicin, a new cytocidal antibiotic produced by Sporothrix sp . FO-4649 . I . Taxonomy, fermentation, isolation and biological activities; Hayashi M et al.; Selective growth inhibition against IL-6 dependent cells was detected in fermentation extracts of a fungal strain FO-4649 which was characterized as Sporothrix species . An active metabolite (1) termed chlovalicin was isolated together with ovalicin and two other ovalicin derivatives (compounds 3 and 4) . Chlovalicin, a ovalicin derivative with a chlorinated methylene moiety at the C-1 position of the cyclohexane ring, dose-dependently inhibited the growth of IL-6 dependent MH60 cells (IC50, 7.5 microM) in the presence of 0.2 U/ml IL-6 and, to a lesser extent, the growth of B16 melanoma cells (IC50, 38 microM) . Among the other three compounds, only ovalicin showed inhibitory activity (IC50, 27 microM) against MH60 cells . These four compounds did not show any antimicrobial activity at a concentration of 1000 micrograms/ml. Indian J Med Res, 1996 Jul, 104, 103 - 14 Epidemiology & management of persistent diarrhoea in children of developing countries; Bhan MK et al.; Diarrhoea that begins acutely but lasts longer than two weeks is defined to be persistent . Revised estimates in developing countries including India showed that acute diarrhoea accounts for 35 per cent, dysentery 20 per cent and non-dysenteric persistent diarrhoea (PD) for 45 per cent of total diarrhoeal deaths . PD also often changes marginal malnutrition to more severe forms . Factors that increase the risk of acute diarrhoea becoming persistent have been identified in India and other developing countries . These include antecedent malnutrition, micronutrient deficiency particularly for zinc and vitamin A, transient impairment in cell mediated immunity, infection with entero aggregative Escherichia coli and cryptosporidium, sequential infection with different pathogens and lack of exclusive breast feeding during the initial four months of life particularly use of bovine milk . Several issues regarding the management of persistent diarrhoea in hospitalized children in India have been resolved . Diets providing modest amounts of milk mixed with cereals are well tolerated . In those who fail on such diets providing carbohydrate as a mixture of cereals and glucose or sucrose hasten recovery . The role of antimicrobial agents and individual micronutrients in PD is currently being investigated . A management algorithm appropriate for India and other developing countries has been developed and found to substantially reduce case fatality in hospital settings to about 2-3 per cent . Recent epidemiological and clinical research related to persistent diarrhoea is also reviewed. Farmaco, 1996 Jul, 51(7), 535 - 8 Synthesis and antimicrobial evaluation of 2 beta-chloromethyl-6 beta-carbamoylmethyl-penam-1,1-dioxide-3-carboxylic acid; Gaviraghi G et al.; A new 2 beta-Chloromethyl-6 beta-carbamoylmethyl-penam-1,1-dioxide-3-carboxylic acid was synthesised and evaluated for its antimicrobial and beta-lactamase inhibitory activity . The compound was found to be inactive. Farmaco, 1996 Jul, 51(7), 513 - 6 Antimicrobial activity of 5,6-dihydrobenzo-{a}-carbazoles . Part II; Segall A et al.; A new series of twenty-two 5,6-dihydrobenzo{a}carbazoles was synthesized, some showing good antibacterial activity . The presence and position of substituents seems to be critical for such activity. Farmaco, 1996 Jul, 51(7), 503 - 12 Synthesis and antimicrobial activities of 4-purpuromycin derivatives; Trani A et al.; Purpuromycin (1) is a natural antibiotic with a broad spectrum of activity encompassing bacteria, fungi and protozoa . A new series of derivatives of 1 was prepared by the modification or replacement of the C-4 hydroxyl group . The physico-chemical characteristics and the in vitro antimicrobial activity of these new semisynthetic purpuromycin derivatives are reported . Attachment of a variety of bulky groups to the C-4 hydroxyl group as well as acylation or mesylation of 1 gave derivatives with significantly reduced antifungal activity, while the antimicrobial activity of these derivatives against Gram-positive and Gram-negative bacteria was only slightly decreased . All compounds were inactive against Escherichia coli . The C-4 epimers showed different in vitro activity as compared with those having the natural configuration, particularly against fungi. Am J Physiol, 1996 Jul, 271(1 Pt 1), G68 - 74 Positional specificity of defensin gene expression reveals Paneth cell heterogeneity in mouse small intestine; Darmoul D et al.; Cryptdins are antimicrobial peptides of the defensin family that are expressed specifically by Paneth cells in small intestinal crypts (M.E . Selsted, S.I . Miller, A.H . Henschen, and A.J . Ouellette . J . Cell Biol . 118: 929-936, 1992), and at least 17 cryptdin isoforms have been reported in mouse small intestine (A.J . Ouellette, M.M . Hsieh, M.T . Nosek, D.F . Cano-Gauci, K.M . Huttner, R.N . Buick, and M.E . Selsted . Infect . Immun . 62: 5040-5047, 1994) . Analysis of cryptdin gene expression in adult mouse small bowel revealed that the cryptdin-4 isoform is differentially expressed along the proximal-to-distal intestinal axis . By peptide-specific reverse transcriptase-polymerase chain reaction-based assays, cryptdin-4 mRNA was found to be absent from the proximal small bowel, increasing to maximal levels in the ileum . In contrast, intestinal content of cryptdin-1 and -5 mRNAs was equivalent in duodenum, jejunum, and ileum, and Northern blot hybridization experiments were consistent with both sets of data . Similarly, individual crypts isolated from duodenum contain cryptdin-1 mRNA but not cryptdin-4 mRNA . Taken together, the results show that Paneth cells are heterogeneous, depending on their position along the longitudinal axis of the small bowel . The positional specificity of defensin gene expression suggests that cryptdins may be useful markers for investigating the establishment and maintenance of this epithelial lineage in the mouse small intestine. Pa Med, 1996 Jul, 99(7), 26 - 7 New treatments for new TB strains; Brennan PJ et al.; Since the discovery of penicillin in the 1930s and antituberculous agents a decade later, antimicrobial chemotherapy has advanced tremendously . New generations of older antibiotics and combinations of drugs have resulted in greater efficacy in the treatment of life-threatening infections . Yet multi-drug resistant tuberculosis remains a threat today, particularly in Pennsylvania. Plant Physiol, 1996 Jul, 111(3), 687 - 97 Uncoupled defense gene expression and antimicrobial alkaloid accumulation in elicited opium poppy cell cultures; Facchini PJ et al.; Treatment of opium poppy (Papaver somniferum L.) cell cultures with autoclaved mycelial homogenates of Botrytis sp . resulted in the accumulation of sanguinarine . Elicitor treatment also caused a rapid and transient induction in the activity of tyrosine/dopa decarboxylase (TYDC, EC 4.1.1.25), which catalyzes the conversion of L-tyrosine and L-dopa to tyramine and dopamine, respectively, the first steps in sanguinarine biosynthesis . TYDC genes were differentially expressed in response to elicitor treatment . TYDC1-like mRNA levels were induced rapidly but declined to near baseline levels within 5 h . In contrast, TYDC2-like transcript levels increased more slowly but were sustained for an extended period . Induction of TYDC mRNAs preceded that of phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) mRNAs . An elicitor preparation from Pythium aphanidermatum was less effective in the induction of TYDC mRNA levels and alkaloid accumulation; however, both elicitors equally induced accumulation of PAL transcripts . In contrast, treatment with methyl jasmonate resulted in an induction of TYDC but not PAL mRNAs . The calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide and the protein kinase inhibitor staurosporine partially blocked the fungal elicitor-induced accumulation of sanguinarine . However, only staurosporine and okadaic acid, an inhibitor of protein phosphatases 1 and 2A, blocked the induction of TYDC1-like transcript levels, but they did not block the induction of TYDC2-like or PAL transcript levels . These data suggest that activation mechanisms for PAL, TYDC, and some later sanguinarine biosynthetic enzymes are uncoupled. Infect Immun, 1996 Jul, 64(7), 2673 - 9 Comparison of in vitro models for the study of Mycobacterium tuberculosis invasion and intracellular replication; Mehta PK et al.; We recently evaluated several tissue culture model systems for the study of invasion and intracellular multiplication of Mycobacterium tuberculosis . These model systems include a human alveolar pneumocyte epithelial cell line, a murine macrophage cell line (J774), and fresh human peripheral blood-derived macrophages . Our data indicated that the initial level of association of M . tuberculosis with human alveolar pneumocyte cells (2%) was less than that observed with fresh human peripheral blood macrophages (9%) or J774 murine macrophages (13%) within 6 h of the addition of the bacteria . M . tuberculosis replicated in association with the pneumocyte cells by more than 55-fold by day 7 postinfection . In contrast, total bacteria} growth in the J774 cells and human macrophages was considerably less, with increases of only fourfold and threefold, respectively, over the same 7-day period . Amikacin, an aminoglycoside antimicrobial agent, was added to inhibit the growth of extracellular bacteria after the initial 6-h infection period . Decreases in viable counts were observed in all three cell cultures within the first 3 days after infection . However, unlike the case with either macrophage culture, intracellular bacterial CFU obtained from the infected pneumocytes increased by fourfold by day 7 after the addition of amikacin . These data indicate that M . tuberculosis infects and multiplies intracellularly in human lung epithelial cells and that these cells may be an alternative in vitro model for the study of intracellular multiplication of M . tuberculosis in the human lung. Clin Exp Immunol, 1996 Jul, 105(1), 125 - 31 Frequency of anti-bactericidal/permeability-increasing protein (BPI) and anti-azurocidin in patients with renal disease; Yang JJ et al.; The major subtypes of anti-neutrophil cytoplasmic antibodies (ANCA) detected by indirect immunofluorescence assay (IFA) are P-ANCA and C-ANCA . In patients with vasculitis, myeloperoxidase (MPO) is the major P-ANCA antigen and proteinase 3 (PR3) is the major C-ANCA antigen . BPI and azurocidin, which are also called 57-kD cationic antimicrobial protein (CAP 57) and 37-kD cationic antimicrobial protein (CAP 37), respectively, have been proposed as less frequent target antigens for C-ANCA and P-ANCA . In patients with renal disease, we determined the frequency of antibodies against BPI and azurocidin . By IFA on alcohol-fixed neutrophils, monoclonal and polyclonal anti-BPI antibodies produced a C-ANCA pattern, whereas rabbit anti-azurocidin antibody produced a P-ANCA pattern . By ELISA, sera from 229 P-ANCA-positive patients, 99 C-ANCA-positive patients and 48 ANCA-negative (by IFA) patients with renal biopsies were tested for reactivity with recombinant human BPI and purified human azurocidin . Of these sera, 17.5% of P-ANCA, 30.3% of C-ANCA and 20.8% of IFA-ANCA-negative sera were positive for anti-BPI; and 8.3% of P-ANCA, 3.0% of C-ANCA and 8.3% of IFA-ANCA-negative sera were positive for anti-azurocidin . There was no statistical difference in frequency of anti-BPI between pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) and other glomerular disease (OGD), and there was a lower frequency of anti-azurocidin in NCGN samples than in OGD samples . By Western blot, anti-BPI-positive sera reacted with a 57-kD BPI band and anti-azurocidin-positive sera with a 29-kD azurocidin band . In conclusion, there is a low frequency of anti-BPI and anti-azurocidin antibodies in ANCA-positive patient sera; however, this does not correlate with NCGN, which is a marker for ANCA-associated small vessel vasculitis, and a similar positivity is found in IFA-ANCA-negative patients with renal disease . Therefore, serologic detection of anti-BPI and anti-azurocidin is not diagnostically specific in patients with renal disease. Arch Surg, 1996 Jul, 131(7), 744 - 8 A cost-effectiveness evaluation of 3 antimicrobial regimens for the prevention of infective complications after abdominal surgery; Anderson G et al.; OBJECTIVE: To measure the cost and effectiveness of 3 established antimicrobial regimens for the prevention of infective complications after abdominal surgery . DESIGN: A prospective randomized trial was performed involving a total of 1070 patients undergoing abdominal surgery . SETTING AND PATIENTS: All patients having upper gastrointestinal tract, colorectal, appendiceal, or biliary surgery at a major teaching hospital in Melbourne, Australia, were considered for entry into the study . INTERVENTIONS: Patients were randomized prior to surgery to receive a single dose of cefotaxime sodium (1 g), ticarcillin plus clavulanic acid (3.1 g), or ceftriaxone sodium, (1 g) . All drugs were given intravenously at the start of anesthesia . MAIN OUTCOME MEASURES: Rates of major wound infections, minor wound infections, other wound problems, and other infective complications . The acquisition and administrative costs of the drugs used and the costs of the infective complications were measured . RESULTS: A Total of 1070 patients were entered into the study . Major wound infections occurred in 21 patients (2.0%) . Twenty-five patients (2.3%) developed a minor wound infection . Other infective complications developed in 107 patients . There were significantly fewer minor wound infections in the ceftriaxone-treated group as compared with the other 2 groups . There was no differences in the frequency of major wound infections, other wound problems, or other infective complications . The acquisition costs of cefotaxime and ticarcillin plus clavulanic acid were less than those of ceftriaxone . The estimated cost of treating the infective complications in the group of patients who received ticarcillin plus clavulanic acid ($128,039) was greater than the cost associated with the groups being treated with cefotaxime ($91,243) or ceftriaxone ($96,095) . CONCLUSIONS: The study indicates that each of the 3 regimens was associated with highly satisfactory control of postoperative infective complications after abdominal surgery . On the basis of the estimated costs of infective complications, cefotaxime and ceftriaxone appear equally effective for the prevention of infective complications after abdominal surgery . Acquisition costs for cefotaxime were lower and it is recommended as the preferred agent on this basis. Hum Reprod, 1996 Jul, 11(7), 1520 - 4 Improved cleavage rate of human embryos cultured in antibiotic-free medium; Magli MC et al.; Retarded development and blastomere fragmentation of human preimplantation embryos represent a common phenomenon in in-vitro culture systems . Even though media composition is generally formulated to meet embryo nutritional requirements, the influence of antibiotic supplementation has not been investigated thoroughly . The present study was performed to evaluate the effects of antibiotics on embryo morphology and growth in modified culture media . A total of 196 zygotes from 18 couples was cultured in three different media: (i) conventional medium (n = 99, control group); (ii) medium modified with half the standard antibiotic concentration (n = 54; and (iii) antibiotic-free medium (n = 43); 49 embryos from the control group were selected at the zygote stage and transferred to the patients on day 2 . The remaining 147 zygotes were cultured to the blastocyst stage for cryopreservation; their morphology and cell number were assessed daily at 40, 64, 88 and 112 h post-insemination . Overall cleavage rate was 95% and embryo scoring revealed 91% grade 1 embryos throughout the culture period in the three media . Significantly higher cleavage rates were obtained in the antibiotic-free medium at each observation, including the blastocyst stage, when compared to the other two groups . In addition, no notable improvement was observed in the embryos cultured in a reduced concentration of antibiotics . In conclusion, antibiotic supplementation of media has an adverse effect on the growth rate of preimplantation embryos, even in reduced concentrations, suggesting that antimicrobial drugs may interfere with the timing of cleavage events either by delaying or blocking embryo development. Proc Natl Acad Sci U S A, 1996 Jun 25, 93(13), 6841 - 5 Identifying functional domains within terpene cyclases using a domain-swapping strategy; Back K et al.; Cyclic terpenes and terpenoids are found throughout nature . They comprise an especially important class of compounds from plants that mediate plant- environment interactions, and they serve as pharmaceutical agents with antimicrobial and anti-tumor activities . Molecular comparisons of several terpene cyclases, the key enzymes responsible for the multistep cyclization of C10, C15, and C20 allylic diphosphate substrates, have revealed a striking level of sequence similarity and conservation of exon position and size within the genes . Functional domains responsible for a terminal enzymatic step were identified by swapping regions approximating exons between a Nicotiana tabacum 5-epi-aristolochene synthase (TEAS) gene and a Hyoscyamus muticus vetispiradiene synthase (HVS) gene and by characterization of the resulting chimeric enzymes expressed in bacteria . While exon 4 of the TEAS gene conferred specificity for the predominant reaction products of the tobacco enzyme, exon 6 of the HVS gene conferred specificity for the predominant reaction products of the Hyoscyamus enzyme . Combining these two functional domains of the TEAS and HVS genes resulted in a novel enzyme capable of synthesizing reaction products reflective of both parent enzymes . The relative ratio of the TEAS and HVS reaction products was also influenced by the source of exon 5 present in the new chimeric enzymes . The association of catalytic activities with conserved but separate exonic domains suggests a general means for generating additional novel terpene cyclases. Am J Med, 1996 Jun 24, 100(6A), 60S - 67S A new therapeutic option for the treatment of pneumonia; McCabe R et al.; Patients with bacterial pneumonia often are treated empirically with parenteral broad-spectrum antimicrobials intended to cover potential gram-negative and gram-positive pathogens . However, beta-lactamase-mediated resistance has developed to many of these antimicrobials, particularly third-generation cephalosporins, and has led to the development of fourth-generation agents that are relatively beta-lactamase stable . The purpose of these studies was to compare the efficacy and safety of the fourth-generation agent, cefepime, with that of the third-generation agent, ceftazidime, in the treatment of hospitalized patients with moderate-to-severe bacterial pneumonia . A total of 336 (97 evaluable) patients were enrolled in an open-label study, and 99 (23 evaluable) patients were enrolled in a blinded study of patients with lower respiratory tract infections (LRTI) including pneumonia . Patients were randomized to receive either cefepime 1 g every 12 hours or ceftazidime 1 g every 8 hours given as an intravenous infusion over 30 minutes . Efficacy analysis included the evaluable patients while the safety analysis included all patients . The results in the open-label study were as follows: In patients with pneumonia, clinical response was satisfactory in 58 (85%) of 68 patients in the cefepime group and 21 (72%) of 29 patients in the ceftazidime group . Bacteriologic eradication occurred for 75 (93%) of 81 pathogens and 30 (94%) of 32 pathogens isolated from the 68 cefepime-treated patients and 29 ceftazidime-treated patients, respectively . The results in the blinded study were as follows: In patients with pneumonia, clinical response was satisfactory in 12 (80%) of 15 cefepime patients and in 7 (88%) of 8 ceftazidime patients, and the bacteriologic eradication rates were 85% (17/20 pathogens) and 73% (8/11 pathogens) isolated from the 15 cefepime-treated patients and the eight ceftazidime-treated patients, respectively . Among the most frequent adverse events in both groups were nausea, diarrhea, vomiting, and abdominal pain . Similar adverse events were noted in the 99 patients in the blinded study . These studies indicate that the efficacy and safety of cefepime administered at 1 g twice daily is comparable to that of ceftazidime administered at 1 g three times daily for treatment of hospitalized patients with pneumonia caused by susceptible pathogens. Eur J Biochem, 1996 Jun 15, 238(3), 769 - 76 Purification and structural characterization of bovine cathelicidins, precursors of antimicrobial peptides; Storici P et al.; Cathelicidins are a novel family of antimicrobial peptide precursors from mammalian myeloid cells . They are characterized by a conserved N-terminal region while the C-terminal antimicrobial domain can vary considerably in both primary sequence and length . Four cathelicidins, proBac5, proBac7, prododecapeptide and proBMAP-28, have been concurrently purified from bovine neutrophils, using simple and rapid methodologies . The correlation of ES-MS data from the purified proteins with their cDNA-deduced sequences has revealed several common features of their primary sequence, such as the presence of N-terminal 5-oxoproline (pyroglutamate) residues and two disulfide bridges in a 1-2, 3-4 arrangement . The N-terminal domains of the cathelicidins present one or two Asp-Pro bonds, which are particularly acid-labile in proBac5 and proBac7, but stable in prododecapeptide . This suggests that the spatial organization around these bonds may vary in different cathelicidins, and favour hydrolysis in some cases . An unexpected feature of the prododecapeptide is that it exists as dimers formed by three possible combinations of its two isoforms . The isolation of a truncated, monomeric form of this protein, lacking the cysteine-containing antimicrobial dodecapeptide, indicates that dimerization occurs via disulfide bridge formation at the level of the C-terminal domain and that the dodecapeptide is likely released as a dimer from its precursor . Sequence-based secondary structure predictions and CD results indicate for cathelicidins a 30-50% content of extended conformation and <20% content of alpha-helical conformation, with the alpha-helical segment placed near the N-terminus . Finally, similarity searching and topology-based structure prediction underline a significant sequential and structural similarity between the conserved N-terminal domain of cathelicidins and cystatin-like domains, placing this family within the cystatin superfamily . When assayed against cathepsin L, unlike the potent cystatin inhibitors, three of the four cathelicidins show only a poor inhibitory activity (Ki = 0.6-3 microM). Proc Natl Acad Sci U S A, 1996 Jun 11, 93(12), 6014 - 8 PR-39, a proline-rich antibacterial peptide that inhibits phagocyte NADPH oxidase activity by binding to Src homology 3 domains of p47 phox; Shi J et al.; Reactive oxygen intermediates generated by the phagocyte NADPH oxidase are critically important components of host defense . However, these highly toxic oxidants can cause significant tissue injury during inflammation; thus, it is essential that their generation and inactivation are tightly regulated . We show here that an endogenous proline-arginine (PR)-rich antibacterial peptide, PR-39, inhibits NADPH oxidase activity by blocking assembly of this enzyme through interactions with Src homology 3 domains of a cytosolic component . This neutrophil-derived peptide inhibited oxygen-dependent microbicidal activity of neutrophils in whole cells and in a cell-free assay of NADPH oxidase . Both oxidase inhibitory and direct antimicrobial activities were defined within the amino-terminal 26 residues of PR-39 . Oxidase inhibition was attributed to binding of PR-39 to the p47phox cytosolic oxidase component . Its effects involve both a polybasic amino-terminal segment and a proline-rich core region of PR-39 that binds to the p47phox Src homology 3 domains and, thereby, inhibits interaction with the small subunit of cytochrome b558, p22phox . These findings suggest that PR-39, which has been shown to be involved in tissue repair processes, is a multifunctional peptide that can regulate NADPH oxidase production of superoxide anion O2- . thus limiting excessive tissue damage during inflammation. Pharm Pract Manag Q, 1996 Jul, 16(2), 9 - 12 Selecting antibiotics based on pharmacokinetic and pharmacodynamic principles; Klutman NE; Key pharmacokinetic and pharmacodynamic parameters influencing antimicrobial selection include the area under the curve (AUC) and minimum inhibitory concentration (MIC) . These concepts can be integrated to describe the unique triangular relationship between the antibiotic, infecting organism, and patient . Antibiotic pharmacodynamics have been described as the ratio of AUC/MIC, maximum concentration to MIC, and time above MIC . These relationships can help define whether an antibiotic class kills by concentration-dependent or concentration-independent mechanisms . For example, aminoglycosides and fluoroquinolones have concentration-dependent killing while beta-lactams are concentration-dependent . This killing is also reflected in the post-antibiotic effect (PAE) that describes the prolonged activity even when the antibiotic levels are undetectable . These principles allow antibiotic classes to be selected and dosed via new strategies such as once daily aminoglycosides and continuous infusion beta-lactams. Pharm Pract Manag Q, 1996 Jul, 16(2), 66 - 70 Methods of documenting cost savings associated with an antibiotic management program; Lacy MK et al.; Documenting the financial impact of an antibiotic management program is important for demonstrating the value of these pharmacy-driven or interdisciplinary services . There are several cost-saving methods that may be utilized in justifying such programs . These include intervention analysis, drug purchasing comparisons, specific agent tracking, patient length of stay analysis, and evaluation of antimicrobial therapy for a specific disease state . Several of these methods have been utilized for successfully documenting the financial impact generated by our institutions antibiotic management program. Pharm Pract Manag Q, 1996 Jul, 16(2), 57 - 61 Single daily dose and simplified dosing regimens as a method to improve antibiotic therapy; McDaniel A; Pharmacists can be an important member of the patient care team by assisting with the development of dosing regimens . By optimizing the pharmacokinetic properties of the antimicrobial agents, regimens can be developed that are simple to manage . Newer approaches to simplifying dosing regimens include once-daily aminoglycoside therapy, continuous infusion beta-lactams, and utilizing agents with long half-lives such as ceftriaxone and azithromycin . These efforts could result in improved compliance and in some instances decrease costs and toxicities associated with antibiotic therapy. Clin Perform Qual Health Care, 1996 Jul-Sep, 4(3), 148 - 53 The epidemiology of missed medication doses in hospitalized patients; Nettleman MD et al.; OBJECTIVE: To identify determinants of missed medication doses in hospitalized patients . DESIGN: A prospective study of 63,031 medication doses was performed . Missed doses were detected through active surveillance . To analyze the potential impact of missed antibiotic doses, we performed a retrospective cohort study of adults with bacterial meningitis . SETTING: A general medical ward and an intensive-care unit in a tertiary-care hospital . PATIENTS: Adult inpatients . RESULTS: There were 906 missed doses (1.4% of all doses) . The risk of missing a dose increased directly with the number of daily doses per patient (P<.01) . An individual dose was more likely to be missed if the medication was short-acting than if it was long-acting (odds ratio, 1.4; 95% confidence interval, 1.2 to 1.6) . Antimicrobials were the most frequently ordered short-acting agents and the most frequently missed class of drug . Patient absences from the floor were common, but only 3% of missed doses occurred during a scheduled absence . A survey revealed that nurses thought missed doses were the predictable result of a system involving multiple personnel and procedural steps . Missed doses were not associated with increased mortality in the cohort study . CONCLUSIONS: Missed doses correlated strongly with the number of daily doses . Efforts to decrease missed doses should focus on minimizing the number of daily doses and streamlining the administration system. Int J Immunopharmacol, 1996 Jun-Jul, 18(6-7), 423 - 6 Immunomodulatory activity of amphiphilic antimicrobials on mouse macrophages; Bukovsky M et al.; A quaternary ammonium salt (1-methyldodecyl)-trimethylammonium iodide, a structurally analogous amine oxide (1-methyldodecyl)-dimethylamine-N-oxide and the amine oxide lacking long alkyl chain trimethylamine-N-oxide were tested for their immunomodulatory activity . Inbred mice strain C57/BL6 were pretreated for 7 days by the compounds under study . The activity of elicited peritoneal macrophages was also tested . Both compounds have a long alkyl chain . In concentrations of 10(-6) M there was a significant increase of the phagocytic, candidacidal and lysozyme activities of the cells . We also observed a suppressed peroxidase activity . The colicidal activity of both the peritoneal and spleen cells were not affected . The amine oxide lacking the long alkyl chain has the same effect at high concentration . A similarity between the effects of the amphiphilic compounds on the macrophages and their antimicrobial efficacy elicits the conclusion that both activities are caused by their ability to interact with the cell membranes. Zentralbl Bakteriol, 1996 Jun, 284(1), 1 - 31 Pharmacokinetics of antimicrobial agents in the respiratory tract; Cruciani M et al.; The ability of antibiotics to penetrate into the respiratory tract has been investigated at several sites, namely, sputum and bronchial secretions, tissue homogenates, pleural fluid and, more recently, epithelial lining fluid and alveolar macrophages . The major reason for such investigations is that these data may be helpful to a more thorough understanding of drug distribution in the lung tissue and fluids and to a more accurate prediction of clinical outcome . However, the study of drug concentration at each of these sites presents problems in terms of methodology and data interpretation . The advantages and disadvantages of each of these methods are considered, and the data on penetration of betalactams, aminoglycosides, macrolides, fluoroquinolones and other antimicrobial agents (including antifungal and antiprotozoan drugs) are reviewed. J Antimicrob Chemother, 1996 Jun, 37(6), 1051 - 61 The use of corticosteroids in the management of bacterial meningitis in adults; Townsend GC et al.; Despite the introduction of newer antimicrobial agents, bacterial meningitis continues to be associated with significant morbidity and mortality . Evidence from in-vitro studies, experimental animal models, and clinical studies indicate that the host inflammatory response is responsible for much of the deleterious consequences of this disease . Thus, there is much interest in the adjunctive use of antiinflammatory agents in the therapy of bacterial meningitis . Although there is considerable evidence from animal models and from clinical trials in children that adjunctive antiinflammatory therapy with corticosteroids is effective in reducing inflammation and in improving long-term outcomes, similar data involving adults are largely lacking . The rationale for the use of corticosteroids in the management of bacterial meningitis, and the applicability to disease in adults, are discussed, and some recommendations for their use in this setting are made. J Pharm Pharmacol, 1996 Jun, 48(6), 651 - 6 Effects of antibiotics on epithelial ion transport in the rabbit distal colon in-vitro; Goldhill JM et al.; One side-effect of the therapeutic use of antimicrobial agents is respiratory paralysis as a result of inhibition of skeletal neuromuscular transmission; cholinergic neuro-effector motor transmission in the gastrointestinal tract is inhibited by the same classes of antimicrobial agent . Study of the effects of several classes of antibiotic compound on intestinal motility has suggested that antibiotic-induced alterations of intestinal motility may be related to the onset of diarrhoea or the development of antibiotic-associated colitis . These compounds may, however, also initiate or exacerbate diarrhoea by altering control of epithelial function, a possibility that has not previously been rigorously investigated . This series of experiments investigated the effect of six antibiotics on rabbit distal colonic epithelial ion transport . Of all the antibiotics studied, only ampicillin was without effect . Clindamycin, erythromycin, gentamicin and lincomycin, each reduced the response of the epithelium to electrical field stimulation . In addition, the lincosamides clindamycin and lincomycin reduced basal short circuit current and the epithelial response to acetylcholine . Vancomycin had no effect on the response to electrical field stimulation or acetylcholine but enhanced the secretory action of prostaglandin E2 . These data suggest that, in addition to their ability to alter intestinal motility, a number of potential antibiotic interactions with the epithelium and its innervation may contribute to the pathogenesis of antibiotic-associated diarrhoea and colitis. AIDS Care, 1996 Jun, 8(3), 373 - 6 Therapeutic and diagnostic procedures in hospitalized AIDS patients with terminal illness; Manfredi R et al.; Clinical charts of 235 consecutive patients with AIDS who died in our in-patient Department between 1985-94 have been evaluated in order to assess the delivery of care during the last week of life, regarding drug administration and diagnostic procedures . The management of the 81 subjects who died between 1985 and 1990 (period A) was compared with that of the 154 patients who died between 1991 and 1994 (period B) . Patients followed during period B were treated with a greater number of antimicrobial agents (p < 0.001), supportive drugs (p < 0.001), and blood and blood products units (p < 0.005), while no significant difference was found for agents used for pain management . When assessing diagnostic procedures, during period B our patients had a greater number of plain radiological and ultrasonographic exams (p < 0.001), tomographic and scintigraphic scans (p < 0.005), while the use of other invasive diagnostic techniques did not change significantly . As suggested by our evaluation of possible indicators of curative or palliative care, during recent years the availability of more advanced, diagnostic techniques and new treatments for AIDS complications seemed to have influenced the management and medication of terminal disease in a potentially curative rather than palliative way. Anticancer Drugs, 1996 Jun, 7(4), 392 - 7 Results of a randomized trial of granulocyte colony-stimulating factor in patients with infection and severe granulocytopenia; Aviles A et al.; A study was carried out to investigate the efficacy and toxicity of granulocyte colony-stimulating factor (G-CSF) in the treatment of infection in 119 severely granulocytopenic patients with hematological malignancies after intensive chemotherapy . Patients were assigned randomly to receive either antibiotics alone (ceftazidime, 2 g, i.v., every 8 h + amikacin 7.5 mg/kg, i.v., every 12 h) or the same antimicrobial regimen plus G-CSF (5 micrograms/kg/day, s.c.) . Measurements were clinical improvement, eradication of infection and toxicity . Patients who received antibiotics plus G-CSF had more clinical responses (82 versus 60%), less superinfections (6 versus 20%), less mortality (5 versus 15 patients), less days in hospital (median 10 versus 27) and reduced antibiotic usage compared to patients who received only antibiotics . Hematological recovery (granulocytes > 1.0 x 10(9)/l) was also shorter in these patients (12 versus 23 days) . Fungal infections occurred only in the group treated with antibiotics alone . Toxicity secondary to G-CSF was absent . We conclude that the addition of G-CSF to broad spectrum antibiotics is useful in selected patients with severe granulocyctopenia after intensive chemotherapy and infection, because if may prove the outcome in these patients. J Antimicrob Chemother, 1996 Jun, 37 Suppl C, 143 - 9 Paediatric safety of azithromycin: worldwide experience; Treadway G et al.; Adverse events and laboratory abnormalities were monitored over 35 days after the commencement of treatment in 45 open studies conducted in Europe, South America, Africa and Asia . These studies were to assess the clinical efficacies of azithromycin and comparator antimicrobial agents in the treatment of paediatric acute bacterial infections . Children (6 months-16 years of age) had been treated with an oral suspension of azithromycin (10 mg/kg given once daily for 3 consecutive days) or with the approved oral dosing regimen of the comparator (amoxycillin, co-amoxiclav, cefixime, cefaclor, clarithromycin, erythromycin, penicillin V, cloxacillin, or roxithromycin) . Adverse events were recorded in 232/2655 (8.7%) children treated with azithromycin and in 180/1844 (9.8%) who received comparator treatment . The majority of the treatment-related adverse events were classed as being of only mild or moderate severity and were gastrointestinal: 140 (5.3%) in azithromycin- and 120 (6.5%) in comparator-treated children . Co-amoxiclav was responsible for proportionately more of such events than any other agent . Treatment was discontinued prematurely due to an adverse event in 34 (1.3%) azithromycin- and in 31 (1.7%) comparator-treated children . Incidences of clinically significant laboratory abnormalities were low and occurred with comparable frequency in both treatment groups . The present analysis confirms that azithromycin can be safely used to treat bacterial infections in children of all ages. J Hosp Infect, 1996 Jun, 33(2), 139 - 44 Evaluation of a wound scoring method for patients undergoing cardiac surgery; Hall JC et al.; The main endpoint of studies evaluating antimicrobial prophylaxis in surgical patients is wound morbidity . This should consist of more than the solitary declaration of the rate of wound infection . In this study, a modified version of ASEPSIS (a wound scoring system) has been prospectively evaluated in 1000 patients undergoing cardiac surgery . Twenty-one patients (2.1%) had an infected sternal wound . The components of ASEPSIS most significantly associated with a sternal wound infection were: the presence of a purulent exudate, a postoperative stay > 14 days, the identification of pathogenic organisms, and the use of antibiotics (P < 0.0001) . Although ASEPSIS is a useful mechanism for conveying information about wounds, it does ignore bleeding into wounds and the extent that troublesome wounds need to be dressed after surgery. J Chemother, 1996 Jun, 8(3), 200 - 6 Overcoming imidazole resistance in Escherichia coli; Simonetti G et al.; We have demonstrated that the high resistance to imidazoles in 60 Escherichia coli strains is overcome by lowering the minimum inhibitory concentration (MIC) in culture from > 3200 to < 0.39 micrograms ml(-1) and, by determining, in contact tests, the disappearance of 10(4) CFU with 25 micrograms ml(-1) of imidazoles after 3 min . Although the contact activity was not the same as growth inhibition due to the different target of the drug in the cell structures, we annulled E . coli imidazole resistance in cultural and direct tests by means of the same non-antimicrobial conditions related to outer membrane functions. Ultrasound Obstet Gynecol, 1996 Jun, 7(6), 435 - 8 Early ultrasound-guided transvaginal drainage of tubo-ovarian abscesses: a randomized study; Perez-Medina T et al.; A prospective study of 40 women diagnosed as suffering from tubo-ovarian abscesses was carried out in order to compare the outcome after treating these abscesses with intensive antibiotic therapy alone or in association with early ultrasound-guided vaginal drainage . Patients were assigned to two groups, distributed on a random basis, with a clinical and ultrasound diagnosis of tubo-ovarian abscess of less than 10 cm maximal diameter . Both groups received an antimicrobial combination of clindamycin and gentamicin . In the study group, we performed, in addition, early transvaginal drainage of the abscess . Both short-term (48-72 h) and medium-term (4 weeks) responses to the treatment were evaluated . In the study group we observed a favorable short-term response in 90% of the cases, whereas this was 65% in the control group . In the medium-term follow up, one patient in the study group and three in the control group had an adnexal mass on transvaginal sonography. Am J Infect Control, 1996 Jun, 24(3), 209 - 18 Triclosan: applications and safety; Bhargava HN et al.; Triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) is a nonionic, broad spectrum, antimicrobial agent that, because of its favorable safety profile, has been incorporated into a variety of many personal care products, including deodorant soaps, underarm deodorants, shower gels, and health care personnel handwashes . Triclosan exhibits a moderate degree of substantivity to the skin, and, in many products, it imparts a remnant antimicrobial effect . Although direct contact with the material under exaggerated exposure conditions causes dermal irritation in laboratory animals, it has only rarely been associated with skin irritation or sensitization in human being in formulated products . Acute, subacute/subchronic, and chronic toxicity profiles have been established to determine that triclosan is neither an acute oral toxicant nor that it acts as a carcinogen, mutagen, or teratogen . A new application for triclosan is in oral dentifrices for plaque control . Currently under investigation in the United States, it is approved for oral care application in Canada and many European countries. J Vet Pharmacol Ther, 1996 Jun, 19(3), 176 - 83 Contribution of alpha 1-acid glycoprotein to plasma protein binding of some basic antimicrobials in pigs; Son DS et al.; Protein binding kinetics of basic antimicrobials including trimethoprim (TMP), erythromycin (EM), lincomycin (LM) and clindamycin (CM) were studied using porcine plasma, albumin and alpha 1-acid glycoprotein (AGP) . Rosenthal plots of these basic drugs in porcine plasma suggest saturable and non-saturable binding . Dissociation constants (kd) and binding capacity (Bmax) for saturable binding were as follows: TMP, kd = 8.58 mumol/L, Bmax = 5.26 mumol/L; EM, kd = 2.72 mumol/L, Bmax = 3.06 mumol/L, LM, kd = 3.96 mumol/L, Bmax = 6.58 mumol/L and CM, kd = 4.43 mumol/L, Bmax = 21.7 mumol/L . The proportionality constants (Bmax2/kd2) for non-saturable binding were 0.29 in TMP, 0.52 in EM, 0.17 in LM and 3.2 in CM . The kds of the drugs in porcine AGP solution were determined by a fluorescence quenching method, using 1-anilino-8-naphthalene sulphonate (ANS) as a fluorescent probe: 9.51 mumol/L in TMP, 1.89 mumol/L in EM, 4.48 mumol/L in LM and 9.69 mumol/L, in CM . Comparable kd values between porcine plasma and AGP solution indicated that AGP is a major saturable binder in porcine plasma . Binding property to porcine albumin presented linearity, showing the following proportionality constants: 0.23 in TMP, 0.38 in EM, 0.01 in LM and 0.76 in CM . The comparable proportionality constants of TMP and EM between porcine plasma and albumin solution indicate that albumin is a major non-saturable binder, whereas proportionality constants of LM and CM in albumin solution compared to those in porcine plasma were low, implying another non-saturable binder, i.e . lipoprotein . Simulation curve of drug-binding percentage vs . AGP concentrations showed that in pigs under a pathologic state, or during early growth stage with high AGP levels, AGP could be a main contributor to drug-plasma protein binding for all drugs examined . The increase of AGP from normal to pathological concentrations induced a decrease in the unbound fraction: LM > CM > EM > TMP in order of AGP contribution to drug binding . Therefore, the disposition and efficacy of basic antimicrobials which bind to AGP with high affinity could be markedly influenced by altered AGP levels, implying AGP contribution to pharmacokinetics and pharmacodynamics. Infect Dis Clin North Am, 1996 Jun, 10(2), 345 - 64 Host immunologic augmentation for the control of infection; Wingard JR et al.; The emergence of resistance to pharmacologic antimicrobial agents and the desire to increase chemotherapy dose-intensity have necessitated the search for alternative means to control infectious disease . Enhancement of host immunity against infection has been permitted through the use of hematopoietic growth factors, which can shorten the duration of neutropenia and reduce the risk for bacterial and fungal infections . Hematopoietic growth factor-mobilized hematopoietic stem cells have also proven to be highly efficacious in permitting high-dose chemotherapy . Interferons, immunoregulatory cytokines, immune globulins, and immune lymphocytes also hold promise to enhance host immunity and reduce susceptibility for serious infectious morbidity. Infect Dis Clin North Am, 1996 Jun, 10(2), 255 - 95 Catheter-related complications of cancer therapy; Greene JN; Although the management of CVC-related infection appears complex and at times the literature seems to be contradictory, simple guidelines can direct the clinician in a stepwise fashion . Knowledge of the pathogenesis of each organism and the immune status of the host is crucial to decide whether catheter removal or retention is indicated . For example, in general, GNB bacteremia does not immediately prompt catheter removal in a neutropenic patient but does in a nonneutropenic host because of the gastrointestinal source of the former and a primary catheter source in the latter . In summary, as more CVCs are inserted in patients undergoing chemotherapeutic, antimicrobial, transfusional, and nutritional supportive care, novel approaches to prevention and treatment of the associated infectious complications inherent with such devices are needed . A multifaceted approach from impregnated catheters to local catheter-site antisepsis was reviewed . We may find, however, that as simple handwashing between patients is crucial to infection control, so too is a trained catheter-care team using total barrier precautions and ensuring proper local catheter maintenance critical to preventing CVC-related infections. J Periodontol, 1996 Jun, 67(6), 572 - 6 The substantivity of a number of oral hygiene products determined by the duration of effects on salivary bacteria; Elworthy A et al.; The persistence of action, or substantivity, of antimicrobial agents in the mouth appears to be a major variable influencing plaque inhibition . Such substantivity can be assessed by measuring the duration and magnitude of suppression of salivary bacterial numbers produced by antimicrobial agents . Although this has been determined for some agents, there is little information on the substantivity of the numerous products which contain these and other antimicrobial agents . This study was commissioned on the basis that efficacy cannot be assumed merely because a product contains a known active agent . Nine formulations or products were chosen: 2 rinses containing chlorhexidine or C31G, 4 rinses containing cetylpyridinium chloride (CPC) (with and without fluoride and/or alcohol), a minus-CPC control rinse, and 2 toothpastes with and without stannous fluoride . Additionally, water was used as a placebo control . Twenty health dentate volunteers took part in this blind, 10 cell randomized, single rinse, cross-over study, which was balanced for carryover . Mouthrinses were 15 ml volumes and toothpastes 3 gm in 10 ml water slurries rinsed for 60 seconds . On the day of each study volunteers suspended oral hygiene habits and at approximately 9:00 a.m . rinsed with the allocated formulation . Unstimulated saliva samples were obtained immediately before and 30, 60, 180, 300, and 420 minutes after rinsing . The samples were immediately processed for total anaerobic bacterial counts . All rinses except water and the minus CPC control rinse produced significant falls in counts to 30 minutes . Of more relevance in this inter-treatment comparison-designed study, the C31G rinse showed significant substantivity compared to water only for 60 minutes . C31G was highly significantly less substantive than chlorhexidine from 30 minutes to 420 minutes . The CPC rinses were similar and significantly more substantive than their control rinse to between 180 and 300 minutes . The stannous fluoride and control pastes were similarly substantive to 300 minutes, with the stannous fluoride paste remaining substantive compared to water to 430 minutes . Based on antimicrobial action these formulations varied considerably in substantivity and this is likely to reflect their comparative plaque inhibitory properties. Rev Prat, 1996 Jun 1, 46(11), 1337 - 43 {Bacteriological diagnosis of tuberculosis}; Grosset J; Ziehl-Neelsen or fluorescence microscopy, culture and drug sensitivity test onto Loewenstein-Jensen medium or with the more rapid radiometric BACTEC system are still the reference diagnostic tests for tuberculosis . However the slow growth of mycobacteria, the severity of the disease caused and the lack of a suitable sub-typing scheme for epidemiological studies have made tuberculosis a popular application for molecular techniques . The four major diagnostic areas molecular techniques have been applied for: rapid identification of cultured mycobacteria; sub-typing of strains by a DNA fingerprinting method in contact tracing; rapid detection of antimicrobial resistance by direct DNA sequencing of target site genes, single strand conformation polymorphism analysis (PCR-SSCP) or line probe assay (LIPA); detection of M . tuberculosis complex in clinical material. Ann Pharmacother, 1996 Jun, 30(6), 676 - 8 Oral antibiotic therapy in infective endocarditis; Fuller RE et al.; The mortality of IE remains fairly high despite the aggressive use of intravenous antibiotics . Oral treatment of IE is an intriguing concept with many potential advantages over conventional intravenous therapy . Unfortunately, there are insufficient data to justify predominantly oral regimens for the treatment of IE . Trials have shown that oral therapy may have a role in follow-up to short courses of parenteral antibiotics, but these trials are limited by the small number of patients studied . It is important to note that most data for oral treatment of IE have been obtained from studies in patients with histories of IVDA and right-sided S . aureus endocarditis . As mentioned previously, the course of IE in this patient population tends to be less severe, which makes extrapolation of these data to the general population difficult . A need exist for the development of oral antimicrobials with the properties previously mentioned, making them appropriate for use in IE . Currently available oral agents require further study before general recommendations regarding their use in patients with IE can be made . Although successful oral treatment of prosthetic valve endocarditis has been reported, such patients in general should not be considered as appropriate candidates for oral therapy . For now, oral antimicrobial therapy may be appropriate only as follow-up to short-course intravenous therapy, or use in combination with intravenous therapy for IE in select populations whose disease course is less severe or in whom prolonged intravenous therapy is impractical (i.e., intravenous drug users). Ann Pharmacother, 1996 Jun, 30(6), 612 - 4 Hypersensitivity anaphylactoid reaction to pefloxacin in a patient with AIDS; al-Hedaithy MA et al.; OBJECTIVE: To report a life-threatening anaphylactoid reaction to oral pefloxacin in a patient with AIDS and to review the pertinent literature . CASE SUMMARY: A 32-year-old woman with AIDS developed an anaphylactoid reaction following a second exposure to oral pefloxacin . This reaction was characterized by severe hypotension, dizziness, itching, and fever . DISCUSSION: Fluoroquinolones are broad-spectrum antimicrobial agents . They are used frequently in patients with AIDS for numerous indications, including treatment of Mycobacterium avium complex . Pefloxacin, a broad-spectrum fluoroquinolone, was introduced in France in 1985 . Since then, many patients with AIDS have been treated with this drug . Several cases of anaphylactoid reactions to ciprofloxacin have been documented in patients with HIV infection . To our knowledge, this is the first reported case of an anaphylactoid reaction to pefloxacin in a patient with AIDS . CONCLUSIONS: There is a need for continued vigilance in the reporting of adverse drug reactions in patients with AIDS, especially with new drug . Also, care must be taken in introducing drugs, including fluoroquinolones, to this patient population. Indian J Exp Biol, 1996 Jun, 34(6), 588 - 9 Isolation and characterisation of bioactive steroid from a prawn; Indap MM et al.; Dried prawns (Nematopalaemon tenuipes) were extracted with various solvents like petroleum ether, chloroform and methanol . Petroleum ether extract (PEP), tested for antimicrobial, larvicidal and haemolytic activity on h