Bactericidal

Chest, 1999 Mar, 115(3 Suppl), 24S - 27S
New intervention strategies for reducing antibiotic resistance; Yates RR; Rising antibiotic resistance rates among bacterial pathogens have resulted in increased morbidity and mortality from nosocomial infections . Widespread use of certain antibiotics, particularly third-generation cephalosporins, has been shown to foster development of generalized beta-lactam resistance in previously susceptible bacterial populations . Reduction in the use of these agents (as well as imipenem and vancomycin) and concomitant increases in the use of extended-spectrum penicillins and combination therapy with aminoglycosides have been shown to restore bacterial susceptibility . Studies have shown that education-based methods, as opposed to coercive measures, are effective in changing the prescribing habits of physicians . Cooperative interaction among infectious-disease physicians, clinical pharmacists, microbiology-laboratory personnel, and infection-control specialists is essential to provide useful suggestions regarding antibiotic choice and dosing to the prescribing physician in real time . Several hospitals have implemented antimicrobial resistance management programs based on these findings . The results of these programs validate the use of a multidisciplinary, education-based, antibiotic-resistance management approach.

Chest, 1999 Mar, 115(3 Suppl), 19S - 23S
Pharmacodynamic principles of antimicrobial therapy in the prevention of resistance; Burgess DS; Pharmacodynamic properties can be used to divide antibiotics into two major classes based on their mechanism of bactericidal action: (1) concentration-dependent drugs, such as aminoglycosides and fluoroquinolones, and (2) concentration-independent drugs, including the beta-lactams . Antibiotics also differ in the postantibiotic effect (PAE) that they exert . In general, concentration-dependent drugs have a more prolonged PAE than concentration-independent drugs, particularly against Gram-negative pathogens . Pharmacodynamic classifications have important implications for the planning of drug regimens . For concentration-dependent drugs, peak concentration to minimal inhibitory concentration (MIC) ratios of approximately 10 are associated with clinical success . Therefore, high drug levels should be the goal of therapy . This is best achieved by high doses taken once daily . This approach, however, is not feasible for the fluoroquinolones owing to dose-limiting CNS toxicity . Concentration-independent agents are most effective when the duration of serum concentrations is higher than the pathogen's MIC (time >MIC) for a significant proportion of the dosing interval . Frequent dosing or continuous infusions can increase the time >MIC . Concentrations of antibiotics that are sublethal can permit the emergence of resistant pathogens . Optimization of antibiotic regimens on the basis of pharmacodynamic principles could thus significantly diminish the emergence of antibiotic resistance.

Tijdschr Diergeneeskd, 1999 Mar 1, 124(5), 142 - 4
{Health council report: "Antimicrobial growth promoters"}; Goettsch W et al.; The Health Council of the Netherlands has issued a report on the risk of development of resistance among bacteria as result of the use of antibiotics as growth promotors in livestock farming . The committee appointed by the Health Council conclude that the use of antimicrobial growth promotors contributes to the problem of resistance among human pathogens . The conclusions are based on evidence regarding the development of resistance in livestock as the result of the use of antimicrobial growth promotors, the possibility of colonisation/infection of humans with resistant bacteria from the intestinal flora of productive livestock, and the transfer of resistance genes from livestock bacteria to human pathogenic microorganisms . Effective measures for the limitation of the public health risk should focus on termination of the use of antimicrobial growth promotors that confer resistance to (related) antibiotics currently used (or which will be available) to treat patients suffering from bacterial infections . In addition, the committee advised ending the use of antimicrobial growth promotors in 3 years.

Biochim Biophys Acta, 1999 Mar 19, 1430(2), 262 - 8
A new antifungal peptide from the seeds of Phytolacca americana: characterization, amino acid sequence and cDNA cloning; Shao F et al.; An antifungal peptide from seeds of Phytolacca americana, designated PAFP-s, has been isolated . The peptide is highly basic and consists of 38 residues with three disulfide bridges . Its molecular mass of 3929.0 was determined by mass spectrometry . The complete amino acid sequence was obtained from automated Edman degradation, and cDNA cloning was successfully performed by 3'-RACE . The deduced amino acid sequence of a partial cDNA corresponded to the amino acid sequence from chemical sequencing . PAFP-s exhibited a broad spectrum of antifungal activity, and its activities differed among various fungi . PAFP-s displayed no inhibitory activity towards Escherichia coli . PAFP-s shows significant sequence similarities and the same cysteine motif with Mj-AMPs, antimicrobial peptides from seeds of Mirabilis jalapa belonging to the knottin-type antimicrobial peptide.

Biochim Biophys Acta, 1999 Mar 4, 1417(2), 211 - 23
Differential scanning calorimetric study of the effect of the antimicrobial peptide gramicidin S on the thermotropic phase behavior of phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol lipid bilayer membranes; Prenner EJ et al.; We have studied the effects of the antimicrobial peptide gramicidin S (GS) on the thermotropic phase behavior of large multilamellar vesicles of dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylethanolamine (DMPE) and dimyristoyl phosphatidylglycerol (DMPG) by high-sensitivity differential scanning calorimetry . We find that the effect of GS on the lamellar gel to liquid-crystalline phase transition of these phospholipids varies markedly with the structure and charge of their polar headgroups . Specifically, the presence of even large quantities of GS has essentially no effect on the main phase transition of zwitterionic DMPE vesicles, even after repeating cycling through the phase transition, unless these vesicles are exposed to high temperatures, after which a small reduction in the temperature, enthalpy and cooperativity of the gel to liquid-crystalline phase transitions is observed . Similarly, even large amounts of GS produce similar modest decreases in the temperature, enthalpy and cooperativity of the main phase transition of DMPC vesicles, although the pretransition is abolished at low peptide concentrations . However, exposure to high temperatures is not required for these effects of GS on DMPC bilayers to be manifested . In contrast, GS has a much greater effect on the thermotropic phase behavior of anionic DMPG vesicles, substantially reducing the temperature, enthalpy and cooperativity of the main phase transition at higher peptide concentrations, and abolishing the pretransition at lower peptide concentrations as compared to DMPC . Moreover, the relatively larger effects of GS on the thermotropic phase behavior of DMPG vesicles are also manifest without cycling through the phase transition or exposure to high temperatures . Furthermore, the addition of GS to DMPG vesicles protects the phospholipid molecules from the chemical hydrolysis induced by their repeated exposure to high temperatures . These results indicate that GS interacts more strongly with anionic than with zwitterionic phospholipid bilayers, probably because of the more favorable net attractive electrostatic interactions between the positively charged peptide and the negatively charged polar headgroup in such systems . Moreover, at comparable reduced temperatures, GS appears to interact more strongly with zwitterionic DMPC than with zwitterionic DMPE bilayers, probably because of the more fluid character of the former system . In addition, the general effects of GS on the thermotropic phase behavior of zwitterionic and anionic phospholipids suggest that it is located at the polar/apolar interface of liquid-crystalline bilayers, where it interacts primarily with the polar headgroup and glycerol-backbone regions of the phospholipid molecules and only secondarily with the lipid hydrocarbon chains . Finally, the considerable lipid specificity of GS interactions with phospholipid bilayers may prove useful in the design of peptide analogs with stronger interactions with microbial as opposed to eucaryotic membrane lipids.

Emerg Infect Dis, 1999 Jan-Feb, 5(1), 18 - 27
Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries; Okeke IN et al.; In developing countries, acquired bacterial resistance to antimicrobial agents is common in isolates from healthy persons and from persons with community-acquired infections . Complex socioeconomic and behavioral factors associated with antibiotic resistance, particularly regarding diarrheal and respiratory pathogens, in developing tropical countries, include misuse of antibiotics by health professionals, unskilled practitioners, and laypersons; poor drug quality; unhygienic conditions accounting for spread of resistant bacteria; and inadequate surveillance.

J Infect Dis, 1999 Mar, 179 Suppl 2, S360 - 5
Endocarditis at the millennium; Hoesley CJ et al.; The members of the Interplanetary Society (Pus Club) have made significant contributions to the understanding of the pathogenesis of infective endocarditis (IE) . Although the incidence of IE has essentially remained unchanged, the spectrum and characteristics of patients potentially affected by this disorder are expanding . Moreover, in addition to the typical microorganisms implicated in IE, there are increasing reports of new or atypical pathogens causing IE, including those that are resistant to standard antibiotic therapy . The infectious diseases community is challenged to continue to provide effective antimicrobial regimens for IE and to further develop diagnostic and surgical strategies to identify and treat patients with this disorder . New information is available regarding the demographics, diagnostic methods, and therapeutic options for the management of IE.

J Infect Dis, 1999 Mar, 179 Suppl 2, S342 - 52
Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: comparisons and potential for use in the treatment of infections in nonneutropenic patients; Root RK et al.; Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhance the antimicrobial functions of mature neutrophils . G-CSF differs from GM-CSF in its specificity of action on developing and mature neutrophils, its effects on neutrophil kinetics, and its toxicity profile . The toxicity profile of recombinant (r) GM-CSF is consistent with priming of macrophages for increased formation and release of inflammatory cytokines, whereas rG-CSF induces production of antiinflammatory factors, such as interleukin-1 receptor antagonist and soluble tumor necrosis factor receptors, and is protective against endotoxin- and sepsis-induced organ injury . The low toxicity of rG-CSF, results of animal models of infection, and extensive experience with neutropenic subjects have promoted clinical studies in nonneutropenic subjects, which indicate that rG-CSF may be beneficial as adjunctive therapy for treatment of serious bacterial and opportunistic fungal infections in nonneutropenic patients, including those with alterations in neutrophil function.

J Infect Dis, 1999 Mar, 179 Suppl 2, S309 - 17
Activation of the neutrophil respiratory burst oxidase; Clark RA; The neutrophil respiratory burst oxidase is a multicomponent activatable enzyme comprising one of the major phagocyte antimicrobial systems . In the genetic disorder chronic granulomatous disease, absent oxidase function is associated with recurrent, severe, and often life-threatening infections . The components of the oxidase system include both membrane-bound and soluble cytosolic proteins . A primary feature of stimulus-dependent activation is the translocation of a complex of cytosolic factors to the membrane, where they associate with a flavocytochrome enzyme . Interactions among the various oxidase components occur through a number of specific regions, including SH3 domains and proline-rich motifs . The fully assembled complex functions as an electron transport system, moving electrons from cytosolic NADPH to molecular oxygen to form superoxide, which, along with subsequent reactive products, exerts microbicidal and cytotoxic activities.

CMAJ, 1999 Feb 23, 160(4), 493 - 9
Candidemia at selected Canadian sites: results from the Fungal Disease Registry, 1992-1994 . Fungal Disease Registry of the Canadian Infectious Disease Society; Yamamura DL et al.; BACKGROUND: Candida species are important bloodstream pathogens that are being isolated with increasing frequency . Despite the availability of effective antifungal therapy, the mortality rate associated with Candida infection remains high . With the objective of describing the epidemiology of candidemia, the Canadian Infectious Disease Society conducted a study of candidemia in Canada . METHODS: Fourteen medical centres across Canada identified all patients with candidemia from March 1992 to February 1994 through blood culture surveillance for Candida spp . Patient-related data for invasive fungal infection were compiled retrospectively by chart review using a standardized data-recording form developed for the Fungal Disease Registry of the Canadian Infectious Disease Society . Cases of Candidemia were studied in relation to underlying medical conditions, predisposing factors, concurrent infection, antimicrobial agents, antifungal treatment and deaths . RESULTS: In total, 415 cases of candidemia were identified, 48 (11.6%) in children and 367 (88.4%) in adults . The causative pathogens were C . albicans in 286 cases (68.9%), C . parapsilosis in 43 (10.4%), C . glabrata in 34 (8.2%), C . tropicalis in 27 (6.5%) and other Candida species in 18 (4.3%); polymicrobial candidemia occurred in 7 cases (1.7%) . The overall mortality rate was 46%, and the rate of deaths clinically related to candidemia was 19% . However, only 13 (27%) of the children died . A univariate analysis indicated that significant risk factors for death were age greater than 60 years, therapy for concomitant bacterial infection, stay in an intensive care unit, concurrent malignant disease, cytotoxic chemotherapy and granulocytopenia, although only age and stay in an intensive care unit emerged as significant risk factors in the multivariate analysis . After adjustment for other predictors of death, only infection with C . parapsilosis was associated with a lower mortality rate than infection with C . albicans . Treatment was given in 352 (84.8%) of cases . Amphotericin B was the preferred agent in 244 cases (69.3% of those treated); fluconazole was used in 101 cases (28.7%) and ketoconazole in 5 cases (1.4%) . INTERPRETATION: Candidemia in Canada is caused predominantly by C . albicans . The mortality rate associated with candidemia is high, but it varies with the species of Candida and is lower in children than in adults . Age greater than 60 years and stay in an intensive care unit were the most significant risk factors for overall mortality.

Chest Surg Clin N Am, 1999 Feb, 9(1), 39 - 61, vii-viii
New directions in antimicrobial therapy; Greene JN et al.; The virulent microorganisms that we try to contain with new antimicrobial agents quickly find the gap in our defenses and exploit it . Resistance to all available antibiotics at the same time, however, rarely occurs . The authors report the most current antimicrobials used as monotherapy or in combination to successfully treat the more resistant pathogens . The higher mortality and subsequent cost to treat these infections are reviewed.

FEMS Microbiol Lett, 1999 Mar 1, 172(1), 41 - 5
Effect on cell surface hydrophobicity and susceptibility of Helicobacter pylori to medicinal plant extracts; Annuk H et al.; Effects on aqueous extracts of medicinal plants on ten Helicobacter pylori strains were studied by the salt aggregation test to determine the possibility to modulate their cell surface hydrophobicity and by an agar diffusion assay for detection of antimicrobial activity . It was established that aqueous extracts of bearberry and cowberry leaves enhance cell aggregation of all H . pylori strains tested by the salt aggregation test, and the extract of bearberry possessed a remarkable bacteriostatic activity . Pure tannic acid showed a result similar to that of bearberry and cowberry extracts which contained a large amount of tannins . In contrast, extracts of wild camomile and pineapple-weed, which blocked aggregation of H . pylori, contained small amounts of tannins and did not reveal any antimicrobial activity . Tannic acid seems to be the component of bearberry and cowberry aqueous extracts with the highest activity to decrease cell surface hydrophobicity as well as in antibacterial activity against H . pylori.

J Chemother, 1999 Feb, 11(1), 11 - 27
Clarithromycin: pharmacokinetic and pharmacodynamic interrelationships and dosage regimen; Periti P et al.; In the last decade three important pharmacodynamic parameters: T>MIC, Cmax/MIC and AUC/MIC, have been shown to correlate well with in-vitro antimicrobial efficacy and that found in animal models, differentiating among groups of antibiotics with diverse mechanisms of action such as exposure time or concentration-dependent effect . The macrolide antimicrobial agents display variable concentration-dependent killing, indicating the increasing importance of the Cmax parameter . Clarithromycin, whose T>MIC and AUC influence its clinical efficacy, is in an intermediate position between its progenitor, erythromycin, and the azalides . This paper reviews pharmacokinetic and pharmacodynamic characteristics of clarithromycin, examining the potential impact of these properties on the dose and the optimal interval between administrations.

FEMS Microbiol Rev, 1999 Jan, 23(1), 69 - 91
Strategies for isolation of in vivo expressed genes from bacteria; Handfield M et al.; The discovery and characterization of genes specifically induced in vivo upon infection and/or at a specific stage of the infection will be the next phase in studying bacterial virulence at the molecular level . Genes isolated are most likely to encode virulence-associated factors or products essential for survival, bacterial cell division and multiplication in situ . Identification of these genes is expected to provide new means to prevent infection, new targets for, antimicrobial therapy, as well as new insights into the infection process . Analysis of genes and their sequences initially discovered as in vivo induced may now be revealed by functional and comparative genomics . The new field of virulence genomics and their clustering as pathogenicity islands makes feasible their in-depth analysis . Application of new technologies such as in vivo expression technologies, signature-tagged mutagenesis, differential fluorescence induction, differential display using polymerase chain reaction coupled to bacterial genomics is expected to provide a strong basis for studying in vivo induced genes, and a better understanding of bacterial pathogenicity in vivo . This review presents technologies for characterization of genes expressed in vivo.

Biochim Biophys Acta, 1999 Feb 2, 1426(3), 439 - 48
Isolation and identification of three bactericidal domains in the bovine alpha-lactalbumin molecule; Pellegrini A et al.; Proteolytic digestion of alpha-lactalbumin by pepsin, trypsin and chymotrypsin yielded three polypeptide fragments with bactericidal properties . Two fragments were obtained from the tryptic digestion . One was a pentapeptide with the sequence EQLTK (residues 1-5) and the other, GYGGVSLPEWVCTTF ALCSEK (residues (17-31)S-S(109-114)), was composed of two polypeptide chains held together by a disulfide bridge . Fragmentation of alpha-lactalbumin by chymotrypsin yielded CKDDQNPH ISCDKF (residues (61-68)S-S(75-80)), also a polypeptide composed of two polypeptide chains held together by a disulfide bridge . The three polypeptides were synthesized and found to exert antimicrobial activities . The polypeptides were mostly active against Gram-positive bacteria . Gram-negative bacteria were only poorly susceptible to the bactericidal action of the polypeptides . GYGGVSLPEWVCTTF ALCSEK was most, EQLTK least bactericidal . Replacement of leucine (23) with isoleucine, having a similar chemical structure but higher hydrophobicity, in the sequence GYGGVSLPEWVCTTF ALCSEK significantly reduced the bactericidal capacity of the polypeptide . Digestion of alpha-lactalbumin by pepsin yielded several polypeptide fragments without antibacterial activity . alpha-Lactalbumin in contrast to its polypeptide fragments was not bactericidal against all the bacterial strains tested . Our results suggest a possible antimicrobial function of alpha-lactalbumin after its partial digestion by endopeptidases.

J Clin Microbiol, 1999 Apr, 37(4), 1144 - 9
Rapid film-based determination of antibiotic susceptibilities of Mycobacterium tuberculosis strains by using a luciferase reporter phage and the Bronx Box; Riska PF et al.; Detecting antibiotic resistance in Mycobacterium tuberculosis is becoming increasingly important with the global recognition of drug-resistant strains and their adverse impact on clinical outcomes . Current methods of susceptibility testing are either time-consuming or costly; rapid, reliable, simple, and inexpensive methods would be highly desirable, especially in the developing world where most tuberculosis is found . The luciferase reporter phage is a unique reagent well-suited for this purpose: upon infection with viable mycobacteria, it produces quantifiable light which is not observed in mycobacterial cells treated with active antimicrobials . In this report, we describe a modification of our original assay, which allows detection of the emitted light with a Polaroid film box designated the Bronx Box . The technique has been applied to 25 M . tuberculosis reference and clinical strains, and criteria are presented which allow rapid and simple discrimination among strains susceptible or resistant to isoniazid and rifampin, the major antituberculosis agents.

Planta Med, 1998 Dec, 64(8), 769 - 71
A new bioactive norquinone-methide triterpene from Maytenus scutioides; Gonzalez AG et al.; By antimicrobial and cytotoxic-guided fractionation, a bioactive norquinone-methide triterpene, 15 alpha-hydroxypristimerin, was isolated from a South American medicinal plant, Maytenus scutioides . Its structure was determined on the basis of spectroscopic evidence . Successful chemical transformation of pristimerin to netzahualcoyene indicates that the 15-hydroxy compounds seems to be a possible percursor of 14(15)-ene-quinone-methide-triterpenoids in the biogenetic pathway.

Arch Oral Biol, 1999 Jan, 44(1), 67 - 79
Enhanced expression of activation-associated molecules on macrophages of heterogeneous populations in expanding periapical lesions in rat molars; Suzuki N et al.; Exudative macrophages are the most prevalent inflammatory cells during the entire pathogenetic process in experimentally induced rat periapical lesions . To clarify the significance of macrophages in the pathogenesis of periapical lesions, the way in which the phenotype of ED1 (a general marker for mononuclear phagocytes)-positive cells is modulated in actively expanding lesions was investigated, by immunoperoxidase staining with a panel of antibodies that recognize several activation-associated molecules on macrophages . Periapical lesions were induced experimentally by exposing the pulp in the lower first molars of Wistar rats . Active lesion expansion with morphological diversification of ED1-positive cells occurred between 14 and 28 days after the injury . Double immunoperoxidase staining revealed that ED1-positive cells coexpressing class II molecules of the major histocompatibility complex (MHC) molecules, inducible nitric oxide synthase (iNOS) and/or CD11a increased during the period of active lesion expansion . Increases of endothelial cells expressing intracellular adhesion molecule-1 and CD25 (interleukin-2 receptor)-expressing lymphocytes were also seen during the same period . Moreover, there existed two particular subpopulations of ED1 + cells in the established lesion at 28 days: (1) ED1++/class II MHC - /iNOS+ cells, located around the periapical abscess, and (2) ED1+/class II MHC+/ iNOS- cells with slender or dendritic morphology, distributed predominantly in the outer portion of the lesion where T lymphocytes were abundant . The first cell type could be a macrophage with potent phagocytic and antimicrobial actions, and the second might possess sufficient antigen-presenting capacity to cause the activation of T lymphocytes . It was concluded that macrophages, when activated, may participate in triggering lesion expansion . Functionally distinct subpopulations of macrophages may occupy different sites within the lesion where they can most effectively exert their specific functions.

J Ethnopharmacol, 1999 Jan, 64(1), 69 - 77
Wide spectrum antibacterial and antifungal activities in the seeds of some coprophilous plants of north Indian plains; Bagchi GD et al.; In a survey at Lucknow, India, the seedlings of plant species which are prescribed in the Indian traditional system of medicine for a variety of infectious diseases were found to predominate on fresh or decomposing cattle dung, a harsh medium for plant growth due to high microbial load and other abiotic factors . Plants of most of the common species did not occur on the cattle dung heaps . It was hypothesized that plant species which are able to grow on cattle dung may have antimicrobial compounds in their seeds to protect them from microbial attack . In confirmation, the seeds of 15 of the coprophilous (kopros--dung, philein--to love) plant species, identified as occurring most frequently on fresh/decomposing cattle dung were directly tested against eight bacterial and three fungal strains . Interestingly, seeds of all the examined species exhibited antimicrobial activity . The seeds of the species found more frequently on the cattle dung heaps possessed higher levels of antimicrobial activities.

Biophys Chem, 1999 Feb 22, 76(3), 161 - 83
Interactions of alpha-helices with lipid bilayers: a review of simulation studies; Biggin PC et al.; Membrane proteins, of which the majority seem to contain one or more alpha-helix, constitute approx . 30% of most genomes . A complete understanding of the nature of helix/bilayer interactions is necessary for an understanding of the structural principles underlying membrane proteins . This review describes computer simulation studies of helix/bilayer interactions . Key experimental studies of the interactions of alpha-helices and lipid bilayers are briefly reviewed . Surface associated helices are found in some membrane-bound enzymes (e.g . prostaglandin synthase), and as stages in the mechanisms of antimicrobial peptides and of pore-forming bacterial toxins . Transmembrane alpha-helices are found in most integral membrane proteins, and also in channels formed by amphipathic peptides or by bacterial toxins . Mean field simulations, in which the lipid bilayer is approximated as a hydrophobic continuum, have been used in studies of membrane-active peptides (e.g . alamethicin, melittin, magainin and dermaseptin) and of simple membrane proteins (e.g . phage Pf1 coat protein) . All atom molecular dynamics simulations of fully solvated bilayers with transmembrane helices have been applied to: the constituent helices of bacteriorhodopsin; peptide-16 (a simple model TM helix); and a number of pore-lining helices from ion channels . Surface associated helices (e.g . melittin and dermaseptin) have been simulated, as have alpha-helical bundles such as bacteriorhodopsin and alamethicin . From comparison of the results from the two classes of simulation, it emerges that a major theoretical challenge is to exploit the results of all atom simulations in order to improve the mean field approach.

Br J Clin Pharmacol, 1999 Jan, 47(1), 23 - 30
The therapeutic monitoring of antimicrobial agents; Begg EJ et al.; AIMS: To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents . METHODS: Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring were reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualisation of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring . RESULTS: There is a strong historical case for monitoring aminoglycosides . The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined . Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this . A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances . CONCLUSIONS: The approach to monitoring aminoglycosides needs to be redefined in the light of once-daily dosing . It is premature to suggest that less stringent monitoring is necessary as toxicity remains a problem with these drugs . The ideal method of monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy . Teicoplanin is monitored occasionally to ensure efficacy while flucytosine is monitored occasionally to avoid high concentrations associated with toxicity . Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.

Drug Dev Ind Pharm, 1999 Mar, 25(3), 391 - 5
Studies of erythromycin maltobionate, a new derivative of erythromycin; Manna PK et al.; Erythromycin maltobionate, a new water-soluble derivative of erythromycin, was prepared, and its physiochemical and biological properties were evaluated . The derivative has considerable solubility in organic solvents . Its partition coefficient data in different organic solvent-water systems indicate it is possibly well distributed in various tissues in vivo . Antimicrobial potency in vitro of the derivative is 589 micrograms/mg, and its antimicrobial spectrum is comparable to that of the parent antibiotic . The LD50 value of the new derivative in mice intraperitoneally is 244.7 mg/kg . Results of this and the previous investigation of pharmacokinetics and protein binding indicate that the new derivative erythromycin maltobionate has a potential for possible clinical application.

Drug Dev Ind Pharm, 1999 Mar, 25(3), 289 - 95
Development and in vitro evaluation of buccoadhesive tablets using a new model substrate for bioadhesion measures: the eggshell membrane; Parodi B et al.; For oral delivery of antimicrobial and anti-inflammatory drug, mucoadhesive tablets based on gelatin/hydroxypropylcellulose (HPC), gelatin/hydroxypropylmethyl-cellulose (HPMC), and gelatin/sodium carboxymethylcellulose (NaCMC) at different ratios were prepared by direct compression of the mixed powders . Metronidazole and benzydamine were used as model drugs . The in vitro bioadhesive properties, evaluated by a commercial tensile tester, were significantly affected by the model substrate employed, that is, a polypropylene (PP) membrane or a biological membrane (eggshell membrane) . The use of the biological substrate seemed to supply more reliable data . All studied formulations showed an erosion-diffusion mechanism of release, anomalous or non-Fickian release, in agreement with the behavior of the swellable systems.

J Infect Dis, 1999 Apr, 179(4), 954 - 66
Persistent chlamydial envelope antigens in antibiotic-exposed infected cells trigger neutrophil chemotaxis; Wyrick PB et al.; An in vitro coculture model system was used to explore conditions that trigger neutrophil chemotaxis to Chlamydia trachomatis infected human epithelial cells (HEC-1B) . Polarized HEC-1B monolayers growing on extracellular matrix (ECM) were infected with C . trachomatis serovar E . By 36 h, coincident with the secretion of chlamydial lipopolysaccharide and major outer membrane protein to the surfaces of infected cells, human polymorphonuclear neutrophils (PMNL) loaded with azithromycin migrated through the ECM and infiltrated the HEC-1B monolayer . Bioreactive azithromycin was delivered by the chemotactic PMNL to infected epithelial cells in concentrations sufficient to kill intracellular chlamydiae . However, residual chlamydial envelopes persisted for 4 weeks, and PMNL chemotaxis was triggered to epithelial cells containing residual envelopes . Infected endometrial cells demonstrated up-regulation of ENA-78 and GCP-2 chemokine mRNA . Thus, despite appropriate antimicrobial therapy, residual chlamydial envelope antigens may persist in infected tissues of culture-negative women and provide one source for sustained inflammation.

Mayo Clin Proc, 1999 Feb, 74(2), 187 - 95
The cephalosporins; Marshall WF et al.; The cephalosporins are a large group of related beta-lactam antimicrobial agents . Favorable attributes of the cephalosporins include low rates of toxicity, relatively broad spectrum of activity, and ease of administration . Various cephalosporins are effective for treatment of many conditions, including pneumonia, skin and soft tissue infections, bacteremia, and meningitis . Differences among the numerous cephalosporin antimicrobial agents are sometimes subtle; however, an understanding of these differences is essential for optimal use of these agents . As a result of widespread use of cephalosporins, bacterial resistance to these drugs is increasingly common . New, fourth-generation agents (such as cefepime) offer an alternative for the treatment of infections caused by some drug-resistant microorganisms.

Clin Cancer Res, 1997 Dec, 3(12 Pt 2), 2660 - 5
The evolution of antibiotic therapy for neutropenic patients; Bodey GP; Considerable progress has been made in the treatment of infections in neutropenic patients during the past three decades . A major contribution to this progress has been the discovery of effective new therapies and their prompt administration . Unfortunately, successful therapy of each important pathogen has resulted in the emergence of new pathogens, usually with unique patterns of antibiotic susceptibility . Unfortunately, antibiotic resistance has become an increasing threat in recent years, raising the possibility of infections that will be difficult to eradicate . Fortunately, there are new classes of antimicrobials that hold promise for therapeutic success in the future.

Kekkaku, 1999 Jan, 74(1), 63 - 70
{In vitro antimicrobial activities of quinolones, rifamycins and macrolides against Mycobacterium tuberculosis and M.avium complex: attempt to establish new assay methods which accurately reflect therapeutic effects of test agents in vivo}; Sato K et al.; Profiles of expression of the antimicrobial activities of LVFX, KRM-1648 (KRM), and CAM against M . tuberculosis (MTB) and M . avium complex (MAC) residing in MONO-MAC-6 human macrophage like cells (MM6-M phi s) and A-549 human type II alveolar pneumocyte cells (A-549 cells) were determined . First, the antimicrobial activities of LVFX, KRM, and CAM against intracellular organisms of MTB Kurono and MAC N-444 strains were examined under conditions in which infected MM6-M phi s and A-549 cells were cultured for up to 7 days or longer in medium containing the antimicrobials at their Cmaxs in the blood, achievable after oral administration of clinical dosages of these drugs . The antimicrobial effects of LVFX and KRM against respectively MTB and MAC within A-549 cells were significantly less than the activities they displayed against the same organisms residing in MM6-M phi s . Notably, it was also found that KRM had a markedly larger MIC (0.25 microgram/ml) for MAC N-444 within A-549 cells than its MIC (0.008 microgram/ml) for the same strain residing in MM6-M phi s . Thus, the profiles of LVFX- and KRM-mediated killing or inhibition of intracellular MTB or MAC organisms in A-549 cells were markedly different from those observed for the organisms residing in MM6-M phi s . Second, invasive and multiplicative phenotypes of MTB and MAC organisms, which had been adapted to either an extracellular or intracellular environment (designated as E- and I-type organisms, respectively), were studied . In the case of MTB, I-type organisms (retrieved from infected MM6-M phi s after bacterial growth within the M phi s during 5-day cultivation) were less efficient than E-type organisms (prepared by cultivating the organisms in 7H9 medium) in entering MM6-M phi s, whereas I-type organisms were more efficient than E-type organisms in invading A-549 cells . On the other hand, in the case of MAC, infectivity of I-type organisms not only in MM6-M phi s but also in A-549 cells was larger than that of E-type organisms . Next, while I-type organisms of MTB and MAC displayed more vigorous replication within MM6-M phi s than E-type organisms, the growth rate of E-type organisms within A-549 cells was more rapid than that of I-type organisms residing in A-549 cells . These findings indicate that there are significant differences between E- and I-type organisms of MTB or MAC in ability to invade and multiply within M phi s (professional phagocytes) and alveolar epithelial cells (nonprofessional phagocytic cells).

Scand J Infect Dis, 1998, 30(5), 519 - 20
Cervicofacial and pulmonary actinomycosis associated with non-Hodgkin's lymphoma; Dentale N et al.; A case of cervicofacial and pulmonary actinomycosis associated with non-Hodgkin's lymphoma (NHL) is reported . The patient underwent antimicrobial treatment and surgical debridement of a palatine lesion . Complete clinical recovery was achieved . The presence of actinomycosis may obscure and delay the diagnosis of NHL.

Scand J Infect Dis, 1998, 30(5), 513 - 7
Lactoferricin of bovine origin is more active than lactoferricins of human, murine and caprine origin; Vorland LH et al.; The antimicrobial peptide lactoferricin is generated by gastric pepsin cleavage of lactoferrin . We have examined the antimicrobial activity of lactoferricins derived from lactoferrin of human, murine, caprine and bovine origin with minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) against E . coli ATCC 25922 and S . aureus ATCC 25923 . We found that lactoferricin of bovine origin (Lf-cin B) was the most efficacious of the lactoferricins tested . By comparing the linear and cyclic Lf-cin B we found the cyclic peptide to be the most active . Lactoferricin B was moderately active against E . coli ATCC 25922 and S . aureus ATCC 25923, but had no activity against P . mirabilis or Y . enterocolitica . Lf-cin B showed good activity against C . albicans, C . tropicalis and C . neoformans.

J Zoo Wildl Med, 1998 Dec, 29(4), 479 - 83
Systemic candidiasis in a cheetah (Acinonyx jubatus); La Perle KM et al.; Systemic candidiasis, with involvement of the spleen, liver, kidneys, and lymph nodes, was diagnosed in a geriatric captive cheetah (Acinonyx jubatus) . The animal had a long clinical history of intermittent chronic gastritis associated with Helicobacter acinonyx and chronic renal failure, both of which were repeatedly treated with broad-spectrum antimicrobial therapy . Following euthanasia, a postmortem examination showed numerous microabscesses and granulomas composed of degenerate eosinophils and containing asteroids or Splendore-Hoeppli material throughout the body . Yeast, pseudohyphae, and infrequently branching septate hyphae, demonstrated with special stains, were identified as a Candida sp . by fluorescent antibody testing . Low genetic variation in cheetahs may increase their susceptibility to infectious agents . Additional factors contributing to the overgrowth and dissemination of Candida sp . in this case may have included changes in the bacterial flora of the alimentary tract as a result of repeated antimicrobial therapy and alterations in the topography of the alimentary mucosa caused by chronic gastritis.

Ned Tijdschr Geneeskd, 1998 Dec 12, 142(50), 2746 - 50
{Imported skin diseases}; Cairo I et al.; In two Dutch subjects who had been on holiday in the tropics, a woman aged 32 and a man of Surinam descent aged 52 years, and in two men aged 21 and 38 years who had arrived from the tropics in the Netherlands, one recently and one 15 years previously, import skin diseases were diagnosed: larva migrans cutanea, cutaneous leishmaniasis, mycetoma and lobomycosis . The diagnosis was based on the anamnesis, the clinical picture and histopathological findings . The patients were cured by administration of antimicrobial agents and (or) excision . When travellers or immigrants from the tropics present with skin lesions, an imported skin disease should be considered.

East Afr Med J, 1998 Dec, 75(12), 703 - 7
Antimicrobial prophylactic practice in surgical patients; al Harbi M; OBJECTIVE: To evaluate the prescribing patterns of surgeons for pre-operative antimicrobial prophylaxis . DESIGN: A retrospective study based on data obtained from case records of surgical patients admitted into the Department of Surgery . SETTING: Department of Surgery, Royal Commission Medical Center, Madinat Yambu Al-Sinayah . SUBJECTS: The study population comprised of 888 surgical patients who received antibiotic therapy either for prophylaxis or treatment during the period 1st November 1992 and 28th February 1995 . RESULTS: A total of 888 surgical patients received antibiotics during the study period, 191 (21.5%) for prophylaxis while 697 (78.5%) were given antibiotics for therapy before and after surgery . Ceftriaxone was the most commonly used antibiotic for prophylaxis, followed by augmentin and cefotaxime, and these were frequently given in multiple doses, extending beyond 24 hours . CONCLUSION: There was unwarranted and over use of prophylactic agents in at least 70% of the patients, with increased costs to the Hospital . Effective prophylaxis can be accomplished with a single dose of a cephalosporin, such as ceftriaxone, cefuroxime or cefazolin, for the common surgical procedures . It is recommended that better compliance with principles of surgical antimicrobial prophylaxis be implemented Prophylactic antibiotic audit measures should be carried out by the control committee . The development of guidelines and standing orders for antimicrobial prophylaxis should help to improve compliance.

East Afr Med J, 1998 Dec, 75(12), 699 - 702
Toxin production and antimicrobial resistance of Escherichia coli river water isolates; Simiyu KW et al.; OBJECTIVES: To establish the types of E . coli isolates that are found in river water around Nairobi and to assess the potential risk of use of this water to human health . DESIGN: Multiple stratified sampling was carried out . Surface sampling was used in the entire study . SETTING: The study was carried out on river waters surrounding Nairobi, Kenya . SUBJECTS: Forty Escherichia coli strains isolated from river water . MAIN OUTCOME MEASURES: Serotyping, toxin gene tests and susceptibility to tetracyclines, ampicillin, chloramphenicol and kanamycin were analysed . RESULTS: None of the isolates could be specifically serotyped using the available antisera . Toxin gene production tests using the colony hybridisation technique revealed that nine (22.5%) of the strains were positive for heat stable (ST) toxin, seven (17.5%) to the heat labile (LT) toxin and two (5%) to both . Using the Agar Disk Diffusion technique, eighty per cent of the strains were susceptible to all four antibiotics, while twenty per cent of the strains showed multiple resistance . None of the strains was resistant to all four antibiotics while no strain showed resistance to kanamycin . CONCLUSION: None of the E . coli isolates was serotypable and it was therefore not possible to determine whether serologically identical strains of ETEC were haboured by man or animals . Toxin gene tests results showed that there is some risk of infection by diarrhoea causing ETEC to man and animals . Toxin gene tests results showed that there is some risk of infection by diarrhoea causing ETEC to man and animals if they consume this water untreated and there is evidence to show resistance of bacteria to antibiotics, hence appropriate health measures should be adhered to.

Histopathology, 1999 Feb, 34(2), 124 - 33
Interobserver agreement in the assessment of gastritis reversibility after Helicobacter pylori eradication; Tepes B et al.; AIM: Our aim was to determine interobserver agreement in the application of the Sydney system to assess reversibility of gastritis after Helicobacter pylori eradication . METHODS AND RESULTS: Forty-three patients with a Helicobacter pylori-positive duodenal ulcer disease were included in the study . All patients included had successful H . pylori eradication after different antimicrobial drug combinations . Biopsy samples were collected from antrum and body, according to the Sydney recommendations, before antimicrobial therapy, 2 months after and at yearly intervals during 2-4 years of follow up . Three pathologists, who were blind to clinical data, evaluated histological changes in 221 antral and 219 body specimens stained with haematoxylin and eosin and with Warthin Starry . The percentage of pairwise agreement, kappa and weighted kappa statistic were used . Agreement in recognizing the presence of H . pylori colonization of the gastric mucosa, activity of inflammation and intestinal metaplasia was over 90% . Agreement in recognizing chronic inflammation in the body and atrophy in the antrum was between 78 and 89% respectively . The kappa values were excellent (more than 0.75) for the grade of H . pylori in the body, good (between 0.50 and 0.75) for the grade of H . pylori in the antrum, grade of inflammatory activity and intestinal metaplasia in the antrum and moderate to good (0.38-0.53) for the grade of chronic inflammation . Kappa values were poor to good (from 0.17 to 0.57) only in evaluation of the grade of atrophy . CONCLUSION: Interobserver agreement in the application of the Sydney system to reversibility of gastritis after H . pylori was good . More strict criteria should be used for atrophy and to differentiate normal and mild chronic inflammation.

Biophys Chem, 1999 Feb 1, 76(2), 145 - 59
Peptide-bilayer interactions: simulations of dermaseptin B, an antimicrobial peptide; La Rocca P et al.; Dermaseptins, a family of antimicrobial peptides, are believed to act by forming amphipathic alpha-helices which associate with the cell membrane, leading to its permeabilisation and disruption . A simple mean field method is described for simulation of the interactions of peptides with lipid bilayers which includes an approximate representation of the electrostatic effects of the head-group region of the bilayer . Starting from an atomistic model of a PC phospholipid bilayer we calculate an average electrostatic potential along the bilayer normal . By combining the interaction of the peptide with this electrostatic potential and with the hydrophobic core of the membrane we arrive at a more complete description of peptide-bilayer energetics than would be obtained using sidechain hydrophobicities alone . Using this interaction potential in MD simulations of the frog skin peptide dermaseptin B reveals that the lipid bilayer stabilises the alpha-helical conformation of the peptide . This is in agreement with FTIR data . A surface associated orientation thus appears to be the most stable arrangement of the peptide, at least at zero ionic strength and without taking account of possible peptide-peptide interactions.

Vet Microbiol, 1999 Feb 12, 64(4), 299 - 305
Susceptibility testing of Actinobacillus pleuropneumoniae in Denmark . Evaluation of three different media of MIC-determinations and tablet diffusion tests; Aarestrup FM et al.; This study was conducted to compare the applicability of three different media in sensitivity testing of Actinobacillus pleuropneumoniae by means of MIC and tablet diffusion tests . The media used were: modified PPLO agar, chocolatized Mueller-Hinton-II and Columbia agar supplemented with NAD . Seven antimicrobial agents were tested: ceftiofur, enrofloxacin, penicillin, spectinomycin, tiamulin, trimethoprim + sulfadiazine and tylosin, against 40 randomly selected A . pleuropneumoniae isolates . In general, good agreement was found between results obtained with all combinations of media, most antimicrobials tested and the two-test systems . Some variations between media were observed for spectinomycin, tiamulin and tylosin . For ceftiofur and trimethoprim + sulfadiazine some isolates with low MIC-values were classified as resistant using tablet diffusion, indicating that the break points of resistance for these antimicrobials using the tablet diffusion tests need adjustment . Using current break points for resistance with MIC-determinations, all isolates tested susceptible to ceftiofur, enrofloxacin, penicillin, tiamulin and trimethoprim + sulfadiazine . A larger number of isolates tested resistant to spectinomycin and tylosin on all three media using both MIC determinations and tablet diffusion.

J Periodontol, 1999 Jan, 70(1), 1 - 7
A six-month comparison of three periodontal local antimicrobial therapies in persistent periodontal pockets; Kinane DF et al.; BACKGROUND: Currently, several local antimicrobial delivery systems are available to periodontists . The aim of this 6-month follow-up parallel study was to evaluate the efficacy of three commercially available local delivery systems as adjuncts to scaling and root planing in the treatment of sites with persistent periodontal lesions . METHODS: Seventy-nine patients with 4 pockets > or = 5 mm and bleeding on probing and/or suppuration were randomized into 4 treatment groups which included: scaling and root planing alone (S) (20 patients), or in conjunction with the application of 25% tetracycline fibers (S+Tet) (19 patients), or 2% minocycline gel (S+Min) (21 patients), or 25% metronidazole gel (S+Met) (19 patients) . Clinical measurements were taken at baseline, 6 weeks, 3 months, and 6 months after antimicrobial application . Treatments were applied using the distributors' recommended protocols . RESULTS: All 4 therapies resulted in significant improvements from baseline in probing depth, attachment level, bleeding on probing, and the Modified Gingival Index (MGI) scores . The improvements in clinical parameters were greater in all 3 adjunctive treatment groups than scaling and root planing alone . The mean probing depth reductions at 6 months were: scaling + tetracycline = 1.38 mm; scaling + metronidazole = 0.93 mm; scaling + minocycline = 1.10 mm; and scaling alone = 0.71 mm . The probing depth reduction at all time points was significantly greater in the scaling plus tetracycline fiber group than the scaling and root planing alone group (P<0.01) . There was also a significant improvement for scaling plus tetracycline fiber application over scaling and metronidazole at both 6 weeks and 3 months, although this did not remain significant at the 6-month visit . While the frequency of sites with suppuration was markedly reduced following all antimicrobial treatments, the most effective reductions were seen in the scaling plus tetracycline fiber group, followed by the minocycline group . CONCLUSIONS: Although all 3 locally applied antimicrobial systems seem to offer some benefit over scaling and root planing alone, a treatment regimen of scaling and root planing plus tetracycline fiber placement gave the greatest reduction in probing depth over the 6 months after treatment.

Can Vet J, 1998 Feb, 39(2), 87 - 96
Antimicrobial drug use and related management practices among Ontario swine producers; Dunlop RH et al.; A mail survey of swine producers in Ontario was undertaken during 1991 to describe the types, frequency, and motives for antimicrobial use . Two hundred operations that marketed fewer than 350 hogs per year, and 800 that marketed more than 350 per year were sent questionnaires, 63% of which were completed and returned . Most operations (86%) added antimicrobials to starter (weanling pig) rations, while fewer (29%) added these drugs to finisher pig rations . The most commonly used antimicrobials were tylosin, carbadox, and furazolidone in weanling pigs, and tylosin, lincomycin, and tetracycline in finishers . Water medication of grower-finisher pigs was practised on 25% of farms; 80% of farms had injected at least some grower-finisher pigs with antimicrobials in the 12 mo preceding the survey . Approximately 20% of operations that added antimicrobials to finisher rations did so for growth promotion purposes only, while others used them for disease treatment, prevention, control, or a combination of reasons . Among those not using antimicrobials in finisher rations, 83% did not believe they were necessary and 37% were concerned about the potential for residues in marketed hogs.

Protein Expr Purif, 1999 Mar, 15(2), 171 - 7
Purification and characterization of a plant antimicrobial peptide expressed in Escherichia coli; Harrison SJ et al.; MiAMP1 is a low-molecular-weight, cysteine-rich, antimicrobial peptide isolated from the nut kernel of Macadamia integrifolia . A DNA sequence encoding MiAMP1 with an additional ATG start codon was cloned into a modified pET vector under the control of the T7 RNA polymerase promoter . The pET vector was cotransformed together with the vector pSB161, which expresses a rare arginine tRNA . The peptide was readily isolated in high yield from the insoluble fraction of the Escherichia coli extract . The purified peptide was shown to have an identical molecular weight to the native peptide by mass spectroscopy indicating that the N-terminal methionine had been cleaved . Analysis by NMR spectroscopy indicated that the refolded recombinant peptide had a similar overall three-dimensional structure to that of the native peptide . The peptide inhibited the growth of phytopathogenic fungi in vitro in a similar manner to the native peptide . To our knowledge, MiAMP1 is the first antimicrobial peptide from plants to be functionally expressed in E . coli . This will permit a detailed structure-function analysis of the peptide and studies of its mode of action on phytopathogens .

Eur J Pediatr, 1999 Feb, 158(2), 144 - 6
The effectiveness of single and multiple applications of triple dye on umbilical cord separation time; Hsu CF et al.; The effectiveness of single and multiple applications of triple dye for umbilical cord care in the umbilical cord separation time (UCST) was evaluated in 180 neonates . Seven neonates were excluded, three where the cord stump separation time was uncertain and four to whom contact was lost . The participating neonates were randomly assigned to two groups . Group 1, 101 neonates, were treated with a regimen of a single application of triple dye . Group 2, 79 neonates, were treated with multiple applications of triple dye . Complete information was obtained from 97 neonates (96.2%) in group 1 and 76 (96%) in group 2 . The UCST was 12.6 +/- 0.45 (mean +/- SE) days in group 1 and 16.68 +/- 0.65 days in group 2 (P < 0.0001) and showed no significant association with infants' gender, mode of delivery, gravidity, gestational age, birth weight, or hospital stay . CONCLUSION: A single application of triple dye may be a more favourable regimen with a similarly antimicrobial effect, a shorter UCST and may be more cost effective than multiple applications of triple dye in umbilical cord care.

Toxicol Lett, 1999 Jan 11, 104(1-2), 43 - 8
Chromosomal aberrations in human lymphocytes exposed in vitro to enrofloxacin and ciprofloxacin; Gorla N et al.; Chromosomal aberrations were evaluated in cultures of human peripheral lymphocytes from eight healthy donors, exposed to the antimicrobial enrofloxacin (EFX) or to its major metabolite ciprofloxacin (CFX) . In both treatments cultures revealed an increase in the chromosomal aberration level, detected as chromatid and chromosome breaks and gaps . Control cultures analysis revealed 3.6 +/- 0.6 chromosomal aberrations per 100 cells while treated cultures exhibited 8.3 +/- 0.8 and 9.6 +/- 1.2 aberrations at 5 and 50 microg/ml of EFX respectively . In CFX treated cultures it was found 5.6 +/- 1.3 and 7.7 +/- 3.5 aberrations/100 cells at 5 and 25 microg/ml antimicrobial concentration . These results suggested a genotoxic effect of EFX and CFX in the system used (P < 0.001) . A reduction in the mitotic index and fuzzy metaphases were observed at 50 microg/ml of CFX, indicating a cytotoxic effect produced by this antimicrobial.

Contact Dermatitis, 1999 Feb, 40(2), 104 - 8
Increase in occupational skin diseases of dental personnel; Kanerva L et al.; Occupational diseases of dentists and dental nurses were compiled from the Finnish Register of Occupational Diseases . The cases were recorded during 3 3-year observation periods, namely 1982-1984, 1986-1988, and 1992-1994 (i.e., 9 observation years) . The relative risk of developing occupational allergic contact dermatitis in different occupations was calculated from the statistics of the years 1986-1991, and was expressed as the age-standardized rate ratio (SRR) . During the 9 observation years, the majority of registered occupational diseases of dentists and dental nurses were skin diseases (221/312; 70.8%), followed by occupational repetitive strain injuries (61/312; 19.6%) and occupational respiratory diseases (20/312; 6.4%) . The incidence rate (IR) for allergic contact dermatoses/10,000 workers (contact urticaria included) increased from 26 (95% confidence interval (CI) 16-40) in 1982-1984 to 79 (95%, CI 64-97) in 1992-1994 . The IR/10,000 of allergic contact dermatoses increased especially for dentists, from 5.4 (95% CI 0.7-19) in 1982 to 67 (95% CI 45-95) in 1992-1994 . The increase of the IR/10,000 dental nurses was smaller: from 43 (95%, CI 26-66) in 1982-1984 to 87 (95% CI 67-111) in 1992-1994 . There was no increase in the IR/10,000 cases of irritant dermatoses . The most common causes of allergic contact dermatitis were plastics, disinfectants and antimicrobials, rubber chemicals, and mercury/mercury salts . The most common causes of irritant contact dermatitis were detergents, wet and dirty work, plastic chemicals and antimicrobials . Currently, Finnish dentists have the highest risk and dental nurses have the 4th highest risk of any occupation for developing occupational allergic contact dermatitis: the risk was 6.4-fold (SRR 6.4) in dentists and 6.1-fold in dental nurses, as compared to the general working population . It is evident that safer acrylics and protective gloves, better product declarations and material safety data sheets, as well as more information about protective measures, including non-touch working techniques, are needed.

J Antibiot (Tokyo), 1998 Dec, 51(12), 1075 - 80
Apicularens A and B, new cytostatic macrolides from Chondromyces species (myxobacteria): production, physico-chemical and biological properties; Kunze B et al.; A novel macrolide, apicularen A, was produced by several species of the genus Chondromyces . Initially it was discovered by bioassay-guided RP-HPLC-fractionation of culture extracts of Chondromyces robustus, strain Cm a13 . Apicularen A showed no antimicrobial activity, but was highly cytotoxic for cultivated human and animal cells, with IC50 values ranging between 0.1 and 3 ng/ml . A cometabolite of apicularen A, the N-acetylglucosamine glycoside apicularen B, was distinctly less cytotoxic with IC50 values between 0.2 and 1.2 microg/ml, and showed weak activity against a few Gram-positive bacteria . Apicularen A is chemically closely related to the salicylihalamides A and B from the marine sponge Haliclona sp.

Wien Med Wochenschr, 1998, 148(21), 481 - 7
{Therapy of febrile neutropenia episodes in systemic hematologic illnesses with new once daily ceftriaxone administration}; Karthaus M et al.; In this open label prospective multicenter trial, 420 patients with neutropenia < 1000/microliter, fever > 38.5 degrees C and hematological malignancies were treated with ceftriaxone . Acute leukemia (n = 238) and high-grade lymphoma patients (n = 182) from 35 centers were enrolled . Between February 1992 and January 1996, patients were treated with 2 g ceftriaxone i.v . per day either as monotherapy (n = 135), or in combination with aminoglycosides (n = 235), glycopeptides (n = 37), or other antimicrobial agents (n = 13) . Patients' median age was 54 years (range 15 to 97) with a median Karnofsky-performance-score of 6.0 . The median neutrophil counts were 400/microliter . Fever was of unknown origin (FUO) in 268 (63.8%) of patients . Clinically defined infections (CDI) were diagnosed in 152 (36.2%) cases, including 74 (17.8%) episodes with pneumonia . Response to the initial approach with ceftriaxone was observed in 56.2% of febrile episodes, including 93 (68.8%) treatment courses with ceftriaxone alone . Concerning defervescence of fever ceftriaxone monotherapy was successful as compared to ceftriaxone in combination . Analysis revealed a low risk characterized by higher neutrophil counts (> or = 500/microliter; p < 0.0001), better Karnofsky-performance-score (> or = 7; p = 0.01), duration of neutropenia (< or = 5 days; p = 0.008) from start of antimicrobial treatment and duration of neutropenia per cycle (< or = 10 days; p = 0.0016) . At the end of the observation, an overall response was obtained in 88.3% of the patients (n = 371) without statistical difference between patients treated with ceftriaxone alone or in combination . Once daily ceftriaxone either alone or in combination was effective in patients with hematological malignancies . Monotherapy was effective in a low risk group characterized by neutrophil counts (> or = 500/microliter), a Karnofsky-performance-score (> or = 7) and a duration of neutropenia (< or = 5 days) at the commencement of treatment.

Curr Opin Microbiol, 1999 Feb, 2(1), 99 - 105
Cytokine responses during mucosal infections: role in disease pathogenesis and host defence; Svanborg C et al.; Mucosal pathogens use diverse and highly specific molecular mechanisms to activate mucosal inflammation . It may even be argued that their virulence depends on the inflammatory response that they induce . Some bacteria target epithelial cells and trigger them to produce inflammatory mediators but others cross the mucosa and activate macrophages or dendritic cells . Although systemic release of inflammatory mediators causes many symptoms and signs of infection, local chemokine production leads to the recruitment of inflammatory cells and lymphocytes that participate directly in the clearance of bacteria from mucosal sites . In this way, mucosal inflammation is a two-edged sword responsible for disease associated tissue destruction and crucial for the antimicrobial defence . Understanding of these pathways should create tools to enhance the defence and interfere with disease.

Curr Opin Immunol, 1999 Feb, 11(1), 23 - 7
Antimicrobial peptides in mammalian and insect host defence; Lehrer RI et al.; During the past year, additional insights into systems that regulate antimicrobial peptide production in Drosophila were reported . Granulysin, a peptide stored in the cytoplasmic granules of human natural killer cells and cytolytic T cells, was shown to kill Mycobacterium tuberculosis . More data implicating antimicrobial peptides in the pathogenesis of bronchopulmonary infections in cystic fibrosis appeared . Studies that examined the potential contributions of antimicrobial peptides to regional innate immunity gained in prominence . Efforts to design peptide analogues to prevent or treat infections continued.

Nippon Rinsho, 1999 Jan, 57(1), 157 - 61
{Long-term endoscopic follow-up for peptic ulcer patients after eradication of H . pylori; comparison with the maintainance therapy by H2-blocker}; Shirai T et al.; This study was aimed to clarify the endoscopic findings and the decline of serum IgG titer after successful eradication of H . pylori in long-term (from 2 to 7 years) . Forty-six H . pylori-positive peptic ulcer (22 GU and 26 DU) cases were eradicated with antimicrobial therapy . Sixty-nine non-eradicated DU cases who received maintainance therapy with H2-blocker were control group . Biopsy urease test (BUT) and culturing was performed to diagnose the H . pylori infection . Anti-H . pylori IgG titer (EIA) were also measured in some cases, pre and 6, 12, 24 months after the eradication . In 3 cases, H . pylori were recrudescent and only in a case, DU recurred during 5 years after eradication . Meanwhile, in 55% of control cases, DU were recurred during same periods . In 62% of eradicated cases, serum IgG-antibody to H . pylori declined below the cut-off level during 2 years after eradication . It was certified that eradication therapy against H . pylori prevents ulcer recurrence for long time, and re-rise of serum IgG titer to H . pylori might predict a recrudescence of infection.

Nippon Rinsho, 1999 Jan, 57(1), 121 - 6
{The treatment strategy of H . pylori infection and the new triple therapy}; Hoshiya S et al.; The strategies against H . pylori infection have been developed very fast . Since the efficacy of mono-therapy (one antimicrobial drug) and dual-therapy (proton-pump inhibitor (PPI) + one antimicrobial drug) were not good, and the safety of classical triple therapy (bismuth + two antimicrobial drugs) was bad, new triple-therapy consisted with PPI + two antimicrobial drugs is considered as a standard regimen of the treatment of H . pylori infection . However there are several questions about this new strategy which we have to answer . The first question is how can we diagnose the cure of H . pylori infection and when we should do it? The second one is which statistical method should we choose for evaluating the success rate? The third one is which drug should we use and how long should the patient continuing to have the drug? A lot of scientific research are need to clarify these questions.

Nippon Rinsho, 1999 Jan, 57(1), 107 - 10
{PCR-monitoring of gastric juice obtained with the capsuled string for the evaluation of H . pylori eradication}; Yoshida H et al.; We have developed a highly sensitive semi-nested PCR assay, URA-PCR, for the detection of H . pylori ureA gene in gastric juice . The primers were designed according to nucleotide sequence analyses of clinical isolates . The PCR assay has higher sensitivity than conventional methods such as culture . Characteristics of culture-negative but PCR-positive patients were similar to those of culture-positive ones . The PCR assay, using gastric juice samples obtained with capsuled strings, detected 97% cases of relapsed infection within eight weeks after antimicrobial therapy.

Nippon Rinsho, 1999 Jan, 57(1), 76 - 80
{Antimicrobial resistance testing of H . pylori epsilometer test and disk diffusion test}; Fukazawa K et al.; The resistance of Helicobacter pylori to antibiotics leaves great influence on treatment outcome . Routine antimicrobial susceptibility testing of H . pylori should be a simple, inexpensive and standardized method to be adopted . Agar and broth dilution techniques are difficult to perform and not practical . E-test and disk diffusion methods have the advantage of allowing the visualization of resistant subpopulations of bacteria within zones of inhibitions . We studied the susceptibility results of 246 H . pylori isolates against metronidazole and clarithromycin using E-test and disk diffusion test . The results of disk diffusion test were well correlated with these of E-test . Our results showed that disk method is cost effective and simple for the screening for antimicrobial resistance of H . pylori.

Nippon Rinsho, 1999 Jan, 57(1), 61 - 6
{In a view of international consensus conference for the treatment of H . pylori infection}; Watanabe K et al.; The first guideline of the treatment of H . pylori infection was reported by the working party of the World Congresses of Gastroenterology in 1990 . Subsequently, many international consensus statements for the indication and the methods of eradication therapy for H . pylori infection were reported . And, now the standard regimens have been developed in European countries and U.S.A . The other hand, in Japan, the Ministry of Welfare has never been to approve the both of testing and treatment of H . pylori . One of the reasons is that there is a few scientific evidence for the benefit of the treatment of H . pylori infection in Japan . Since the resistant strains of H . pylori against antimicrobial agents are increasing in our country, we have to develop a strong and safety therapeutic regimen in Japan.

Nippon Rinsho, 1999 Jan, 57(1), 53 - 60
{The role and significance of acid suppressive drugs in the eradication of H . pylori}; Yakabi K et al.; Recently a new triple therapy with PPI and two antimicrobials is widely accepted instead of classical triple therapy . PPI has direct and indirect effects on H . pylori . Practically a single use of PPI is almost noneffective for eradication of H . pylori . In the combination therapy PPI is supposed to contribute to successful eradication through the inhibition of acid secretion . Because a raise of pH in stomach protects antimicrobials from the degradation by acidic environment . The decrease in the volume of gastric juice also contributes to concentrate antibiotics . Recently interaction between PPI and clarithromycin on metabolic enzyme in liver was reported that explains the synergistic effects of these drugs . The heterogeneity of genotype of metabolic enzyme was also elucidated which might be responsible for the difference in the effect of PPI between the patients . To accomplish successful eradication, full inhibition of acid secretion has to be done . To consider the interactions between PPI and antimicrobials and the heterogeneity of genotype of metabolic enzyme may improve eradication therapy of H . pylori.

J Am Dent Assoc, 1999 Feb, 130(2), 236 - 51
Adverse drug interactions in dental practice: interactions involving antibiotics . Part II of a series; Hersh EV; BACKGROUND: The prudent use of antibiotics is an integral part of dental practice . While these agents generally are considered safe in the dental setting, their use can result in interactions that can lead to serious morbidity in dental patients . METHODS: The faculty of a symposium entitled "Adverse Drug Interactions in Dentistry: Separating the Myths From the Facts" did an extensive literature review on drug interactions . Through this, they were able to establish a significance rating of alleged adverse drug interactions as they relate to dentistry, based on their scientific documentation and severity of effect . The author of this article focused on antibiotics . RESULTS: Most of the reported drug interactions discussed in this article are well-documented by clinical studies . It is particularly important that dentists be aware of the potentially serious and life-threatening interactions of the antibiotics erythromycin, clarithromycin and metronidazole, and of the antifungal agents ketoconazole and itraconazole, with a host of other drugs whose metabolism is impaired by these antimicrobial agents . In contrast, the alleged ability of commonly employed antibiotics to reduce the effectiveness of oral contraceptive agents is not adequately supported by clinical research . It still is recommended, however, that clinicians discuss this possible interaction with their patients, as it might represent a relatively rare event that cannot be discerned in clinical trials . CONCLUSIONS: Potentially serious adverse drug interactions can occur between antimicrobial agents used in dental practice and other drugs patients are taking for a variety of medical conditions . CLINICAL IMPLICATIONS: It is important that dentists stay abreast of potential drug interactions involving antibiotics to avoid serious morbidity among their patients.

Adv Nurse Pract, 1999 Jan, 7(1), 34 - 9
Repairing lacerations in children . Suture, staple or secure?
Behr J.
The challenges of pediatric laceration repair include the probability of an uncooperative participant, tense or frantic parents and a busy setting . Linear lacerations of the scalp, trunk and extremities are excellent sites for staples . Stapling may be less traumatic because it is generally quicker than suturing . Suture repair is necessary for lacerations of the face, over joints, on the hands and feet, and other areas that impede the use of a stapling device . The most common methods of anesthesia for laceration repair include topical agents, direct infiltration and blocks . All wounds that are deep, dirty or may contain a foreign body should be locally cleansed with antimicrobial agents and irrigated vigorously.

J Ethnopharmacol, 1998 Dec, 63(3), 253 - 63
Antimicrobial properties of Honduran medicinal plants; Lentz DL et al.; Ninety-two plants used in the traditional pharmacopoeia of the Pech and neighboring Mestizo peoples of central Honduras are reported . The results of in vitro antimicrobial screens showed that 19 of the extracts from medicinal plants revealed signs of antifungal activity while 22 demonstrated a measurable inhibitory effect on one or more bacterial cultures . Bioassay-guided fractionation of extracts from Mikania micrantha, Neurolaena lobata and Piper aduncum produced weak to moderately active isolates . The broad spectrum of activity of the extracts helps to explain the widespread use of these plants for wound healing and other applications.

Am J Health Syst Pharm, 1999 Jan 15, 56(2), 142 - 57
ASHP national survey of pharmacy practice in acute care settings: prescribing and transcribing--1998 . American Society of Health-System Pharmacists; Ringold DJ et al.; Results of the 1998 ASHP national survey of pharmacy practice in acute care settings that pertain to prescribing and transcribing practices are presented . Pharmacy directors at 1058 general and children's medical-surgical hospitals in the United States were surveyed by mail . Data on hospital characteristics were supplied by SMG Marketing Group, Inc.; the survey sample was drawn from SMG's hospital database . The response rate was 51.8% . Respondents reported that at least 90% of hospital and health-system pharmacy and therapeutics (P&T) committees are responsible for formulary development and management, drug policy development, medication-use evaluation, adverse-drug-reaction reporting, and medication error monitoring . More than 90% of the facilities use pharmacoeconomic, clinical and therapeutic, and cost information in formulary development; 83% have a medication-use-evaluation program designed to improve prescribing; more than 95% have P&T committees, infection control committees, and quality control committees; and more than 80% provide pharmacist consultations on drug information, dosage adjustments for patients with renal impairment, antimicrobials, and pharmacokinetics . A majority of respondents reported that accurate transcription of medication orders is ensured by use of standardized physician order forms, clarification of illegible orders, reconciliation of medication administration records (MARs) and pharmacy profiles at least daily, and use of computer-generated MARs . The 1998 ASHP survey results suggest that pharmacists in acute care settings have positioned themselves well to improve the prescribing and transcription components of the medication-use process.

J Calif Dent Assoc, 1998 Nov, 26(11), 842 - 5
Effect of doxycycline on the apical seal of retrograde filling materials; Barkhordar RA et al.; In this study, we examined the effect of doxycycline hydrochloride (DH) on the apical seal . Results indicated that teeth that were retrofilled with IRM or amalgam following doxycycline irrigation had significantly less dye penetration (p < 0.05) . Due to its antimicrobial activity, smear layer removal ability, and improvement of apical seal, doxycycline solution may be used as an irrigant.

Mol Diagn, 1998 Jun, 3(2), 81 - 91
Comparative Evaluation of Cleavase Fragment Length Polymorphism With PCR-SSCP and PCR-RFLP to Detect Antimicrobial Agent Resistance in Mycobacterium tuberculosis; Sreevatsan S et al.; Background: Several molecular methods potentially useful in the detection of Mycobacterium tuberculosis mutations, specifically in rpoB and katG, were compared . Methods and Results: DNA from 24 M . tuberculosis clinical isolates, with mutations associated with resistance to rifampin and/or isoniazid, was analyzed . A 128 bp amplicon, spanning the 81 bp rpoB region containing most mutations leading to rifampin resistance, was analyzed by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and a recently introduced mutation scanning method, cleavase fragment length polymorphism (CFLP) analysis . Also, a 350 bp amplicon encompassing that region was analyzed by the CFLP method . CFLP analysis of the 350 bp amplicon (23 isolates) identified 14 of 17 mutants; however, CFLP analysis of the 128 bp amplicon accurately identified all mutants as did PCR-SSCP with interpretative difficulty for two codon 513 mutations . CFLP and PCR-restriction fragment length polymorphism (RFLP) analyses of a 623 bp amplicon encompassing katG codons 315 and 463 showed that the CFLP method identified single and dinucleotide codon 315 substitutions with or without codon 463 (CGG-->CTG) changes, whereas PCR-RFLP (MspI) missed one codon 315 polymorphism (AGC-->ACA) in three isolates . Conclusion: Both PCR-SSCP and CFLP analyses were sensitive in identifying all mutations on short sequences in the rpoB mutants . CFLP appears to be more efficient than SSCP and RFLP for the detection of mutations in large amplicons .

J Dent Res, 1999 Feb, 78(2), 690 - 8
Construction and characterization of human salivary histatin-5 multimers; Situ H et al.; Human salivary histatin-5 (Hsn-5), a 24-amino acid polypeptide, is a potent candidacidal molecule . In this study, we have explored the following two hypotheses: More potent Hsn molecules may be achieved by duplication of the functional domain of Hsn-5 (C16, residues 9-24 of Hsn-5), and Hsn may act like other cationic peptides which aggregate and form channels across the target membrane . A PCR-based gene splicing by overlap extension (SOE) method was used to construct the DNA fragments encoding the following fusion molecules: Hsn-5--Hsn-5, Hsn-5--C16, and C16--C16 . These constructs were expressed in E . coli, the proteins produced were purified, and their anticandidal activities as well as secondary structures were determined . Contrary to our hypotheses, results showed that none of the multimers possessed increased candidacidal activity . Specifically, C16--C16 and Hsn-5--C16 displayed candidacidal activity comparable with that of Hsn-5, while Hsn-5--Hsn-5 possessed significantly decreased candidacidal activity, yet all molecules retained an alpha-helical structure in a hydrophobic environment . Additionally, the circular dichroism data showed that Hsn-5 in an alpha-helical conformation does not aggregate in a hydrophobic environment, not even at 14- to 18-fold its physiological concentration . Our results suggest that the development of enhanced Hsn-5 molecules may not be achieved by duplication of its functional domain, and that Hsns may not act like other antimicrobial cationic peptides which aggregate and form channels across the target membrane.

Eur J Surg Suppl, 1998, (582), 90 - 8
Medical therapy of inflammatory bowel disease for the 21st century; Robinson M; Inflammatory bowel disease therapy can be considered in several subcategories, and this review is designed to provide selective updates for some of the most important therapeutic entities currently marketed or soon to be available for the medical management of IBD . Although conventional corticosteroids have been a major component of acute inflammatory bowel disease management, steroids have many serious disadvantages; and toxicity is heightened with chronic steroid therapy . Newer corticosteroids, particularly budesonide, may be less toxic than older agents such as prednisone . Budesonide may be used as an enema in active distal ulcerative colitis (UC) or as delayed release tablets in Crohn's disease (CD) . However, budesonide is not completely free from steroid side effects, and may share in some of the toxicity of older corticosteroids, particularly when high dose budesonide is administered . Topical and oral aminosalicylates are widely utilized for the treatment of mild to moderate active UC and mild active CD, and they also are efficacious for maintenance of IBD remission . Recent data continue to support the concept that higher doses and prolonged use of mesalamine-based drugs are therapeutically superior to lower doses and short term treatment . In addition, the combination of oral and rectal aminosalicylate formulations often succeeds in patients refractory to either used alone . The immunomodulatory drugs azathioprine and 6-mercaptopurine are particularly effective in treating both CD and UC, and methotrexate has also shown some promise in CD therapy . Immunosuppressive therapy for inflammatory bowel disease initially met with strong physician resistance . However, views have shifted in response to positive data on the utility of immunosuppressive agents in many cases of IBD . Although cyclosporine may be used as a 'rescue' medication in some severe IBD cases, it has been associated with severe toxic reactions . Possible candidates for cyclosporine treatment should be offered such therapy only in academic centers highly experienced with the nuances of this modality . Clinical trials of the newer entities IL-10, IL-11, tacrolimus, and anti-TNFalpha, have demonstrated variable efficacy in refractory IBD patients . Anti-TNFalpha has been very impressive, particularly in the presence of fistulizing Crohn's disease . Many physicians have utilized various antibiotics empirically as part of their 'general' management of IBD . Only metronidazole has been adequately studied in controlled CD trials, but other antibiotic studies are pending . Further exploration of antimicrobial treatment for IBD is clearly warranted . Many other investigational agents in disparate pharmaceutical categories have been employed in IBD therapy; and some of these also show varying degrees of promise, including the aloe vera derivative acemannan, several formulations of heparin, and both transdermal and intra-rectal nicotine . Despite the growing list of medications and formulations promoted for the treatment of IBD, no single drug or recognized combination has yet been confirmed as dependably clinically effective . Many additional investigations of IBD medical therapy are needed, including permutations of conventional medications, along with newer agents that may be more precisely targeted to specific aspects of IBD pathophysiology . All physicians who care for UC and CD patients enthusiastically await more optimal regimens for these challenging disorders.

Eur J Surg Suppl, 1998, (582), 16 - 26
Antimicrobial treatment of H . pylori infection--a pooled efficacy analysis of eradication therapies; Unge P; OBJECTIVE: To evaluate the clinical efficacy of available therapies directed towards Helicobacter pylori eradication . DESIGN: Pooled overall analyses of a limited number of drug combinations regardless of dosage, duration, formulation etc . SUBJECTS: Helicobacter pylori infected patients with or without complications . INTERVENTIONS: Efficacy data from all studies included in the analysis are transformed to or retained as intention to treat data . MAIN OUTCOME: Efficacy is presented as proportion of patients cured from the infection . Confidence intervals are enlarged by 1.5 due to the inferior strength of a pooled analysis . RESULTS: Dual therapies are ineffective . Triple therapies cure 70-90% of the patients . Well documented high efficacy is shown for a proton pump inhibitor plus two antimicrobials . Less studied but effective alternatives are ranitidine-bismuth plus two antimicrobials . CONCLUSION: A proton pump inhibitor plus two antimicrobials is the best validated highly effective type of eradication therapy.

J AOAC Int, 1999 Jan-Feb, 82(1), 79 - 84
Validation of the LacTek test applied to spiked extracts of tissue samples: determination of performance characteristics; Mitchell JM et al.; LacTek tests are competitive enzyme-linked immunosorbent assays intended for rapid detection of antimicrobial residues in bovine milk . In this study, the LacTek test protocol was modified for use with extracts of bovine tissue to detect beta-lactam, tetracycline, and sulfamethazine residues . Test performance characteristics--precision, accuracy, ruggedness, practicability, and analytical specificity and sensitivity--were investigated . Results suggest that LacTek tests can be easily adapted to detect antimicrobial residues in extracts of lean ground beef . However, positive samples may not contain residues at violative concentrations (i.e., Canadian maximum residue limits), and therefore, additional analysis would be required for final confirmation and quantitation (e.g., chromatography).

Jpn J Antibiot, 1998 Nov, 51(11), 625 - 81
{Thirteen-week intravenous repeated dose toxicity study of T-3762, a novel parenteral quinolone antimicrobial agent, and four-week recovery test in cynomolgus monkeys}; Nagai A et al.; A thirteen-week intravenous repeated dose toxicity study of T-3762, parenteral quinolone antimicrobial agent, and four-week recovery test was carried out in male and female cynomolgus monkeys at dosages of 26, 52 and 104 mg/kg . The following results were obtained . 1) There was no death of animals during administration period at any dose levels . In general signs, there was no abnormality at any dose levels . 2) In appetite, body weights and ophthalmological examination, there was no abnormality attributable to the treatment . 3) In urinalysis, hematological examination and biochemical examination, there was no abnormality attributable to the treatment . 4) In organ weights, macroscopic findings and histopathological findings, there was no abnormality attributable to the treatment . 5) From these results in this study, no-toxic dose level of T-3762 for cynomolgus monkeys is considered over 104 mg/kg.

Ned Tijdschr Geneeskd, 1998 Nov 14, 142(46), 2512 - 5
{Optimizing of antibiotics policy in the Netherlands . III . SWAB guidelines for antimicrobial therapy in adults hospitalized with bronchitis . Foundation Antibiotics Policy Work Group}; van Kasteren ME et al.; The Stichting Werkgroep Antibioticabeleid (SWAB, Foundation Antibiotics Policy Team) has issued guidelines for empirical antimicrobial therapy of adult patients with bronchitis in hospital . Acute bronchitis is rarely caused by bacteria: therefore antibiotic treatment is not indicated in most cases . In an exacerbation of asthma or chronic obstructive pulmonary disease (COPD), the primary treatment aims at combating the inflammatory reaction and the bronchospasm . In case of increasing dyspnoea, (increase of) sputum production and (increase of) purulence of the sputum, antibiotic treatment may lead to shortening of the symptoms and sickness duration . Doxycycline is to be preferred because of its spectrum, easy dosage and favourable price . If the patient has not had antibiotics earlier, amoxicillin also is a good choice . Macrolide antibiotics are no preparations of first choice because large-scale use readily leads to resistance.

Chest, 1999 Feb, 115(2), 462 - 74
Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients; Kollef MH et al.; STUDY OBJECTIVE: To evaluate the relationship between inadequate antimicrobial treatment of infections (both community-acquired and nosocomial infections) and hospital mortality for patients requiring ICU admission . DESIGN: Prospective cohort study . SETTING: Barnes-Jewish Hospital, a university-affiliated urban teaching hospital . PATIENTS: Two thousand consecutive patients requiring admission to the medical or surgical ICU . INTERVENTIONS: Prospective patient surveillance and data collection . MEASUREMENTS AND RESULTS: One hundred sixty-nine (8.5%) infected patients received inadequate antimicrobial treatment of their infections . This represented 25.8% of the 655 patients assessed to have either community-acquired or nosocomial infections . The occurrence of inadequate antimicrobial treatment of infection was most common among patients with nosocomial infections, which developed after treatment of a community-acquired infection (45.2%), followed by patients with nosocomial infections alone (34.3%) and patients with community-acquired infections alone (17.1%) (p < 0.001) . Multiple logistic regression analysis, using only the cohort of infected patients (n = 655), demonstrated that the prior administration of antibiotics (adjusted odds ratio {OR}, 3.39; 95% confidence interval {CI}, 2.88 to 4.23; p < 0.001), presence of a bloodstream infection (adjusted OR, 1.88; 95% CI, 1.52 to 2.32; p = 0.003), increasing acute physiology and chronic health evaluation (APACHE) II scores (adjusted OR, 1.04; 95% CI, 1.03 to 1.05; p = 0.002), and decreasing patient age (adjusted OR, 1.01; 95% CI, 1.01 to 1.02; p = 0.012) were independently associated with the administration of inadequate antimicrobial treatment . The hospital mortality rate of infected patients receiving inadequate antimicrobial treatment (52.1%) was statistically greater than the hospital mortality rate of the remaining patients in the cohort (n = 1,831) without this risk factor (12.2%) (relative risk {RR}, 4.26; 95% CI, 3.52 to 5.15; p < 0.001) . Similarly, the infection-related mortality rate for infected patients receiving inadequate antimicrobial treatment (42.0%) was significantly greater than the infection-related mortality rate of infected patients receiving adequate antimicrobial treatment (17.7%) (RR, 2.37; 95% CI, 1.83 to 3.08; p < 0.001) . Using a logistic regression model, inadequate antimicrobial treatment of infection was found to be the most important independent determinant of hospital mortality for the entire patient cohort (adjusted OR, 4.27; 95% CI, 3.35 to 5.44; p < 0.001) . The other identified independent determinants of hospital mortality included the number of acquired organ system derangements, use of vasopressor agents, the presence of an underlying malignancy, increasing APACHE II scores, increasing age, and having a nonsurgical diagnosis at the time of ICU admission . CONCLUSIONS: Inadequate treatment of infections among patients requiring ICU admission appears to be an important determinant of hospital mortality . These data suggest that clinical efforts aimed at reducing the occurrence of inadequate antimicrobial treatment could improve the outcomes of critically ill patients . Additionally, prior antimicrobial therapy should be recognized as an important risk factor for the administration of inadequate antimicrobial treatment among ICU patients with clinically suspected infections.

Infection, 1999 Jan-Feb, 27(1), 42 - 3
Hemophilus influenzae biotype III cellulitis in an adult; Lev EI et al.; The case of a patient with systemic lupus erythematosus presenting with severe leg cellulitis caused by Hemophilus influenzae non-B biotype III is reported . Skin infections caused by H . influenzae in general, and of the extremities in particular, seem to be rare in adults . This is the first reported case of cellulitis caused by H . influenzae biotype III . The infection was treated successfully with antibiotics . This case highlights the importance of blood cultures and prompt antimicrobial treatment in febrile adults with cellulitis, especially immunocompromised patients.

Infect Immun, 1999 Mar, 67(3), 1386 - 92
Role of iron in Nramp1-mediated inhibition of mycobacterial growth; Zwilling BS et al.; Innate resistance to mycobacterial growth is mediated by a gene, Nramp1 . We have previously reported that Nramp1 mRNA from macrophages of Mycobacterium bovis BCG-resistant (Bcgr) mice is more stable than Nramp1 mRNA from macrophages of BCG-susceptible (Bcgs) mice . Based on these observations and on reports that show that the closely related Nramp2 gene is a metal ion transporter, we evaluated the effect of iron on the growth of Mycobacterium avium within macrophages as well as on the stability of Nramp1 mRNA . The addition of iron to macrophages from Bcgs mice resulted in a stimulation of mycobacterial growth . In contrast, iron increased the capacity of macrophages from Bcgr mice to control the growth of M . avium . When we treated recombinant gamma interferon (IFN-gamma)-activated macrophages with iron, we found that iron abrogated the growth inhibitory effect of IFN-gamma-activated macrophages from Bcgs mice but that it did not affect the capacity of macrophages from Bcgr mice to control microbial growth . A more detailed examination of the effect of iron on microbial growth showed that the addition of small quantities of iron to resident macrophages from Bcgr mice stimulated antimicrobial activity within a very narrow dose range . The effect of iron on the growth inhibitory activity of macrophages from Bcgr mice was abrogated by the addition of catalase or mannitol to the culture medium . These results are consistent with an Fe(II)-mediated stimulation of the Fenton/Haber-Weiss reaction and hydroxyl radical-mediated inhibition of mycobacterial growth.

Infect Immun, 1999 Mar, 67(3), 1251 - 60
Dysregulated production of interleukin-8 in individuals infected with human immunodeficiency virus type 1 and Mycobacterium tuberculosis; Meddows-Taylor S et al.; Interleukin-8 (IL-8) production in vivo was monitored in four study groups: normal blood donors, patients with pulmonary tuberculosis (TB), patients with human immunodeficiency virus type 1 (HIV-1) infection, and dually infected (HIV/TB) patients . We show that whereas there was evidence of detectable levels of cell-associated IL-8 (mRNA and protein) in peripheral cells of healthy individuals, this was largely lost in the disease states studied . Coupled with this finding was significantly increased circulating levels of IL-8 in HIV-1-infected individuals with or without concomitant pulmonary TB (P < 0.001) . On the other hand, the capacity of peripheral mononuclear cells to produce IL-8 spontaneously ex vivo was enhanced in HIV-1 and TB patients (P < 0.05) and many of the HIV/TB group, but their corresponding capacities to respond to various stimuli, in particular phytohemagglutinin, were significantly diminished compared to those of normal donors (P < 0.05) . Circulating levels of IL-8 in a group of HIV/TB patients were significantly positively correlated with the percentage of polymorphonuclear leukocytes (PMN) in the peripheral circulation (r = 0.65; P = 0.01), the proportions of IL-8 receptor A (IL-8RA)-expressing (r = 0.86; P < 0.01) and IL-8RB-expressing (r = 0.77; P < 0.01) PMN, and the capacity of PMN to migrate in response to IL-8 as chemoattractant (r = 0.68; P < 0 . 01) . IL-8RB fluorescence intensity, however, was negatively correlated with plasma IL-8 levels (r = -0.73; P < 0.01) . Our results suggest that altered regulation of IL-8 in HIV-1 may have important implications for antimicrobial defenses and for normal immune processes.

Immunity, 1999 Jan, 10(1), 21 - 8
An antiviral mechanism of nitric oxide: inhibition of a viral protease; Saura M et al.; Although nitric oxide (NO) kills or inhibits the replication of a variety of intracellular pathogens, the antimicrobial mechanisms of NO are unknown . Here, we identify a viral protease as a target of NO . The life cycle of many viruses depends upon viral proteases that cleave viral polyproteins into individual polypeptides . NO inactivates the Coxsackievirus protease 3C, an enzyme necessary for the replication of Coxsackievirus . NO S-nitrosylates the cysteine residue in the active site of protease 3C, inhibiting protease activity and interrupting the viral life cycle . Substituting a serine residue for the active site cysteine renders protease 3C resistant to NO inhibition . Since cysteine proteases are critical for virulence or replication of many viruses, bacteria, and parasites, S-nitrosylation of pathogen cysteine proteases may be a general mechanism of antimicrobial host defenses.

J Am Vet Med Assoc, 1999 Feb 1, 214(3), 382 - 90
Characteristics and risk factors for failure of horses with acute diarrhea to survive: 122 cases (1990-1996); Cohen ND et al.; OBJECTIVE: To characterize horses with acute diarrhea and determine risk factors for failure to survive . DESIGN: Retrospective study . ANIMALS: 122 adult horses admitted for acute diarrhea at the teaching hospital between Jan 1, 1990 and Dec 31, 1996 . PROCEDURE: Medical records of horses with acute diarrhea were reviewed to abstract information regarding signalment, history, physical examination, clinicopathologic testing, treatment, and outcome . RESULTS: 91 of 122 (74.6%) horses lived and were discharged from the hospital . Horses with history of administration of antimicrobials for a problem preceding diarrhea were approximately 4.5 times less likely to survive . The following variables that had been determined at the time of admission were significantly associated with failure to survive: administration of antimicrobial drugs for another illness, serum creatinine concentration > 2.0 mg/dl, PCV > 45%, tachycardia (heart rate > 60 beats/min), and low serum total protein concentration . Prevalence of laminitis was 11.5% . CLINICAL IMPLICATIONS: Diarrheic horses that are azotemic and have clinicopathologic findings consistent with hemoconcentration and hypoproteinemia have a poor prognosis for survival . Antimicrobial administration may induce diarrhea, and antimicrobial-associated diarrhea may have a worse prognosis than other types of acute diarrhea.

Sex Transm Infect, 1998 Jun, 74 Suppl 1, S34 - 7
Specificity of dysuria and discharge complaints and presence of urethritis in male patients attending an STD clinic in Malawi; Dallabetta G et al.; OBJECTIVE: This study evaluated the specificity of discharge and dysuria for laboratory confirmed urethritis in symptomatic men presenting to an urban STD clinic in Malawi for treatment and returning for follow up evaluation . METHODS: Clinical treatment trial where consecutive consenting men with urethritis were enrolled and administered a questionnaire, examined, tested, and given one of five urethritis treatments with an efficacy range of 33-95% . Men returning for follow up were questioned, examined, and tested . RESULTS: The presence of both discharge and dysuria were highly specific for laboratory confirmed urethritis (over 90%) . Compared with men who had complaints of both discharge and dysuria, men with complaints of dysuria alone were more likely to have reported prior treatment, 72% v 48% (p = 0.003), and less likely to have had gonorrhoea, 64% v 83% (p = 0.04) . Men with complaints of discharge or dysuria without evidence of discharge were rare but half of them had documented urethritis . Among men who returned for follow up, 72% had no symptoms of either discharge or dysuria . However, among the 238 men with no symptoms at follow up, laboratory documented gonorrhoea occurred in 9% and non-gonococcal urethritis in 21% . DISCUSSION: In this population of men discharge or dysuria were specific symptoms for urethritis . The symptom of dysuria should be added as an entry criterion for evaluation for urethritis in the World Health Organisation's treatment recommendations . The high prevalence of asymptomatic infection at follow up in a population of men who received suboptimal antimicrobial therapy suggests that the most effective therapy available should be given at the first visit.

Medicine (Baltimore), 1999 Jan, 78(1), 38 - 63
Lymphocutaneous syndrome . A review of non-sporothrix causes; Smego RA Jr et al.; The lymphocutaneous syndrome can be caused by a number of diverse microorganisms requiring very different antimicrobial therapy for resolution . The epidemiology and geographic occurrence of the infection often can provide important first clues to the microbiologic etiology . Accurate diagnosis can be accomplished usually by punch or wedge biopsy of a primary lesion or proximal subcutaneous nodule submitted for histopathologic examination and culture . The microbiology laboratory staff should be alerted to the diagnostic possibilities so that appropriate cultural and incubation techniques, procedures, and precautions can be initiated . Provision of a correct microbiologic diagnosis and institution of appropriate antimicrobial therapy will result in a complete cure in almost all instances . Adjunctive surgical debridement may be required for certain organisms such as Nocardia or Mycobacterium chelonae.

Arch Histol Cytol, 1998 Dec, 61(5), 427 - 32
Immunohistochemical localization of secretory immunoglobulins in the main excretory duct of the human submandibular gland; Perra MT et al.; The localization of IgA, IgG, and IgM was investigated immunohistochemically in the mucosal surface of the main excretory duct of the human submandibular gland in order to verify the possible antimicrobial properties of this duct . Only secretory IgA-immunoreactivity was recognized in the epithelial cells of the duct . An intense immunoreactivity was observed in the cytoplasm of some cells and at the luminal surface of most of the cells . Clusters of IgA-positive immuno-competent cells were also recognizable in the subepithelial layers . No reactivity for IgG and IgM was noticed . The results suggest that the ductal epithelium may actively be involved in the release of secretory IgA, which could play a prominent role in the local defense mechanism of the duct.

J Cell Physiol, 1999 Mar, 178(3), 379 - 86
SP-A as a cytokine: surfactant protein-A-regulated transcription of surfactant proteins and other genes; Korutla L et al.; Pulmonary surfactant is a mixture of phospholipids and surfactant-associated proteins made by alveolar type II cells that is necessary for normal lung function . Surfactant secretion and reuptake by type II cells are regulated in part by interaction of surfactant protein-A (SP-A) with a specific receptor (SPAR) on type 11 cells . Several chemicals and hormones affect both surfactant secretion and also surfactant gene expression, but consequences of SP-A-SPAR interaction beyond regulating surfactant secretion and reuptake are unknown . Accordingly, we studied the effects of SP-A on surfactant protein gene transcription, mRNA levels, and transcript stability . SP-A elicited new transcription of surfactant proteins SP-A, SP-B, and SP-C and SPAR and c-Jun but had no effect on beta-actin or c-fos transcription . Antibody against SP-A receptor blocked SP-A-induced transcription, confirming that these actions of SP-A were receptor-mediated . SP-A effects on overall transcript levels were more complex . However, SP-A, SP-B, and SP-C mRNA levels doubled in SP-A-treated cells compared to controls . SP-A is known to stabilize surfactant, control its secretion and reuptake by type II cells, and augment host antimicrobial defenses . These data indicate that SP-A also acts as an autocrine cytokine: it binds its receptor and specifically regulates transcription of surfactant proteins and other genes.

Brain Pathol, 1999 Jan, 9(1), 57 - 67
Oxidative stress in bacterial meningitis; Koedel U et al.; Fifty years after the advent of antibiotics for clinical use, the rates of morbidity and mortality associated with bacterial meningitis remain high . The unfavourable clinical outcome is often due to intracranial complications including cerebrovascular insults, raised intracranial pressure, hydrocephalus, and brain edema . Reactive oxygen species (ROS) are known effector molecules in the antimicrobial armature of polymorphonuclear and mononuclear phagocytes . However, over the last decade, there has been a substantial body of work implicating a central role of ROS in the development of intracranial complications and brain damage in bacterial meningitis . Recently, it also became evident that reactive nitrogen species (RNS), especially nitric oxide, are important mediators of meningitis-associated pathophysiological changes, at least during the early phase of the disease . There is now substantial evidence that much of the oxidative injury associated by simultaneous production of superoxide and nitric oxide is mediated by the strong oxidant peroxynitrite . ROS and peroxynitrite can be cytotoxic via a number of independent mechanisms . Their cytotoxic effects include initiation of lipid peroxidation and induction of DNA single strand breakage . Damaged DNA activates poly(ADP-ribose) polymerase (PARP) . Recent experimental data propose a role of lipid peroxidation and PARP activation in the development of meningitis-associated intracranial complications and brain injury . Agents which interfere with the production of ROS and peroxynitrite, as well as with PARP activation and lipid peroxidation may represent novel, therapeutic strategies to limit meningitis-associated brain damage, and, thus, to improve the outcome of this serious disease.

Zentralbl Bakteriol, 1998 Dec, 288(4), 441 - 9
Characterization of the periodontal microflora by the fatty acid profile of the broth-grown microbial population; Muller KD et al.; The applicability of fatty acid analysis to the characterization of periodontal microflora was investigated using gas-liquid chromatography (GLC) and the software of the Sherlock Microbial Identification System (MIS) from MIDI Inc . Sulcus fluid was collected with paper points and anaerobically cultured in broth at 35 degrees C for four days . The broth-grown microbial population was extracted and the fatty acid methyl esters (FAME) were separated by GLC . The investigation of 67 specimens from asymptomatic sulci and of 32 specimens from inflamed sulci showed that the patterns of FAME profiles, the clustering of FAME profiles by computerized 2-D plot procedure, and the determination of the peak area index (PAI) of the FAME profiles differentiate between normal and pathological sulcus flora . Comparison of the clinical sulcus rating and the FAME data indicated that a pathological FAME profile may precede manifest periodontitis, and the normalization of the FAME profile may precede healing . It is concluded that the FAME analysis of sulcus fluid is a diagnostic aid for periodontological surveillance, for the initiation of preventive treatment of periodontitis, and for controlling the antimicrobial efficiency of therapeutic measures.

Med Mycol, 1998, 36 Suppl 1, 129 - 36
Selected animal models: vaginal candidosis, Pneumocystis pneumonia, dermatophytosis and trichosporosis; Sobel JD et al.; A clear understanding of the pathogenesis of fungal disease remains elusive . While technological advances in molecular biology and microbial genetics have provided scientists with major new insights into both microbial virulence factors as well as host susceptibility to infection, there is currently no substitute for animal models in elucidating microbe-host interactions . Animal models are also essential for the evaluation of new antimicrobial agents, including studies of efficacy, adverse reactions and pharmacokinetics . The single most important advance in animal models in the last decade, has been the availability of genetically unique strains of animals as alternative to animals treated with immunosuppressive drugs for use in studies on microbial virulence and host defence mechanisms . These unique strains of test animals also enhance our understanding of the modes of action of antifungal drugs and their metabolism . Some of these advances will be discussed in this symposium.

Med Mycol, 1998, 36 Suppl 1, 26 - 37
Nocardia, nocardiosis and mycetoma; Boiron P et al.; The recent emergence of invasive infections due to Nocardia spp., including nosocomial outbreak, is now evident . Newer molecular diagnostic and typing methods are developed . Although sulfonamide-based therapy is generally effective, optimal treatment may be guided by antimicrobial susceptibility testing of isolates . The improved classification of nocardiae and other related genera such as actinomadurae, using the 16S ribosomal RNA sequencing, provide a sound basis for improved diagnostic methods for the identification of members of clinically significant species . The commonest cause of eumycetoma in Sudan is Madurella mycetomatis, and Streptomyces somaliensis and Actinomadura madurae for actinomycetoma . The humoral immunity response in actinomycetoma patients and in experimental mice was measured and significant titre of anti-P24 antibody was demonstrated.

Compr Ther, 1999 Jan, 25(1), 20 - 9
Antimicrobial resistance in community-acquired respiratory tract pathogens; Lark RL et al.; Antimicrobial resistance among common respiratory pathogens has become a significant problem . However, there remain multiple treatment options, including the newer macrolides, third-generation cephalosporins, beta-lactam/beta-lactamase inhibitor antibiotics, and the newer fluoroquinolones.

J Immunol, 1999 Feb 1, 162(3), 1851 - 8
CD1 expression by dendritic cells in human leprosy lesions: correlation with effective host immunity; Sieling PA et al.; A potential role for the CD1 family of lipid Ag-presenting molecules in antimicrobial immunity in vivo was investigated in human leprosy skin lesions . Strong induction of three CD1 proteins (CD1a, -b, and -c) was observed in dermal granulomas in biopsy samples of involved skin from patients with the tuberculoid form of leprosy or with reversal reactions, which represent clinical patterns of disease associated with active cellular immunity to Mycobacterium leprae . In contrast, lesions from patients with the lepromatous form of the disease who lack effective cell-mediated immunity to the pathogen did not show induction of CD1 proteins . Thus, expression of CD1 correlated directly with effective immunity to M . leprae, as assessed by the clinical course of infection . CD1a, -b, and -c could be induced to similar levels on monocytes from the blood of either tuberculoid or lepromatous leprosy patients . This suggested that the absence of expression in lepromatous lesions was most likely due to local factors at the site of infection as opposed to a primary defect of the CD1 system itself . The majority of cells expressing CD1 in leprosy lesions were identified as a population of CD83+ dendritic cells . Initial in vitro studies of the Ag-presenting function of CD1+CD83+ monocyte-derived dendritic cells showed that such cells were highly efficient APCs for CD1-restricted T cells . These results indicate that the CD1 system can be up-regulated in human infectious diseases in vivo, and may play a role in augmenting host defense against microbial pathogens.

Biosci Biotechnol Biochem, 1998 Nov, 62(11), 2273 - 6
Antimicrobial activity of 4-hydroxybenzoic acid and trans 4-hydroxycinnamic acid isolated and identified from rice hull; Cho JY et al.; Two antimicrobial substances in rice hull were isolated and identified as 4-hydroxybenzoic acid and trans 4-hydroxycinnamic acid by LC-MS, and 1H- and 13C-NMR . An evaluation of 50% inhibition of growth (IC50) revealed that the two substances had different inhibition profiles against various microorganisms . Most of the gram-positive and some gram-negative bacteria were sensitive to trans 4-hydroxycinnamic acid and 4-hydroxybenzoic acid at IC50 concentrations of 100-170 and 160 micrograms/ml, respectively.

Adv Dent Res, 1998 Nov, 12(2), 159 - 65
Therapeutic potential of tetracycline derivatives to suppress the growth of abdominal aortic aneurysms; Thompson RW et al.; Abdominal aortic aneurysms (AAA) represent a potentially lethal disorder associated with aging and atherosclerosis . Although current management of AAA is predicted on early detection and elective surgical repair, routine screening for AAA is infrequent, because most AAA are too small to warrant repair when first detected and because there are no therapeutic approaches proven to suppress aneurysm expansion . Basic research on this problem suggests that chronic inflammation and increased local production of elastin-degrading proteinases play prominent roles in the process of aneurysmal degeneration . Members of the matrix metalloproteinases (MMP) family appear to be the most prominent elastases produced in human AAA, suggesting that unique therapeutic targets might exist for aneurysm disease . Studies using a representative animal model for AAA support this view, providing a means for further development of pharmacological approaches to suppress aneurysm expansion . Indeed, recent work indicates that tetracycline derivatives have the potential to interrupt the progressive connective tissue destruction that occurs in AAA, by virtue of their non-antimicrobial properties as MMP inhibitors, and they do so at clinically achievable dose schedules . These findings support the view that MMPs are potentially important pharmacotherapeutic targets in AAA and, moreover, that tetracyclines might be useful in suppressing aneurysm expansion in vivo . Because tetracycline derivatives offer a number of distinct advantages as MMP inhibitors for patients with small AAA, prospective clinical trials of this novel therapeutic strategy can be anticipated in the near future.

Adv Dent Res, 1998 Nov, 12(2), 152 - 8
Tetracyclines inhibit protein glycation in experimental diabetes; Ryan ME et al.; Glycation of proteins, which is accelerated in the diabetic state, has been implicated in many of the long-term complications of diabetes . This process can be inhibited by members of the tetracycline family of compounds . This novel finding is supported by studies conducted on drug (streptozotocin)induced Type I and genetic (ZDF/Gmi-fa/fa) Type II diabetic rats . These animals were orally gavaged daily with 5 mg of doxycycline and a variety of non-antimicrobial chemically modified tetracycline derivatives for time periods of 3 weeks to 11 months, while control untreated diabetic and nondiabetic animals were gavaged with vehicle alone (2% CMC) . Blood and tissue samples were collected and analyzed for glucose and glycated proteins . None of the treatments had any effect on the severity of hyperglycemia or the intracellular glycation of hemoglobin of either Type I or II diabetic animals . However, the tetracycline analogues did affect the extracellular glycation of several proteins such as those found in the serum as well as skin collagen . In the Type II (ZDF) animals, initial mortality (3-5 months) was seen only in the doxycycline-treated animals, associated with infection by tetracycline-resistant micro-organisms, which was eventually surpassed by mortality rates in the untreated diabetics (6-9 months) . CMT treatment not only decreased mortality but also increased longevity in the Type II diabetic animals, most likely by preventing the development of a number of long-term complications of uncontrolled diabetes, including glycation of proteins, that eventually lead to the demise of untreated diabetic animals.

Adv Dent Res, 1998 Nov, 12(2), 149 - 51
How do tetracyclines work?
Ryan ME, Ashley RA.
This paper is a summary of a panel discussion by the following panelists: L . Golub, J . te Koppele, G . Nieman, M . Nelson, R . Ashley, T . Sorsa, and S . Simon . The panel discussed the mechanisms by which the tetracyclines and their non-antimicrobial counterparts may provide therapeutic efficacy in a variety of chronic and acute diseases.

Adv Dent Res, 1998 Nov, 12(2), 131 - 5
The effects of chemically modified tetracyclines (CMTs) on human keratinocyte proliferation and migration; Makela M et al.; Chemically modified non-antimicrobial tetracycline derivatives and other low-molecular-weight synthetic matrix metalloproteinase (MMP) inhibitors inhibited keratinocyte migration . Since 72-kDa gelatinase-A (MMP-2) was the major gelatinase in our culture conditions, the results suggest that this MMP may be important in the regulation of keratinocyte mobility . On the other hand, we measured only gelatinase activities (MMP-2 and -9) present in culture medium, and therefore the results do not reveal how the inhibitors affect other MMPs as well as MMP levels close to the cell membranes . Overall, CMTs were found to be efficient in the inhibition of keratinocyte migration.

Adv Dent Res, 1998 Nov, 12(2), 114 - 8
Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells; Hanemaaijer R et al.; Doxycycline is a commonly used broad-spectrum antibiotic . Recently, it has been shown that it also inhibits the activity of mammalian collagenases and gelatinases, an activity unrelated to its antimicrobial efficacy . In this study, we show that doxycycline not only inhibits MMP-8 and MMP-9 (gelatinase B) activity, but also the synthesis of MMPs in human endothelial cells . Doxycycline (50 microM) completely inhibited the phorbol-12-myristate-13-acetate (PMA)-mediated induction of MMP-8 and MMP-9, as measured by Western blotting and gelatin zymography, respectively . The inhibition was also observed at the mRNA level . No effect was observed on the expression of MMP-2 and of the MMP inhibitors TIMP-1 and TIMP-2 . Chemically modified tetracyclines (CMTs) showed an inhibition similar to that of doxycycline, albeit less efficient . These observations demonstrate that endothelial cells display a specific regulation of MMPs, which may have implications for the pharmaceutical interaction in angiogenesis and angiogenesis-related diseases.

Adv Dent Res, 1998 Nov, 12(2), 76 - 81
Long-term therapy with a new chemically modified tetracycline (CMT-8) inhibits bone loss in femurs of ovariectomized rats; Sasaki T et al.; The effect of a new non-antimicrobial analog of tetracycline (CMT-8) on bone loss in ovariectomized (OVX) rats was examined . Three-month-old female rats were ovariectomized, and one week later, were distributed into 3 groups: sham-operated non-OVX controls, vehicle-treated OVX controls, and CMT-8-treated OVX rats . After 145 days of daily CMT-8 administration, the intact femurs were dissected and examined by several histological and histomorphometric techniques . OVX significantly (p < 0.01) decreased trabecular bone volume by 53.4% in the metaphyses compared with sham-operated controls . CMT-8 therapy produced a significant (p < 0.05) inhibition of trabecular bone loss and also induced bone formation in the OVX rats . Of interest, the newly synthesized bone in the CMT-treated OVX rats was found to increase the "connectivity" of the trabecular "struts" by bridging the adjacent longitudinal bone trabeculae, forming dense, plate-like bone trabeculae . These results strongly suggest that long-term CMT-8 therapy effectively inhibits bone loss after OVX, not only by inhibiting bone resorption but also by inducing new bone formation in the trabecular areas of long bones.

Adv Dent Res, 1998 Nov, 12(2), 56 - 62
Effects of tetracyclines on bone metabolism; Vernillo AT et al.; The anti-resorptive properties of tetracyclines (TCs) and their non-antimicrobial, chemically modified analogues (CMTs) have enormous therapeutic potential in medicine and dentistry . Osseous destructive diseases associated with excessive mammalian collagenase (matrix metalloproteinase) activity and collagen breakdown include malignancy, arthritis, and periodontitis . However, apart from the significant antimatrix metalloproteinase effects of TCs, TCs/CMTs are also potent inhibitors of osteoclast function (i.e., anti-resorptive) . Thus, TCs can affect several parameters of osteoclast function and consequently inhibit bone resorption by (1) altering intracellular calcium concentration and interacting with the putative calcium receptor; (2) decreasing ruffled border area; (3) diminishing acid production; (4) diminishing the secretion of lysosomal cysteine proteinases (cathepsins); (5) inducing cell retraction by affecting podosomes; (6) inhibiting osteoclast gelatinase activity; (7) selectively inhibiting osteoclast ontogeny or development; and (8) inducing apoptosis or programmed cell death of osteoclasts . TCs/CMTs, as anti-resorptive drugs, may act similarly to bisphosphonates and primarily affect osteoclast function.

Adv Dent Res, 1998 Nov, 12(2), 51 - 5
The potential role of doxycycline in the treatment of osteoarthritis of the temporomandibular joint; Israel HA et al.; Collagenase and gelatinase are matrix metalloproteinases (MMPs) which play an important role in tissue destruction in arthritic joints . Studies have demonstrated that tetracyclines can inhibit MMPs and prevent tissue destruction independent of their antimicrobial activity . The purpose of this pilot study is to assess the potential therapeutic role of Doxycycline in patients with advanced osteoarthritis of the temporomandibular joint (TMJ) . This ongoing investigation includes patients with a diagnosis of osteoarthritis of the TMJ based on clinical and diagnostic imaging findings, symptoms (localized TMJ pain, limited mobility, dysfunction) for a minimum of 36 months, and failure of previous non-surgical and surgical modalities to alleviate the symptoms . A synovial fluid sample is collected by a saline injection and aspiration technique, followed by diagnostic arthroscopy . Patients are placed on Doxycycline 50 mg BID for three months and then undergo repeat diagnostic arthroscopy and synovial fluid collection . The samples are stored at -80 degrees C . Collagenase activity is determined by a combination of SDS-polyacrylamide gel electrophoresis and fluorography and calculated based on the percentage of collagen alpha chains that are degraded into alphaA breakdown products . Three patients have completed the three-month course of Doxycycline thus far, and 5 joints with osteoarthritis have been analyzed . All patients were female (mean age = 35, mean duration of symptoms = 132 months) and had undergone previous bilateral arthroscopies . One patient had undergone unilateral arthroplasty . The mean collagenase activity showed 55% collagen lysis prior to Doxycycline treatment and 19% after three months of therapy . The mean gelatinase activity was 28% prior to Doxycycline treatment and 7% after three months of therapy . The mean interincisal opening was 33 mm initially and 41 mm after three months of Doxycycline . Subjectively, two of the three patients reported significant improvement in their overall symptoms, which they had not experienced over the previous three years . One patient did not experience any change in symptoms, in spite of a marked reduction in collagenase activity from 86.4% to 9.6% . Because of the very small numbers of patients enrolled in this pilot study so far, no statistically significant differences could be appreciated . However, the dramatic reduction in collagenase activity in these patients, with a long history of TMJ symptoms from osteoarthritis, suggests the potential promising role of Doxycycline in the management of osteoarthritis, and further investigation is warranted.

Adv Dent Res, 1998 Nov, 12(2), 43 - 50
Root-surface caries in rats and humans: inhibition by a non-antimicrobial property of tetracyclines; Ramamurthy NS et al.; The incidence of root caries has been found to increase as the population ages and as edentulism becomes less prevalent due to improved dental awareness and care, and as exposure of roots due to gingival recession has also increased in the elderly . The mechanism of root caries is thought to be mediated by both bacterial and mammalian proteases produced by plaque and the periodontal tissues, respectively . In the current study, a rat model of periodontal disease was used in which gnotobiotic rats were infected intra-orally with a periodontal pathogen (P . gingivalis) . Infecting the rats with P . gingivalis increased the collagenase activity in the gingival tissue in association with severe alveolar bone loss . Treating P . gingivalis-infected rats with doxycycline or CMT-1 prevented the destruction of the periodontium by MMPs, thus preventing exposure of roots to subgingival bacterial plaque and host tissue collagenases and the subsequent development of root caries . In addition, a low-dose doxycycline (LDD, 20 mg bid, non-antimicrobial dose) for 3 months was used in humans predisposed to increased root caries as the result of heavy use of smokeless (chewing) tobacco, causing gingival recession, subgingival plaque accumulation with Gram-negative bacteria, increased gingival crevicular fluid flow (GCF), and elevated GCF collagenase . Daily administration of LDD in smokeless tobacco patients reduced the GCF collagenase and prevented the further development of root caries.

Adv Dent Res, 1998 Nov, 12(2), 27 - 31
Safety and efficacy of sub-antimicrobial-dose doxycycline therapy in patients with adult periodontitis; Ciancio S et al.; The objectives of the studies presented here were to assess the safety and efficacy of the adjunctive administration of sub-antimicrobial-dose doxycycline (SDD) for the treatment of adult periodontitis and to confirm the optimal dosing regimen . The studies summarized included four double-blind, placebo-controlled, randomized clinical trials, conducted over a period of 9 to 12 months . Analysis of efficacy data demonstrated that adjunctive SDD treatment resulted in: (1) increases in clinical attachment levels; (2) decreases in probing pocket depths; and (3) reductions in bleeding on probing in patients with adult periodontitis . There were no significant adverse events or unwanted long-term antimicrobial effects associated with orally administered SDD . The results of these clinical trials indicate that the adjunctive use of SDD 20 mg BID is an effective and well-tolerated regimen which can significantly improve several indices of periodontal health.

Adv Dent Res, 1998 Nov, 12(2), 12 - 26
Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms; Golub LM et al.; A seminal experiment involving a germ-free rat model of connective tissue breakdown (followed soon thereafter by a series of in vitro studies) identified an unexpected non-antimicrobial property of tetracyclines (TCs) . This ability of TCs to inhibit matrix metalloproteinases (MMPs) such as collagenase was found to reflect multiple direct and indirect mechanisms of action, and to be therapeutically useful in a variety of dental (e.g., adult periodontitis) and medical (e.g., arthritis, osteoporosis, cancer) diseases . The site on the TC molecule responsible for its MMP-inhibitory activity was identified which led to the development of a series of chemically modified non-antimicrobial analogs, called CMTs, which also have therapeutic potential but do not appear to induce antibiotic side-effects . Longitudinal double-blind studies on humans with adult periodontitis have demonstrated that a sub-antimicrobial dose of doxycycline (previously reported to suppress collagenase activity in the periodontal pocket) is safe and effective and has recently been approved by the FDA as an adjunct to scaling and root planing.

Mol Biotechnol, 1998 Dec, 10(3), 237 - 45
Origins and development of peptide antibiotic research . From extracts to abstracts to contracts; Spitznagel JK; That cationic proteins might be factors on the antimicrobial defenses of mammalian hosts and are apparently associated with the cytoplasmic granules of phagocytic leukocytes first became evident on the late nineteenth century . It remained, however, for development of sophisticated microanalytic techniques in microbiology, cell biology and protein biochemistry to place these hypotheses in the realm of established theory . This article is a brief summary of significant steps in the development of this theory . It also attempts to outline the firmly established scope and significance of these developments both for the theory of immunity to infection in the different phyla and for the now global quest for new antibiotics.

J Emerg Med, 1999 Jan-Feb, 17(1), 213 - 20
Opportunities for mupirocin calcium cream in the emergency department; Williford PM; Mupirocin calcium cream is a newly reformulated topical antibiotic with a bactericidal spectrum specific for the pathogens that frequently cause secondary infections in superficial wounds . Both the calcium cream and ointment formulations have demonstrated efficacy in the treatment of secondarily infected traumatic lesions and dermatoses, including eczema, burns, wounds, bites, and ulcers . Mupirocin has a low risk of systemic and topical complications . To date, antimicrobial resistance is rare among target pathogens . The use of mupirocin to treat secondary wound infection has a profile of high efficacy and does not impair the normal healing in traumatized skin.

EXS, 1998, 85, 57 - 71
Opioid peptides from frog skin; Amiche M et al.; The skin of the South American frogs Phyllomedusa secretes, in addition to numerous mammalian-like hormones and neuropeptides, several gene-encoded opioid peptides that contain a D-amino acid in position 2 of their sequence . Dermorphin, Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2, dermenkephalin/deltorphin A, Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 and the deltorphins, Tyr-D-Ala-Phe-Xaa-Val-Val-Gly-NH2 (where Xaa is either Asp or Glu) are highly potent at, and exquisitely selective, for the mu- and delta-opioid receptors . D-Ala and D-Met present in dermorphin and related peptides are coded for by the usual codons in the corresponding messenger RNAs . Prepro-dermorphin/dermenkephalin and prepro-deltorphins have considerable sequence identities to precursors encoding 10-46-residue-long antimicrobial peptides--dermaseptins, brevinins, temporins, esculentins and gaegurins--originating from various amphibian species . The similarity between the prepro-regions of precursors encoding end products with strikingly different structures and biological activities supports the suggestion that the genes encoding these peptides are all members of the same family.

EXS, 1998, 85, 29 - 36
Occurrence and function of D-amino acid-containing peptides and proteins: antimicrobial peptides; Mignogna G et al.; Antimicrobial peptides are widely distributed in living organisms, where they represent a constitutive defence system acting as a first line of response against infections . The number of such peptides discovered has increased rapidly in the last few years, and more than 100 have been described from different sources . So far, antimicrobial peptides containing a D-amino acid have only been found in the skin secretions of frogs belonging to the genus Bombina . In the second position of the sequence of the mature peptides either D-alloisoleucine or D-leucine were detected . The D-amino acids are derived from the corresponding L forms by an as yet unknown posttranslational reaction.

Am J Infect Control, 1999 Feb, 27(1), 10 - 9
Antimicrobial prescribing in long-term care facilities: prospective evaluation of potential antimicrobial use and cost indicators; Mylotte JM; BACKGROUND: Few studies exist regarding methods of monitoring antimicrobial prescribing in the long-term care setting . METHODS: Data were collected monthly in 4 long-term care facilities (LTCFs) for 20 to 26 months . The data included incidence (No . of antimicrobial courses started per 1000 resident care days) of antimicrobial use, antimicrobial utilization ratio (ratio of the number of antimicrobial-days to the number of resident care days), cost of antimicrobial-day, and cost of therapy per resident care day . In one facility, physician-specific data were also collected . RESULTS: Seasonal variation in the incidence of antimicrobial use was identified, with the highest rates occurring in the winter months . Significant differences in the mean incidence of antimicrobial use, mean antimicrobial utilization ratio, mean cost per antimicrobial-day, and mean cost per resident care day were identified among the 4 LTCFs during the study period . A significant correlation existed between incidence of antimicrobial use or antimicrobial utilization ratio and the overall infection rate or site-specific rates when the data from all 4 LTCFs were aggregated for analysis . Monthly variation in cost per antimicrobial-day was best explained by the monthly variation in prescribing of high-cost (>$15 per day) agents . With these same parameters for use and cost, considerable variation in prescribing and cost of therapy was noted among 7 physicians in the same facility . CONCLUSIONS: The parameters evaluated detected significant differences in prescribing and cost of antimicrobials among 4 LTCFs . If these findings are verified in larger studies, these parameters may be useful for monitoring trends in prescribing and for interfacility comparisons after adjustment for case-mix differences.

Otolaryngol Head Neck Surg, 1999 Feb, 120(2), 219 - 24
Alternative to endoscopic sinus surgery in the management of pediatric chronic rhinosinusitis refractory to oral antimicrobial therapy; Buchman CA et al.; We determined the safety, feasibility, and efficacy of a treatment regimen consisting of maxillary sinus aspiration and irrigation with or without adenoidectomy, followed by culture-directed intravenous antibiotics and oral prophylaxis, for children with chronic rhinosinusitis refractory to oral antimicrobial therapy . Twenty-seven children (age 1-12 years, mean 6.7 years) with symptomatic (mean duration 16 months) and computed tomography-proven sinus disease, which persisted despite at least 1 month of oral antibiotics, were treated . Twenty-four patients (89%) had complete resolution of their presenting symptoms after intravenous therapy; in 3 (11%), intravenous therapy failed and endoscopic sinus surgery was required . Follow-up data were available for 26 of the children (96%); 23 of them had initial complete resolution . At last follow-up (mean 282 days, range 26-1095 days), 10 of these 23 patients (44%) remained asymptomatic, and 13 (57%) had had at least one other episode of sinusitis (mean 1.0, range 1-3) treated with oral antibiotics, with resolution . Treatment-related complications included superficial thrombophlebitis (7%), diarrhea (7%), intravenous catheter guide-wire kink requiring venotomy (4%), and serum sickness-like syndrome (4%) . These preliminary results suggest that this treatment plan is relatively safe and feasible and that it may be a reasonable alternative to endoscopic sinus surgery in children with chronic rhinosinusitis unresponsive to orally administered antimicrobial therapy.

Z Naturforsch {C}, 1998 Nov-Dec, 53(11-12), 1045 - 8
Preliminary report on the effects of propolis on wound healing in the dental pulp; Bretz WA et al.; The purpose of this investigation was to determine the antimicrobial and healing potential of propolis on direct dental pulp exposures . This study used 25 adult male rats . Pulp exposures were performed and animals were allocated to propolis and calcium hydroxide (Ca(OH)2 groups . Animals were killed on days 5, 7, 10, and 14 . The teeth were routinely processed for histological evaluation . Non-parametric tests were employed to analyze the data . No significant differences were found between study groups on the wound healing of the dental pulp . Both substances were comparable in exhibiting normal reorganization of the pulp and no increased vascularity, and were equally efficacious in maintaining a low inflammatory and microbial cell population as well as in stimulating the formation of reparative dentin.

Am J Surg, 1998 Dec, 176(6A Suppl), 4S - 7S
Overview of quinolones in the treatment and prevention of surgical infection; Weigelt JA; Postoperative infection remains a complication of surgical procedures, resulting in increased morbidity, mortality, and cost . The frequent polymicrobial etiology and emerging patterns of resistance continue to compromise cure rates . Although quinolones have many attractive properties for the surgical setting, combination therapy is routinely indicated for appropriate coverage . Advanced-generation quinolones, such as trovafloxacin, offer an increased antimicrobial spectrum, including activity against important surgical pathogens, and longer elimination half-lives . These newer agents may be used intravenously or orally as once-daily single-agent therapy for surgical prophylaxis, and in place of combination therapy for complex intra-abdominal and pelvic infections.

J Burn Care Rehabil, 1999 Jan-Feb, 20(1 Pt 1), 33 - 6
Topical sulfamylon reduces engraftment of cultured skin substitutes on athymic mice; Boyce ST et al.; Sulfamylon (mafenide acetate) remains extremely valuable for the control of the bacterial contamination of burn wounds, but it is cytotoxic to cultured keratinocytes used for wound closure . Because composite skin substitutes develop a partial epidermal barrier in vitro, they may hypothetically tolerate the use of topical Sulfamylon . To test this hypothesis, cultured skin substitutes were prepared from cultured human fibroblasts; keratinocytes were attached to these collagen-based substrates, which were grafted to full-thickness wounds in athymic mice (n = 8 per group) . Wounds were irrigated twice daily with 5% (wt/vol) Sulfamylon solution or with a formulation of noncytotoxic antimicrobials (0% Sulfamylon) . On day 9 after grafting, the wounds were treated with dry dressings and assessed at 4 weeks for expression of human leukocyte antigens-A, B, C and at 2, 3, and 4 weeks for percentage of original wound area and surface electrical capacitance in picofarads (pF) . Data were analyzed for statistical significance (P < .05) by Fisher's exact test, Student's t test, and repeated measures analysis of variance: {table: see text} The data demonstrate that irrigation of cultured skin substitutes with a solution of 5% Sulfamylon results in smaller wound area, fewer wounds that contain human cells, and greater surface hydration (higher surface electrical capacitance) than irrigation with noncytotoxic antimicrobial agents . These results support the conclusion that cultured skin substitutes of this type do not tolerate the chemical toxicity of Sulfamylon as well as skin autografts . Further improvements in the properties of the epidermal barrier of cultured skin substitutes may facilitate the use of Sulfamylon or other potent antimicrobial agents for the management of microbial contamination during engraftment of transplanted skin cells.

J Biomater Appl, 1999 Jan, 13(3), 206 - 23
In vitro antimicrobial activity of a new antiseptic central venous catheter; Li C et al.; A central venous catheter coated with a new antiseptic combination, silver chloride (AgCl) and benzalkonium chloride (BKC) in a polymer matrix, was developed . The antimicrobial efficacy and the ability to prevent surface colonization, after elution in both serum and saline, were evaluated and compared to catheters coated with silver sulfadiazine/chlorhexidine . The results of in vitro assays demonstrated that the AgCl-BKC coated catheters had a broad spectrum of activity against bacteria and C . albicans and prolonged antimicrobial activity for extraction periods of up to 30 days . These data suggest that AgCl-BKC coated catheters may provide another solution for reduction of catheter-related infections.

Rev Cubana Enferm, 1998 May-Aug, 14(2), 107 - 11
{Results of preoperative preparation with mannitol in colorectal surgery . January-December 1995}; Torres Panuncia B et al.; A study on the results obtained in 20 patients selected by the simple randomized method, who were preoperatively prepared for colorectal surgery with the oral administration of manitol and complementary antimicrobial therapeutics at the ASaturnino Lora@ Provincial Teaching Hospital, in Santiago de Cuba, from January to December, 1995, was conducted aimed at evaluating the results attained with the use of manitol in the preoperative preparation for colorectal surgery, determining its complications, analyzing its advantages, and assessing the patient, nurse and surgeon's opinion about the new procedure . The following variables were taken into account: age, preoperative diagnosis and previous operations . The percentage statistical method was used . Most of the patients were elderly, who were able to undergo surgery . There were no complications in connection with the preoperative preparation, which has the following advantages: it is simpler and more efficient that the traditional use of enemas, it is easy to apply, it saves time and resources on reducing the preoperative stay, it is considered as more comfortable for patients and nurses, and it is much more economic and effective, which was proved by surgeons during the operation.

Planta Med, 1998 Dec, 64(8), 746 - 7
Antimicrobial flavonoids from Glycyrrhiza glabra hairy root cultures; Li W et al.; A new compound named licoagrodione was isolated from the hairy root cultures of Glycyrrhiza glabra (Fabaceae) together with five known prenylated flavonoids . The structure of licoagrodione has been elucidated on the basis of spectral evidence and it was found to have antimicrobial activity indicated by disc diffusion method.

Z Naturforsch {C}, 1998 Nov-Dec, 53(11-12), 939 - 45
Five new bioactive sesquiterpenes from the fungus Radulomyces confluens (Fr.) Christ; Fabian K et al.; The three protoilludanes radulone A (1), radulone B (2) and radudiol (3), the illudalane radulactone (4) and the illudane radulol (5) were isolated from the extracts of the culture fluids of the basidiomycete Radulomyces confluens . The structures of the five new compounds were determined by spectroscopic techniques . Radulone A (1) is a potent inhibitor of human and bovine platelet aggregation stimulated by different agonists, inhibiting preferentially the aggregation of human platelets induced by ADP with an IC50 value of 2 microM . In addition 1 exhibits cytotoxic and antimicrobial activities . The other four compounds exhibited weak antimicrobial and cytotoxic activity.

Phytochemistry, 1999 Feb, 50(3), 407 - 15
Chemical, physical and antimicrobial properties of essential oils of Leptospermum scoparium and Kunzea ericoides; Porter NG et al.; The major components of commercial New Zealand essential oils of Leptospermum scoparium (manuka) and Kunzea ericoides (kanuka) are identified . In the manuka oil, monoterpenes are present at low levels (< or = 3%) . Sesquiterpene hydrocarbons are predominant (> or = 60%) and include groups possessing cubebene/copaene, elemene, gurjunene/aromadendrene, farnesene/ caryophyllene, selinene, calamenene and cadinene skeletons . Oxygenated sesquiterpenes and triketones are present (< or = 30%) . The antimicrobial activity of the manuka oil was associated with a fraction containing three major and three trace triketones, two of the latter were previously unreported . Kanuka oil was characterized by high levels of alpha-pinene (> 50%) and lower levels (< 10%) of viridiflorol and viridiflorene . GC-MS and GC-FID detector responses to the same components were noticeably different for some major components, including the triketones . Non-commercial manuka oils from different sites differed widely in composition and could be separated into four groups by the presence and levels of distinctive components . The density and refractive index of manuka and kanuka oils were closely correlated with the total sesquiterpene levels . The density of the commercial manuka oil was closely correlated with the level of the triketones . Simple density measurements enabled discrimination between the commercial oil and oils from other sites, and prediction of antimicrobial activity.

Arch Orthop Trauma Surg, 1998, 118(3), 174 - 5
Intraosseous fat necrosis simulating septic arthritis and osteomyelitis in a patient with chronic pancreatitis; Kotilainen P et al.; A woman with a 20-year history of alcohol abuse and chronic pancreatitis developed an osteoarticular involvement of her right ankle in association with subcutaneous nodules . Histopathological examination of the tissue samples obtained during surgical revision of the ankle showed necrotic fat and connective tissue . Microbiological cultures remained negative . The patient was administered long-term antimicrobial treatment without any apparent benefit . Four months later, she died of pancreatic insufficiency and pneumonia . Postmortem examination showed numerous foci of intra-abdominal fat necrosis . Histopathological examination of the bone samples from the right ankle showed fat necrosis with lipophages . Based on these findings, we consider that the osteoarticular involvement in this patient was caused by intraosseous fat necrosis . This case reminds us of the importance of considering the possibility of this condition whenever a patient with chronic pancreatic disease develops sterile osteoarthritis.

Langenbecks Arch Chir Suppl Kongressbd, 1998, 115, 612 - 4
{Treatment of an infected focus, considerations and facts on duration of antibiotic therapy}; Lorenz D; Contamination does not require postoperative antibiotics, as the infective source is dealt with operatively . In "resectable infections" (appendicitis) a postoperative antimicrobial 24-h course should be administered . We have to grade infections according to their severity . Even established peritonitis does not require postoperative antibiotic administration for more than 5 days . "Severe" infections (infected pancreatic necrosis, peritonitis with planned relaparotomies) require more than 5 days of antibiotic therapy.

Eksp Klin Farmakol, 1998 Nov-Dec, 61(6), 58 - 61
{The chemico-pharmacological patterns in the action of plants from the family of Pyrolaceae}; Briukhanov VM et al.; The effect of leaf decoctions of three plants of the Pyrolaceae family, namely, umbrella wintergreen, one-side ortilia, and round-leaf Pyrola was studied in rat experiments . All plants under study were found to contain approximately equal amounts of tannins and arbutin glycoside . Their concentration was comparable though rather lower than in common bearberry, a well-known plant with diuretic and antiseptic activity . When given for a long time, all Pyrolaceae increased urination and sodium excretion . Besides, their decoctions caused an antimicrobial effect . Only round-leaf Pyrola weakened the development of experimental inflammation . Its anti-inflammatory effect was probably due the presence of flavonoids the content of which in Pyrola was maximum.

Proc AMIA Symp . 1998;:175-9.
MYCIN II: design and implementation of a therapy reference with complex content-based indexing; Kim DK et al.; We describe the construction of MYCIN II, a prototype system that provides for content-based markup and search of a forthcoming clinical therapeutics textbook, Antimicrobial Therapy and Vaccines . Existing commercial search technology for digital references utilizes generic tools such as textword-based searches with geographical or statistical refinements . We suggest that the drawbacks of such systems significantly restrict their use in everyday clinical practice . This is in spite of the fact that there is a great need for the information contained within these same references . The system we describe is intended to supplement keyword searching so that certain important questions can be asked easily and can be answered reliably (in terms of precision and recall) . Our method attacks this problem in a restricted domain of knowledge-clinical infectious disease . For example, we would like to be able to answer the class of questions exemplified by the following query: "What antimicrobial agents can be used to treat endocarditis caused by Eikenella corrodens?" We have compiled and analyzed a list of such questions to develop a concept-based markup scheme . This scheme was then applied within an HTML markup to electronically "highlight" passages from three textbook chapters . We constructed a functioning web-based search interface . Our system also provides semi-automated querying of PubMed using our concept markup and the user's actions as a guide.

Eur Neuropsychopharmacol, 1998 Dec, 8(4), 255 - 9
Behavioural and neurochemical evidence that the antimicrobial agent oxolinic acid is a dopamine uptake inhibitor; Garcia de Mateos-Verchere J et al.; The antimicrobial agent oxolinic acid, injected i.p . in mice, induced a dose dependent increase in locomotor activity . This stimulation culminated at the 32 mg/kg dose and became smaller for higher doses (64-128 mg/kg) . When opposed to increasing doses (50-100-200 microg/kg i.p.) of haloperidol (D2 dopamine receptor antagonist), the stimulant locomotor effect of 32 mg/kg oxolinic acid was not significantly reversed . On the contrary increasing doses (7.5-15-30 microg/kg s.c.) of SCH 23390 (D1 dopamine receptor antagonist) inhibited the stimulant locomotor effect . In mice made completely akinetic by a pretreatment with reserpine (4 mg/kg s.c., 18 h before testing), dexamphetamine (2 mg/kg s.c.) reversed this akinesia and even displayed a stimulant activity, similar to that observed in mice not treated by reserpine . On the contrary, oxolinic acid (32 mg/kg) did not reverse the reserpine induced akinesia and even opposed the reversion induced by dexamphetamine . In a synaptosomal fraction prepared from striatum of rats, oxolinic acid inhibited the 3H dopamine uptake with an IC50 = 4.3+/-0.6 x 10(-6) M . Finally, in mice injected i.v . with a tracer dose of 3H WIN 35428 (1 microCi) (a dopamine uptake blocker), 32 mg/kg oxolinic acid, i.p . administered, reduced by about 50% the specific binding of the radioligand to striatal dopamine carriers . It is concluded that the stimulant locomotor effect of oxolinic acid depends on the blockade of the neuronal dopamine uptake complex.

Annu Rev Genet, 1998, 32, 255 - 78
Molecular mechanisms of bacteriocin evolution; Riley MA; Microorganisms are engaged in a never-ending arms race . One consequence of this intense competition is the diversity of antimicrobial compounds that most species of bacteria produce . Surprisingly, little attention has been paid to the evolution of such extraordinary diversity . One class of antimicrobials, the bacteriocins, has received increasing attention because of the high levels of bacteriocin diversity observed and the use of bacteriocins as preservatives in the food industry and as antibiotics in the human health industry . However, little effort has been focused on evolutionary questions, such as what are the phylogenetic relationships among these toxins, what mechanisms are involved in their evolution, and how do microorganisms respond to such an arsenal of weapons? The focus of this review is to provide a detailed picture of our current understanding of the molecular mechanisms involved in the process of bacteriocin diversification.

Proc Natl Acad Sci U S A, 1999 Feb 2, 96(3), 1152 - 6
The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance; Austin DJ et al.; The threat to human health posed by antibiotic resistance is of growing concern . Many commensal and pathogenic organisms have developed resistance to well established and newer antibiotics . The major selection pressure driving changes in the frequency of antibiotic resistance is the volume of drug use . However, establishing a quantitative relationship between the frequency of resistance and volume of drug use has proved difficult . Using population genetic methods and epidemiological observations, we report an analysis of the influence of the selective pressure imposed by the volume of drug use on temporal changes in resistance . Analytical expressions are derived to delineate key relationships between resistance and drug consumption . The analyses indicate that the time scale for emergence of resistance under a constant selective pressure is typically much shorter than the decay time after cessation or decline in the volume of drug use and that significant reductions in resistance require equally significant reductions in drug consumption . These results highlight the need for early intervention once resistance is detected.

Plant Cell, 1999 Feb, 11(2), 191 - 206
The Arabidopsis ssi1 mutation restores pathogenesis-related gene expression in npr1 plants and renders defensin gene expression salicylic acid dependent; Shah J et al.; The Arabidopsis NPR1 gene was previously shown to be required for the salicylic acid (SA)- and benzothiadiazole (BTH)-induced expression of pathogenesis-related (PR) genes and systemic acquired resistance . The dominant ssi1 (for suppressor of SA insensitivity) mutation characterized in this study defines a new component of the SA signal transduction pathway that bypasses the requirement of NPR1 for expression of the PR genes and disease resistance . The ssi1 mutation caused PR (PR-1, BGL2 {PR-2}, and PR-5) genes to be constitutively expressed and restored resistance to an avirulent strain of Pseudomonas syringae pv tomato in npr1-5 (previously called sai1) mutant plants . In addition, ssi1 plants were small, spontaneously developed hypersensitive response-like lesions, accumulated elevated levels of SA, and constitutively expressed the antimicrobial defensin gene PDF1.2 . The phenotypes of the ssi1 mutant are SA dependent . When SA accumulation was prevented in ssi1 npr1-5 plants by expressing the SA-degrading salicylate hydroxylase (nahG) gene, all of the phenotypes associated with the ssi1 mutation were suppressed . However, lesion formation and expression of the PR genes were restored in these plants by the application of BTH . Interestingly, expression of PDF1.2, which previously has been shown to be SA independent but jasmonic acid and ethylene dependent, was also suppressed in ssi1 npr1-5 plants by the nahG gene . Furthermore, exogenous application of BTH restored PDF1.2 expression in these plants . Our results suggest that SSI1 may function as a switch modulating cross-talk between the SA- and jasmonic acid/ethylene-mediated defense signal transduction pathways.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 1999 Jan, 87(1), 50 - 4
Clarithromycin as a single-modality treatment in mycobacterial avium-intracellular infections; Lindeboom JA et al.; Atypical mycobacterial infections are frequently associated with chronic cervical lymphadenopathy, particularly in children between 1 and 5 years of age . The treatment of choice is regarded to be "optimal" surgical treatment, which often requires wide excision of affected lymph nodes . Although surgical excision is a reliable treatment, it has obvious drawbacks . Because branches of the peripheral facial nerve may be intimately involved in the inflammatory reaction, damage is a potential complication . In addition, keloid scars and wound breakdown are possible complications . Successful drug treatment is hampered by poor susceptibility of the Mycobacterium avium-intracellulare and Mycobacterium scrofulaceum strains to antimicrobial drugs . Reports of results with clarithromycin in the treatment of patients with AIDS who are infected with the M avium complex, however, are promising . The cases of 2 children with infections caused by the M avium complex, resulting in preauricular and cervical lymphadenitis, are described . Treatment with clarithromycin as a monotherapy led to complete healing without recurrence.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 1999 Jan, 87(1), 44 - 9
In vitro activities of antimicrobial agents against Candida species; Giuliana G et al.; OBJECTIVE: Antimicrobial mouthrinses may represent a valid alternative to topical antifungal agents . However, the action of antimicrobials could be affected by the different ingredients incorporated into mouthrinse products . The purpose of the present study was to investigate the in vitro antifungal and fungicidal activities of antimicrobials alone . STUDY DESIGN: A broth macrodilution method was used to determine the minimum inhibitory concentration of 4 antimicrobial agents against Candida species . Minimum fungicidal concentration was also determined . RESULTS: All antimicrobials showed antifungal activity against all tested organisms, but cetylpyridinium chloride received significantly lower minimum inhibitory concentrations (P < .005) . Cetylpyridinium chloride also showed a greater fungicidal activity than chlorhexidine digluconate and hexetidine (P< .005), whereas sanguinarine chloride appeared to be less fungicidal against most of the isolates tested . CONCLUSIONS: These findings suggest that cetylpyridinium chloride may be used as a topical antifungal agent . Clinical trials are now required to assess its value in the management of oral candidosis.

Med Sci Sports Exerc, 1999 Jan, 31(1), 57 - 66
Exercise and cellular innate immune function; Woods JA et al.; Epidemiological evidence suggests a link between the intensity of exercise and infectious and neoplastic disease . One likely way by which exercise exerts its effect on cancer and infection is by altering the function of the immune system . Cells of the innate immune system (i.e., macrophage {Mphi}, natural killer {NK} cell, and polymorphonuclear neutrophils {PMN}) are first-line defenders against cancer and infectious disease by nature of their phagocytic, cytolytic, and antimicrobial properties . The purpose of this review is to define the role of cells of the innate immune system (i.e., Mphi, PMN, and NK cells) in infection and cancer, present current information regarding the effects of acute and chronic exercise on the quantification and functional activities of these cells, and briefly to discuss potential mechanisms as to how exercise affects these cells and describe how these changes may potentially affect susceptibility to infection and cancer . The effects of exercise on the number, functions, and characteristics of cells of the innate immune system are complex and are dependent several factors, including 1) the cell function or characteristic being analyzed; 2) the intensity, duration and chronicity of exercise; 3) the timing of measurement in relation to the exercise bout; 4) the dose and type of immunomodulator used to stimulate the cell in vitro or in vivo; and 5) the site of cellular origin . Further studies are needed to determine whether the exercise-induced changes in immune function alter incidence or progression of disease . Likewise, the mechanisms as to how exercise alters innate immune function are as yet unresolved.

J La State Med Soc, 1998 Dec, 150(12), 587 - 95
Tuberculosis in Louisiana: an update; George RB et al.; The incidence of tuberculosis in the United States declined steadily until 1985 when increases were seen, in part due to the AIDS epidemic . Although the decline resumed in 1992, tuberculosis remains a public health problem in Louisiana and nationally . In Louisiana in 1997, HIV infection was present in 14% of persons with tuberculosis whose HIV status was known . In that year there were 16 cases of tuberculosis that were resistant to at least one first-line anti-tuberculous drug . Infection with Mycobacterium tuberculosis is diagnosed with the tuberculin skin test; the size of induration considered positive varies with the risk status of the person tested . TB infection in immunocompetent persons under age 35 is treated with 6 months of isoniazid . TB disease is generally treated with 4 drugs until antimicrobial sensitivities are known . Directly observed therapy is an inexpensive way to ensure compliance and is routinely used for patients in Louisiana.

Pediatrics, 1999 Feb, 103(2), 395 - 401
Parents, physicians, and antibiotic use; Bauchner H et al.; BACKGROUND: Emergence of resistant bacterial pathogens has increased concerns about antibiotic prescribing patterns . Parent expectations and pressure may influence these patterns . OBJECTIVE: To understand how parents influence the prescribing patterns of physicians and what strategies physicians believe are important if we are going to reduce inappropriate use of oral antimicrobial agents . DESIGNS AND METHODS: One thousand pediatricians who are members of the American Academy of Pediatrics were asked to complete a semi-structured questionnaire . The physicians were chosen randomly by the American Academy of Pediatrics . RESULTS: Nine hundred fifteen pediatricians were eligible and 610 surveys were analyzable, for a response rate of 67% . The majority of respondents were male (56%), worked in a group practice (51%), saw an average of 114 patients per week and were in practice for 14 years . Forty percent of the pediatricians indicated that 10 or more times in the past month a parent had requested an antibiotic when the physician did not feel it was indicated . Forty-eight percent reported that parents always, most of the time, or often pressure them to prescribe antibiotics when their children are ill but antibiotics are not indicated . In follow-up questions, approximately one-third of physicians reported they occasionally or more frequently comply with these requests . Seventy-eight percent felt that educating parents would be the single most important program for reducing inappropriate oral antibiotic use and 54% indicated that parental pressure, in contrast to concerns about legal liability (12%) or need to be efficient in practice (19%), contributed most to inappropriate use of oral antibiotics . CONCLUSIONS: Pediatricians acknowledge prescribing antimicrobial agents when they are not indicated . Pediatricians believe educating parents is necessary to promote the judicious use of antimicrobial agents.

J Pharm Biomed Anal, 1999 Jan, 18(6), 1057 - 67
Comparison of the complexation of fluoroquinolone antimicrobials with metal ions by nuclear magnetic resonance spectroscopy; Sakai M et al.; The complexation of fluoroquinolone antimicrobials with various metal ions have been studied in aqueous solution (pD 2.5, 37 degrees C) by 1H and 13C-NMR spectroscopy . The compounds examined are levofloxacin, ciprofloxacin and lomefloxacin . In each drug, new signals have appeared by the addition of Al3+, suggesting that the complexes are formed between the drug and Al3+ and that the ligand exchange is slow on the NMR time scale . Solution structure of the major species in the presence of 2.0 mol equiv of Al3+ has been proposed based on the large downfield shifts of some specific protons . Signals of both the coordinated and free drugs have shown slight broadening at 90 degrees C due to the enhanced rate in ligand dissociation process, though the coalescence phenomena are not observed even at this temperature . Thus, the complexes are supposed to be stable at the physiological condition . Titration experiments have revealed that the binding ability of levofloxacin toward Al3+ is much stronger than that of ciprofloxacin and lomefloxacin at pD 2.5 . In contrast to the complexation with Al3+, the binding of these drugs with other metal ions such as Ca2+ and Mg2+ is much weaker; NMR signals have shown no appreciable downfield shift by the addition of Ca2+ and Mg2+ . Based on these results, it is concluded that the fluoroquinolone antimicrobials examined in the present study at pD 2.5 exist as stable complexes in the presence of Al3+ and the absorptivity of the drugs on oral administration could be affected by Al3+.

Biochem Cell Biol, 1998, 76(2-3), 247 - 56
NMR studies of the antimicrobial salivary peptides histatin 3 and histatin 5 in aqueous and nonaqueous solutions; Brewer D et al.; Conformational studies of the salivary peptides histatin 3 (H3) and histatin 5 (H5) were performed by NMR and circular dichroism (CD) in aqueous and nonaqueous solutions . Histatin 5 has no defined structure in H2O but adopts a more helical conformation in dimethyl sulfoxide and aqueous trifluoroethanol . This is in agreement with the CD analysis, which shows no secondary structure in H2O but increasing helical content in the presence of trifluoroethanol . CD analysis shows that H3 has less propensity to form a helical structure than H5 in similar conditions . The NMR analysis of H3 in H2O at pH 7.4 reveals that its conformational mobility is less than that of H5 as indicated by the observation of backbone cross peaks alphaN (i, i + 1) and NN (i, i + 1) and the slow exchanging amide protons in the C-terminus . However, H3 remains essentially unordered as suggested by the lack of longer range nuclear Overhauser effects (NOEs) in the NOESY spectrum . H3 becomes much more ordered in a mixture of 50:50 H2O-dimethyl sulfoxide as indicated by the numerous NOEs, including several side chain to side chain and side chain to backbone connectivities . Our data suggest that in these conditions H3 contains a turn in the region of K13 to K17 and possibly a 3(10) helix at the C-terminus . This study demonstrates that H3 and H5 are both conformationally mobile and that each adopt different types of conformations in aqueous and nonaqueous solutions.

Biochem Cell Biol, 1998, 76(2-3), 235 - 46
Structure-function relationships of antimicrobial peptides; Hwang PM et al.; Antimicrobial peptides are ubiquitously produced throughout nature . Many of these relatively short peptides (6-50 residues) are lethal towards bacteria and fungi, yet they display minimal toxicity towards mammalian cells . All of the peptides are highly cationic and hydrophobic . It is widely believed that they act through nonspecific binding to biological membranes, even though the exact nature of these interactions is presently unclear . High-resolution nuclear magnetic resonance (NMR) has contributed greatly to knowledge in this field, providing insight about peptide structure in aqueous solution, in organic cosolvents, and in micellar systems . Solid-state NMR can provide additional information about peptide-membrane binding . Here we review our current knowledge about the structure of antimicrobial peptides . We also discuss studies pertaining to the mechanism of action . Despite the different three-dimensional structural motifs of the various classes, they all have similar amphiphilic surfaces that are well-suited for membrane binding . Many antimicrobial peptides bind in a membrane-parallel orientation, interacting only with one face of the bilayer . This may be sufficient for antimicrobial action . At higher concentrations, peptides and phospholipids translocate to form multimeric transmembrane channels that seem to contribute to the peptide's hemolytic activity . An understanding of the key features of the secondary and tertiary structures of the antimicrobial peptides and their effects on bactericidal and hemolytic activity can aid the rational design of improved analogs for clinical use.

Eur J Clin Microbiol Infect Dis, 1998 Nov, 17(11), 761 - 6
Strain-specific differences in the amount of Shiga toxin released from enterohemorrhagic Escherichia coli O157 following exposure to subinhibitory concentrations of antimicrobial agents; Grif K et al.; There is no consensus regarding the benefit versus harm of antibiotic therapy for treatment of disease due to enterohemorrhagic Escherichia coli O157 . The effects in vitro of subinhibitory concentrations of 13 antimicrobial agents on the release of Shiga toxin (Stx) by three different Escherichia coli O157 strains expressing Stx 1 or Stx 2 either alone or in combination were investigated . The Stx-induced cell death of Vero cells was determined using a colorimetric assay based on the measurement of lactate dehydrogenase (LDH) released into the supernatant from the cytosol of damaged cells . Growth of all O157 strains in broth cultures containing subinhibitory concentrations of cotrimoxazole, trimethoprim, azithromycin, or gentamicin was accompanied by a marked increase in the release of Stx . Exposure to cefixime, ceftriaxone, or erythromycin caused a marked increase in the release of Stx by the O157 strain producing Stx 2 alone, but decreased toxin production was observed with the Stx 1 producer and the strain producing Stx 1 and Stx 2 . Exposure to ampicillin caused increased Stx release in the Stx 2-producing strain but had no effect on Stx production in the other two test isolates . Exposure to penicillin G, streptomycin, ciprofloxacin, fosfomycin, or sulfamethoxazole caused an increase in toxin production in two of the three test strains in each case, while decreases were observed for the other isolates . The response of Escherichia coli O157 isolates to subinhibitory concentrations of antibiotics seems to be highly dependent on the nature of the strain involved.

Arch Pharm (Weinheim), 1998 Dec, 331(12), 385 - 8
Synthesis of 2,5-disubstituted-1,4-benzoquinone derivatives as potential antimicrobial and cytotoxic agents; Hassan MA et al.; A number of 2,5-disubstituted-1,4-benzoquinone derivatives were prepared and characterized by elemental analysis, infrared (IR), nuclear magnetic resonance (1H-NMR), and mass spectra (MS) . These compounds and their synthetic precursors were evaluated for their in vitro antimicrobial and cytotoxic activity . The most potent antimicrobial compound was the thiadiazolyl derivative 4b, which was 2- to 4 times more active than the antimicrobial drug sulfathiazole . All the tested compounds were active in the Brine Shrimp Lethality (BS) Test . Compound 4e which was the most active in the BS test was also found to possess a significant cytotoxicity against two tumor cell lines . Some of the compounds were found to be mutagenic at relatively high concentration.

World Health Organ Tech Rep Ser, 1998, 882, 1 - 77
The use of essential drugs . Eighth report of the WHO Expert Committee (including the revised Model List of Essential Drugs).
{Antibiotic prophylaxis in adult critically ill patients in intensive care units}
Tonnesen EK, Toft P.

Arhus Universitetshospital, Arhus Kommunehospital, anaestesiologisk-intensiv afdeling . akh.grp02s.eto@aaa.dk

OBJECTIVES: To determine whether antibiotic prophylaxis reduces respiratory tract infections (RTI) and overall mortality in an unselected adults intensive care population . SEARCH STRATEGY: Systematic literature search in peer-reviewed journals indexed in MEDLINE, examination of relevant proceedings of scientific meetings and personal contact with trialists . SELECTION CRITERIA: All randomised clinical trials (RCTs), published and unpublished, comparing different forms of antibiotic prophylaxis used to reduce RTIs and mortality in unselected adult intensive care units (ICUs) populations . DATA COLLECTION AND ANALYSIS: Out of the 32 RCTs eligible for this review data have been extracted from published reports and then complemented with information provided by study investigators for 29 trials . Data were available only from published reports in the remaining three RCTs . For each trial the following information has been sought: a) method of randomisation; b) use of blinding techniques; c) number of randomised patients; d) number of patients with RTIs; e) number of deaths; f) number of patients excluded from the published analysis; g) number of RTIs and number of deaths among excluded patients . Pooled estimates of treatment effects across trials have been calculated after grouping RCTs in two main, mutually exclusive, categories: a) 15 trials testing the effect of a combination of a topical and a systemic antibiotic against no prophylactic treatment; b) 17 trials where the experimental treatment was a topical antimicrobial preparation . Crude proportions of RTIs and mortality were used to calculate the overall treatment effect . We also computed the number of ICU patients who need to be treated in order to prevent one infection and one death . MAIN RESULTS: Overall 32 RCTs including 5639 patients were identified . Pooled estimates of the 15 RCTs (including 3273 patients) testing the effect of the topical and systemic antibiotic combination indicate a strong significant reduction of both RTIs (OR = 0.36, 95% CI = 0.30-0.43) and total mortality (OR = 0.80, 95% CI = 0.68-0.93) . Five and 23 patients need to be treated to prevent one infection and one death, respectively, using this treatment . When data on the effect of the combination based on topical antimicrobials were pooled from the 17 available trials (including 2366 patients) a marked reduction on RTIs (OR = 0.57, 95% CI = 0.46-0.69) also emerged but no corresponding effect on overall mortality (OR = 1.01; 95% CI = 0.84-1.22) was found . CONCLUSIONS: After 15 years of clinical research this meta-analysis of 32 RCTs shows that a regimen of antibiotic prophylaxis based on a combination of a systemic and topical antibiotic can reduce both RTIs and overall mortality in ICU patients in a way that is both statistically significant and humanly worthwhile . Over and above their personal opinions intensivists should take this evidence into account when defining their policies.

Neoplasma, 1998, 45(5), 336 - 42
Candida parapsilosis fungemia in cancer patients--incidence, risk factors and outcome; Krcmery V Jr et al.; The paper presents an analysis of fungemia cases which were caused by C . parapsilosis in a cancer center within 10 years, with the aim to compare risk factors and the outcome with fungemias caused by C . albicans and other non-albicans Candida spp . fungemias . Before 1990 (1988-1989) in our institutes C . parapsilosis fungemias were not observed at all . During 1990-1997, the proportion of C . parapsilosis among fungemias increased, in 1990-1993 from 0% to 7.1% in 1996-1997 to 14.2-15% . It represents 25% out of non-albicans Candida spp . fungemias and 7.9% out of all fungemias and is the third commonest pathogen after C . albicans (50.5%) and C . krusei (9.9%) . Two from eight (25%) C . parapsilosis fungemias were breakthroughs, one appeared during prophylaxis with ketoconazol and one with fluconazol . Considering the proportion of C . parapsilosis among blood cultures, 13 of 170 blood cultures contained C . parapsilosis (6.6% among all yeasts from blood cultures) . C . parapsilosis was the second commonest fungal organism isolated from blood cultures (after C . albicans) in our cancer center . Infected vascular catheters were surprisingly not the major risk factor: central venous catheters were documented as a source in two cases only . The commonest risk factors were similar to those occurring with other fungemias--such as preceding antimicrobial therapy (62.5%), neutropenia (50%) and prior prophylaxis with azoles.

Biochemistry, 1998 Dec 22, 37(51), 17923 - 30
Reaction of myeloperoxidase compound I with chloride, bromide, iodide, and thiocyanate; Furtmuller PG et al.; Myeloperoxidase plays a fundamental role in oxidant production by neutrophils . The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids . This study for the first time presents transient kinetic measurements of the oxidation of these halides and thiocyanate by the myeloperoxidase intermediate compound I, using the sequential mixing stopped-flow technique . At pH 7 and 15 degrees C, the two-electron reduction of compound I to the native enzyme by Cl- has a second-order rate constant of (2.5 +/- 0.3) x 10(4) M(-1) s(-1), whereas reduction of compound I by SCN- has a second-order rate constant of (9.6 +/- 0.5) x 10(6) M(-1) s(-1) . Iodide {(7.2 +/- 0.7) x 10(6) M(-1) s(-1)} is shown to be a better electron donor for compound I than Br- {(1.1 +/- 0.1) x 10(6) M(-1) s(-1)} . The pH dependence studies suggest that compound I reduction by (pseudo-)halides is controlled by a residue with a pKa of about 4.6 . The protonation of this group is necessary for optimum (pseudo-)halide anion oxidation . These transient kinetic results are underlined by steady-state spectral and kinetic investigations . SCN- is shown to be most effective in shifting the system myeloperoxidase/hydrogen peroxide from the peroxidatic cycle to the halogenation cycle, whereas iodide is shown to be more effective than bromide which in turn is much more effective than chloride . Decreasing pH increases the rate of this transition . Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity.

Biochim Biophys Acta, 1998 Dec 8, 1429(1), 129 - 41
Direct evidence of the generation in human stomach of an antimicrobial peptide domain (lactoferricin) from ingested lactoferrin; Kuwata H et al.; The ability to define specific alterations in the structure and function of proteins as they are introduced and processed in vivo remains an important goal . We have evaluated the generation, in vivo, of an antimicrobial peptide (lactoferricin) derived from ingested bovine lactoferrin by surface-enhanced laser desorption/ionization (SELDI) . SELDI was used in the affinity mass spectrometry operational mode to detect and quantify lactoferricin directly from unfractionated gastric contents using a chemically defined ligand with a terminal n-butyl group as the lactoferricin affinity capture device . By this method, we were able to detect and quantify lactoferricin directly upon examination of unfractionated gastric contents recovered from an adult subject 10 min after ingestion of bovine lactoferrin (200 ml of 10 mg/ml (1.2 x 10(-4) mol/l) solution) . Lactoferricin produced in vivo was directly captured by a surface-enhanced affinity capture (SEAC) device composed of molecules with a terminal n-butyl group and analyzed by laser desorption/ionization time-of-flight mass spectrometry . The recovery of standard lactoferricin or lactoferrin added to an aliquot of the gastric contents was determined to be nearly 100%, confirming the efficiency of this method . The amount of lactoferricin detected in the gastric contents was 16.9+/-2.7 microg/ml (5.4+/-0.8 x 10(-6) mol/l) . However, a large proportion of ingested lactoferrin was found to be incompletely hydrolyzed . Lactoferrin fragments containing the lactoferricin region were analyzed by in situ pepsin hydrolysis after being captured on the SEAC device . Partially degraded lactoferrin fragments containing the lactoferricin region, including fragments corresponding to positions 17-43, 17-44, 12-44, 9-58 and 16-79 of the bovine lactoferrin sequence, were found to be present at concentrations as high as 5.7+/-0.7 x 10(-5) mol/l . These results suggest that significant amounts of bovine lactoferricin would be produced in the human stomach following ingestion of food, such as infant formula, supplemented with bovine lactoferrin . We propose that physiologically functional quantities of human lactoferricin could be generated in the stomach of breast-fed infants, and possibly, in the case of adults, from lactoferrin secreted into saliva.

Can Vet J, 1999 Jan, 40(1), 52 - 3
Isolation of Actinobacillus suis from a cat's lung; Daignault D et al.; Actinobacillus suis has been isolated from the lungs of 9-month-old cat . The bacterium was characterized biochemically as well as genetically, and its sensitivity profile to different antimicrobial agents was established . The role of this isolate in the cat's condition is discussed.

Ann Acad Med Singapore, 1998 Sep, 27(5), 738 - 43
Emerging therapies for sepsis and septic shock; Oh HM; Despite advances in antimicrobial therapy and medical support, septic shock remains a leading cause of death . Emerging adjunctive therapy for septic shock can be divided into those directed against bacterial components, those directed against host-derived inflammatory-mediators and those designed to limit tissue damage . All trials of new adjunctive therapies for sepsis and septic shock conducted to data have failed to show efficacy . Therapies against endotoxin, tumour necrosis factor, interleukin-1 and platelet activating factor did not reduce mortality . Future effective therapies will probably use combination of agents depending upon the nature of the infection and the type of patient.

Biochem Biophys Res Commun, 1999 Jan 19, 254(2), 281 - 3
Synthetic peptides corresponding to the beta-hairpin loop of rabbit defensin NP-2 show antimicrobial activity; Thennarasu S et al.; Mammalian defensins, a class of antibacterial peptides, are composed of 29-35 amino acids with six cysteines which form three disulfide bonds . Structural studies indicate a triple stranded beta-sheet structure with a well defined beta-hairpin loop at the C-terminal region . It is demonstrated in this report that 18 and 26 residue synthetic peptides corresponding to the beta-hairpin region, constrained by a single disulfide bond, have potent antimicrobial activity without hemolytic activity . Circular dichroism spectroscopy indicates that the single S-S bridge appears to constrain the peptides to a beta-structure . Peptides corresponding to the beta-hairpin region of defensins could thus be attractive candidates as therapeutic agents as well as good model compounds for investigation of the various physiological actions of defensins .

Biochem Biophys Res Commun, 1998 Dec 30, 253(3), 600 - 3
Antimicrobial peptides of the brevinin-2 family isolated from gastric tissue of the frog, Rana esculenta; Wang Y et al.; Four structurally related peptides with potent growth-inhibitory activity towards Escherichia coli were isolated from an extract of the stomach of the European green frog Rana esculenta, and were identified as members of the brevinin-2 family . Two peptides, termed brevinin-2Eg (GIMDTLKNLA10 KTAGKGALQS20 LLNHASCK LS30GQC) and brevinin-2Eh (GIMDTLKNLA10 KTAGKGALQS20 LLNHASCKL S30 KQC) have not been described previously . One peptide is identical to brevinin-2Ec, previously isolated from R . esculenta skin secretions, and one peptide is identical to brevinin-2Ef whose structure has been deduced from a cloned cDNA prepared from a R . esculenta skin cDNA library . The data demonstrate that certain peptides of the brevinin-2 family, like the magainins in the toad, Xenopus laevis, may play an important role in protecting the gastrointestinal tract of Ranid frogs against microbial invasion.

J Antibiot (Tokyo), 1998 Nov, 51(11), 991 - 8
Topostatin, a novel inhibitor of topoisomerases I and II produced by Thermomonospora alba strain No . 1520 . I . Taxonomy, fermentation, isolation and biological activities; Suzuki K et al.; A novel inhibitor of topoisomerases designated as topostatin was isolated from the culture filtrate of Thermomonospora alba strain No . 1520 . Topostatin inhibited the relaxation of supercoiled pBR322 DNA by calf thymus topoisomerase I, and also inhibited the relaxation of supercoiled pBR322 DNA and decatenation of kinetoplast DNA by human placenta topoisomerase II . Topostatin had neither ability to stabilize the cleavable complex nor ability to intercalate into DNA strands . The inhibitor exhibited growth inhibitory activity against the tumor cells (SNB-75 and SNB-78) of central nervous system, but did not exhibit any antimicrobial activity against Gram-positive and Gram-negative bacteria, yeasts and fungi.

Clin Obstet Gynecol, 1998 Dec, 41(4), 864 - 9
Antibiotic therapy in preterm premature rupture of membranes; Locksmith GJ; Good quality evidence supports the use of antibiotic therapy in women with preterm PROM for whom expectant management is planned . The best evidence supports the choice of an extended-spectrum agent or combination administered intravenously for 2 days followed by an extended spectrum or combination of oral agents for several more days . Despite the effectiveness of antimicrobial therapy in this setting, the potential risks of systemic antibiotic administration, such as allergic reactions, overgrowth of commensal organisms, and emergence of resistant pathogens, much always be kept in mind . Nevertheless, in the majority of cases, assuming the patient is a good candidate for expectant management, the benefits of antibiotic therapy outweigh the risks.

Ann N Y Acad Sci, 1998 Sep 29, 856, 243 - 51
Proinflammatory cytokines and treatment of disease; van der Meer JW et al.; Bacterial infections in the immunocompromised host cause considerable mortality, and even recently developed antimicrobial strategies often fail to cure these infections, especially in granulocytopenic patients . Cytokines and hematopoietic growth factors have been shown to stimulate host defense mechanisms in vitro and in vivo . The possible role of the proinflammatory cytokines interleukin (IL)-1, tumor necrosis factor-alpha, IL-6, and IL-8 as modulators of host resistance to bacterial infections is discussed . Interleukin-1 has been effective in various animal models of potentially lethal bacterial infection, even during severe granulocytopenia . The protective mechanism of IL-1 may be mediated by downregulation of cytokine receptors and cytokine production and induction of acute phase proteins . Moreover, in subacute and chronic infections IL-1 interferes with microbial outgrowth via mechanisms that have only been partly elucidated.

Ann N Y Acad Sci, 1998 Sep 29, 856, 22 - 32
Immunomodulatory properties of interferon-gamma . An update; Billiau A et al.; During the early aspecific phase of host defense, production of interferon (IFN)-gamma by natural killer cells plays an important role in bringing about acute inflammation, mainly because of the activating effects of IFN-gamma on adhesive properties of endothelial cells and on mediator production by mononuclear phagocytes (MPCs) . In the subsequent antigen-specific phase of the immune response, IFN-gamma acts as a regulator of antigen presentation and of proliferation and differentiation of lymphocyte populations . Immunosuppressive as well as immunostimulatory effects may result from these actions . High-level production of IFN-gamma during this phase of host defense is now classically seen as a hallmark of a T-helper 1 (TH1)-type reaction, characterized by activation of antimicrobial activity of macrophages and by inflammatory reactions with a DTH character . Development of TH1-type lymphocyte populations producing IFN-gamma is regulated by other cytokines including interleukin (IL)-12 . In many systems IL-12 and IFN-gamma act in a similar fashion, and a current subject of debate is the question of whether all activities of IL-12 are mediated by IFN-gamma . Another question is whether IFN-gamma, by its ability to potentiate MPCs' ability to produce IL-12, plays a role in bringing about or stabilizing TH1 type responses . In two model systems of autoimmune disease, experimental autoimmune encephalomyelitis and collagen-induced arthritis, IL-12 and IFN-gamma were found to act independently.

J Mol Biol, 1999 Jan 29, 285(4), 1363 - 9
Folding of amphipathic alpha-helices on membranes: energetics of helix formation by melittin; Ladokhin AS et al.; Membranes have a potent ability to promote secondary structure formation in a wide range of membrane-active peptides, believed to be due to a reduction through hydrogen bonding of the energetic cost of partitioning peptide bonds . This process is of fundamental importance for understanding the mechanism of action of toxins and antimicrobial peptides and the stability of membrane proteins . A classic example of membrane-induced folding is the bee-venom peptide melittin that is largely unstructured when free in solution, but strongly adopts an amphipathic alpha-helical conformation when partitioned into membranes . We have determined the energetics of melittin helix formation through measurements of the partitioning free energies and the helicities of native melittin and of a diastereomeric analog with four d-amino acids (d4,l-melittin) . Because D4,l-melittin has little secondary structure in either the free or bound forms, it serves as a model for the experimentally inaccessible unfolded bound form of native melittin . The partitioning of native melittin into large unilamellar phosphocholine vesicles is 5.0(+/-0.7) kcal mol-1 more favorable than the partitioning of d4,l-melittin (1 cal=4.186 J) . Differences in the circular dichroism spectra of the two forms of melittin indicate that bound native melittin is more helical than bound d4, l-melittin by about 12 residues . These findings disclose that the free energy reduction per residue accompanying the folding of melittin in membrane interfaces is about 0.4 kcal mol-1, consistent with the hypothesis that hydrogen bonding reduces the high cost of partitioning peptide bonds . A value of 0.6 kcal mol-1 per residue has been observed for beta-sheet formation by a hexapeptide model system . These two values provide a useful rule of thumb for estimating the energetic consequences of membrane-induced secondary structure formation .

J Nat Prod, 1999 Jan, 62(1), 114 - 8
Three new metabolites from marine-derived fungi of the genera coniothyrium and microsphaeropsis
Holler U, Konig GM, Wright AD.
The marine sponges Ectyplasia perox and Myxilla incrustans were investigated for associated fungal strains . Among others, a Coniothyrium sp., from E . perox, and a Microsphaeropsis sp., from M . incrustans, were isolated, cultured, and investigated for their biologically active secondary metabolite contents . The new compound microsphaeropsisin (1) together with the known compounds (R)-mellein (4), (3R,4S)-hydroxymellein (5), (3R,4R)-hydroxymellein (6), and 4, 8-dihydroxy-3,4-dihydro-2H-naphthalen-1-one (7) were isolated from the Microsphaeropsis sp . From culture extracts of the Coniothyrium sp., the new compounds (3S)-(3',5'-dihydroxyphenyl)butan-2-one (2) and 2-(1'(E)-propenyl)-octa-4(E),6(Z)-diene-1,2-diol (3), together with the six known metabolites (3R)-6-methoxymellein (8), (3R)-6-methoxy-7-chloromellein (9), cryptosporiopsinol (10), phenylethanol, (p-hydroxyphenyl)ethanol, and 2-(hydroxymethyl)furan, were obtained . All structures were determined using spectroscopic methods . With the exception of 3, all compounds were tested for their antimicrobial properties, and all but 10 demonstrated significant antimicrobial activity in agar diffusion assays.

J Nat Prod, 1999 Jan, 62(1), 35 - 40
Isolation, identification, and enantioselective synthesis of octane-1,3,7-triol: determination of its absolute configuration
Beuerle T, Engelhard S, Bicchi C, Schwab W.
Extracts obtained by solid-phase extraction from apples were separated by multilayer countercurrent chromatography . In the most polar fractions, the novel octane-1,3,7-triol was identified by 1H and 13C NMR as well as LC-MS and by comparison with the synthesized racemic reference compound . Resolution of the enantiomers was achieved after acetylation of the triol followed by GC separation . The enantioselective synthesis of the stereoisomers of octane-1,3, 7-triol was performed using the building blocks (R)- and (R, S)-butane-1,3-diol and (S)- and (R,S)-butane-1,2,4-triol . Comparison with the isolated products indicated that the natural compound consisted of a mixture of (3R,7S)- and (3R,7R)-octane-1,3,7-triol in a ratio of 2:3 . Since the C3 chiral center is enantiomerically pure, the triol might be biogenetically related to the known antimicrobial (R)-(+)-octane-1,3-diol, the major volatile compound of some apple cultivars.

Clin Ther, 1998 Nov-Dec, 20(6), 1149 - 58
Effect of Maalox on the oral absorption of sparfloxacin; Johnson RD et al.; Sparfloxacin is a broad-spectrum oral fluoroquinolone antimicrobial agent with a long elimination half-life (t(1/2)) . Concurrent treatment with antacids has demonstrated a reduction in the oral absorption of many quinolones . This study was undertaken to determine an optimal time for dosing antacids in relation to sparfloxacin administration to minimize antacid-induced reduction in sparfloxacin bioavailability . This open-label, single-dose, randomized, four-way crossover study was conducted in 20 healthy male volunteers between the ages of 18 and 38 years . Treatments consisted of single 400-mg oral doses of sparfloxacin alone and with Maalox 30 mL given 2 hours before, 2 hours after, and 4 hours after oral administration of sparfloxacin . All 20 subjects completed the study . A 400-mg single oral dose of sparfloxacin was well tolerated both given alone and with Maalox . Maalox given 4 hours after sparfloxacin administration was the only regimen that did not cause a statistically significant reduction in the rate and extent of sparfloxacin absorption . The 90% confidence intervals comparing sparfloxacin alone with the preceding regimen in terms of area under the concentration-time curve from zero to infinity (AUC(0-infinity)) and maximum plasma concentration (Cmax) were within the range 80% to 125% . Administration of Maalox 2 hours before, 2 hours after, and 4 hours after sparfloxacin caused mean decreases in AUC(0-infinity) of 23%, 17%, and 5%, respectively . Corresponding decreases in mean Cmax values were 29% with Maalox administered 2 hours before sparfloxacin and 13% with Maalox administered 2 hours after sparfloxacin . The mean Cmax value was un affected when Maalox was administered 4 hours after sparfloxacin administration . The 90% confidence intervals for these comparisons with sparfloxacin alone were outside the 80% to 125% range and did not include 100% . Time to Cmax and t(1/2) were similar for all four regimens . The elimination rate of sparfloxacin was unaffected by concomitant administration with Maalox in healthy male volunteers.

Clin Ther, 1998 Nov-Dec, 20(6), 1115 - 29
Efficacy and tolerability of cefprozil versus amoxicillin/clavulanate for the treatment of adults with severe sinusitis; Adelglass J et al.; Cefprozil is a beta-lactamase-stable oral cephalosporin with an antimicrobial spectrum that includes gram-positive and gram-negative pathogens commonly associated with acute bacterial sinusitis, one of the most common upper respiratory tract infections among adults . We conducted a multicenter, open-label study to compare the efficacy and safety of cefprozil and amoxicillin/clavulanate in the treatment of adults with severe acute bacterial sinusitis diagnosed by clinical and radiographic criteria . A total of 278 patients entered the study, 140 (59 males, 81 females) in the cefprozil group and 138 (69 males, 69 females) in the amoxicillin/clavulanate group . Patients were randomized to 10 days of treatment with either cefprozil 500 mg BID or amoxicillin/clavulanate 500 mg/125 mg TID . Clinical severity was assessed at study entry, and patients were stratified based on symptom grade . Efficacy was evaluated using a 10-point questionnaire administered during, at the end of, and 2 weeks after completing therapy . At the end of treatment, 84.5% (71/84) of patients with severe sinusitis treated with cefprozil had a satisfactory clinical response, which was not significantly different from the 89.9% (80/89) of patients in the amoxicillin/clavulanate group who had a satisfactory clinical response . Two weeks after completing treatment, 80.8% (63/78) of cefprozil-treated patients and 81.0% (64/79) of amoxicillin/clavulanate-treated patients with severe sinusitis had a satisfactory response . Relapse was more common among amoxicillin/clavulanate patients (6/70; 8.6%) than among cefprozil patients (2/65; 3.1%), but the difference was not statistically significant . Significantly more amoxicillin/clavulanate-treated patients experienced adverse events compared with cefprozil-treated patients (P < 0.001), including diarrhea (P < 0.001), nausea (P < 0.042), and rash (P < 0.035) . Three times as many amoxicillin/clavulanate patients discontinued treatment because of adverse events . Cefprozil demonstrated comparable clinical efficacy to amoxicillin/clavulanate in the treatment of adults with severe sinusitis; however, cefprozil was associated with a significantly lower incidence of diarrhea, nausea, and rash.

Burns, 1998 Dec, 24(8), 751 - 3
A study of the concentration of orally administered sparfloxacin found in exudates from suture wounds beneath occlusive dressings; Yotsuyanagi T et al.; The concentration of orally administered sparfloxacin (SPFX), an antimicrobial agent, in exudates from the suture wounds beneath occlusive dressings has been measured . Twenty-one patients who received oral therapy with 100 mg of SPFX prior to surgery and 200 mg/day of SPFX after surgery were studied . During the operations, the suture wounds were covered by occlusive film . 48h post-operation, wound exudates under the dressings were drawn and measured using high performance liquid chromatography . SPFX values were 0.801+/-0.340 microg/ml (mean+/-SD) . The results suggest that wound exudates beneath the occlusive dressing have concentrations of SPFX high enough to prevent infection in most cases when administered orally.

Arch Phys Med Rehabil, 1999 Jan, 80(1), 118 - 21
Nonselective debridement and antimicrobial cleansing of a venting ductal breast carcinoma; Nash MS et al.; A woman with a moderately differentiated carcinoma that erupted through the skin and amputated her breast was treated with whirlpool, topical antimicrobials, radiation, and chemotherapy . The draining, necrotic, and septic wound was treated for 5 months with a whirlpool containing dilute povidone-iodine solution and intravenous chemotherapy . Wet bandages, necrotic tissue, and softened eschar were removed by whirlpool agitation or mechanically debrided . To start treatment the wound was dressed with Debrisan crystals and sterile gauze for 1 week . Afterwards, wet-to-dry dressings wetted with Dakin's solution were applied . Tissue ingrowth at the wound margin started after 2 weeks, with whirlpool treatments effecting a tissue-reddening hyperemia . Wound drainage ceased after 2 months, with granulation and revascularization resulting . Eleven months later the wound was closed, aseptic, and undergoing dry flaking . The patient was cancer free with a completely healed wound 2 years after treatment . In this case, nonspecific debridement using whirlpool and topical antimicrobials promoted healing of an open fungating wound from a breast carcinoma.

Jpn J Antibiot, 1998 Oct, 51(10), 583 - 99
{Single dose intravenous toxicity studies of T-3762, a novel parenteral quinolone antimicrobial agent, in rats, dogs and monkeys}; Nagai A et al.; Single dose intravenous toxicity studies of T-3762, a novel parenteral quinolone antimicrobial agent, were conducted in rats, dogs and monkeys . The following results were obtained . 1 . In the rat study, all males and females given 260 mg/kg survived and all males and 3 of 5 females given 391 mg/kg died . Approximate lethal doses in male and female rats were between 260 and 391 mg/kg . In survived animals, decrease in locomotor activity and irregular respiration were observed . These clinical signs were recovered within 1 hour after dosing . In female rats given 260 mg/kg, no abnormalities were observed in general signs . In dead animals, decrease in locomotor activity, irregular respiration, staggering gait and tonic convulsion were observed and died within about 90 minutes after dosing . Macroscopic examinations in dead animals showed dark red discoloration in lung and had white foamy liquid in trachea . In histopathological examinations of dead animals, congestion, hemorrhage and edema were observed in lung . 2 . In the dog study, 2 animals given 260 mg/kg survived and 2 animals given 521 mg/kg died . Approximate lethal dose in dogs was between 260 and 521 mg/kg . In the 260 and 521 mg/kg groups, decrease in locomotor activity, lateral position, vomiting, salivation and decrease in body temperature were observed . In the 521 mg/kg group, one animal died at 4 minutes and another 7 days after dosing . Histopathological examinations in 2 dead animals showed congestion or hemorrhage in heart, lung, liver, kidney, spleen and digestive tract . Erosion and necrosis at cartilage layer and cluster of chondrocyte were observed in scapular fossa and head of humerus in the 260 and 561 mg/kg groups . 3 . In the monkey study, 2 animals given 260 mg/kg survived and 2 animals given 520 mg/kg died . Approximate lethal dose in monkeys was between 260 and 520 mg/kg . In the 260 mg/kg group, soft feces was observed . In the 520 mg/kg group, paleness mucosa of oral cavity, muscle weakness, mydriasis and dyspnea were observed and animals died within 4 minutes after dosing . Macroscopic and histopathological examinations in 2 dead animals showed congestion in lung, liver and kidney.

Eur J Biochem, 1999 Jan, 259(1-2), 360 - 9
A comparative study on the structure and function of a cytolytic alpha-helical peptide and its antimicrobial beta-sheet diastereomer; Oren Z et al.; Antimicrobial peptides which adopt mainly or only beta-sheet structures have two or more disulfide bonds stabilizing their structure . The disruption of the disulfide bonds results in most cases in a large decrease in their antimicrobial activity . In the present study we examined the effect of d-amino acids incorporation on the structure and function of a cytolytic alpha-helical peptide which acts on erythrocytes and bacteria . The influence of a single or double d-amino acid replacement in alpha-helical peptides on their structure was reported previously in 50% 2,2,2, trifluoroethanol/water {Krause et al . (1995) Anal . Chem . 67, 252-258} . Here we used Attenuated Total Reflectance Fourier-Transform Infrared (ATR-FTIR) spectroscopy and found that the predominant structure of the wild-type peptide is alpha-helix in phospholipid membranes, whereas the structure of the diastereomer is beta-sheet . However, the linear, beta-sheet diastereomer preserved its cytolytic activity on bacteria but not on erythrocytes . Previous studies have shown that the ability of antimicrobial peptides to lyse bacteria but not normal mammalian cells correlated with their ability to disintegrate preferentially negatively charged, but not zwitterionic phospholipid membranes . In contrast, the diastereomer described here disrupts zwitterionic and negatively charged vesicles with similar potencies to those of the hemolytic wild-type peptide . Interestingly, whereas addition of a positive charge to the N-terminus of the wild-type peptide (which caused a minor effect on its structure) increased activity only towards some of the bacteria tested, similar modification in the diastereomer increased activity towards all of them . Furthermore, the modified wild-type peptide preserved its potency to destabilize zwitterionic and negatively charged vesicles, whereas the modified diastereomer had a reduced potency on zwitterionic vesicles but increased potency on negatively charged vesicles . Overall our results suggest that this new class of antimicrobial diastereomeric peptides bind to the membrane in 'carpet-like' manner followed by membrane disruption and breakdown, rather than forming a transmembrane pore which interfere with the bacteria potential . These studies also open a way to design new broad-spectrum antibacterial peptides.

Int J Clin Pract, 1998 Sep, 52(6), 414 - 7
The management of skin and skin structure infections in children, adolescents and adults: a review of empiric antimicrobial therapy; Wilson SE; This article reviews the diagnosis and management of mild-to-moderate skin and skin structure infections in children, adolescents and adults in a general practice setting . Therapies reviewed are those in current use: penicillins; beta-lactamase stable penicillins, including flucloxacillin, oxacillin, and amoxicillin-clavulanate; oral quinolones; macrolides; and oral cephalosporins . Consideration is given to duration of therapy, side-effect profile and compliance.

Arzneimittelforschung, 1998 Dec, 48(12), 1179 - 84
Investigation of serum minimal inhibitory concentrations of some benzimidazole, imidazole and benzothiazole derivatives and their effects on liver and renal functions; Durmaz R et al.; In previous studies many benzimidazole, imidazole and benzothiazole derivatives had been synthesized and their antimicrobial activities were tested in vitro conditions . Four of these compounds showed minimal inhibitory concentrations (MIC) of 5-25 micrograms/ml against standard strains and clinical isolates . In order to determine whether these four compounds can be used for therapeutic purpose, their serum MIC values and side effects on hepatic and renal functions were determined . Different concentrations of the compounds were tested on Wistar rats . Compound 1 was administered orally, intramuscularly and intravenously; compounds 2, 3 and 4 were given orally and intramuscularly . Blood samples were taken 4 and 24 h after administration of the compounds . Serum MIC values were investigated by bioassay and serum levels of biochemical parameters by autoanalyzer . None of the tested compounds showed antimicrobial activity at their serum concentrations . Although creatinine activity was found at normal levels in all experiments, compounds 1 and 2 caused a significant increase in blood urea nitrogen (BUN) level . The values of aspartate aminotransferase and/or alanine aminotransferase and/or alkaline phosphatase which are characteristic for liver function were generally found at high levels . According to these results, it can be concluded that the tested compounds caused damage in liver and biliary tracts without antimicrobial activity by their serum concentrations.

Drug Metabol Drug Interact, 1997, 14(2), 109 - 22
The inhibitory effects of the fluoroquinolone antimicrobials norfloxacin and enrofloxacin on hepatic microsomal cytochrome P-450 monooxygenases in broiler chickens; Shlosberg A et al.; The fluoroquinolone antimicrobials norfloxacin and enrofloxacin were found to inhibit hepatic microsomal cytochrome P-450 monooxygenases in the livers of broiler chickens using dosages as given in commercial flocks . Norfloxacin inhibited the process of N-demethylation of aminopyrine to a greater degree, while enrofloxacin more markedly inhibited hydroxylation of aniline.

J Eur Acad Dermatol Venereol, 1998 Sep, 11 Suppl 1, S13 - 9; discussion S28-9
Transdermal absorption of topical anti-acne agents in man; review of clinical pharmacokinetic data; van Hoogdalem EJ; BACKGROUND: Apart from oral drug treatment, drug therapy in acne vulgaris comprises topical treatment with agents with a primarily keratolytic action (e.g . tretinoin and benzoylperoxide), and with antibiotics (clindamycin, erythromycin, and erythromycin-zinc complex) . The acne grade in the particular patient usually determines the selection of the preferred route of administration, viz . topical or oral, or a combination of both, and topical treatment is usually preferred in mild to moderate acne . The fact that a topically applied compound may also become systemically available to a quantifiable extent, is not generally considered . AIM: The present paper reviews the clinical data on transdermal uptake of anti-acne agents in man, also with respect to their relevance for daily clinical practice . OUTCOME: The majority of published data on transdermal penetration of topical anti-acne agents focuses on the retinoid tretinoin, and on the antimicrobial agent clindamycin . This interest emerges from the fact that these agents have been associated with embryotoxicity/teratogenicity, and pseudomembranous colitis, respectively . For both compounds the extent of systemic availability after topical application is low, viz . 5-7% and 8%, respectively, at its highest . The height and variability in endogenous retinoid levels is very likely to outweigh any contribution of exogenously applied tretinoin, but a full consensus on the safe use of topical tretinoin in pregnancy is still lacking . With respect to clindamycin, the suggested association between its topical use and the occurrence of pseudomembranous colitis appears not to be of clinical relevance . In order to reduce systemic exposure to clindamycin as much as possible, topical application of clindamycin phosphate is to be preferred over clindamycin hydrochloride salt . Regarding other topical anti-acne agents, it has been suggested that topical zinc-erythromycin is to be preferred over erythromycin, both from clinical efficacy and safety viewpoints . With respect to the currently used compounds like benzoylperoxide, azelaic acid, and adapalene, available clinical pharmacokinetic data are scarce, and significant safety concerns did not emerge as yet . CONCLUSION: The limited transdermal uptake of topical anti-acne agents underpins their safe use in daily clinical practice . With respect to topical retinoids, formal consensus is lacking regarding their use in pregnancy.

Cancer Treat Res, 1999, 99, 195 - 226
Hematopoietic growth factors and acute leukemia; Rowe JM et al.; Over the past decade, with the advent of hematopoietic growth factors, major strides have been made and multiple studies have attempted to define the use of these cytokines in acute leukemia . It is perhaps disappointing that, after so many studies, so many questions remain . Nevertheless, the role of cytokines in induction therapy seems to be established, although questions remain around the issue of priming therapy . Intriguing data regarding the potential for enhancing antimicrobial function should hopefully be resolved over the next few years . What is perhaps most reassuring is that the issue of safety, which for a considerable period of time precluded the development of clinical trials in acute leukemia, has been firmly laid to rest . The use of growth factors to protect normal stem cells during treatment of leukemia and to induce leukemic cell differentiation has not yet been the subject of many clinical trials . Also, growth factors are likely targets for the interruption of autocrine leukemic blast or progenitor cell growth, but again, few clinical observations are published . With the ongoing cloning of new growth factors active both in normal hematopoiesis and in leukemogenesis, the role of growth factor use in the treatment of AML will likely be the basis for much future preclinical and clinical activity.

Annu Rev Microbiol, 1998, 52, 41 - 79
Lantibiotics: biosynthesis and biological activities of uniquely modified peptides from gram-positive bacteria; Sahl HG et al.; A plethora of novel gene-encoded antimicrobial peptides from animals, plants and bacteria has been described during the last decade . Many of the bacterial peptides possess modified building blocks such as thioethers and thiazoles or unsaturated and stereoinverted amino acids, which are unique among ribosomally made peptides . Genetic and biochemical studies of many of these peptides, mostly the so-called lantibiotics, have revealed the degree to which cells are capable of transforming peptides by posttranslational modification . The biosynthesis follows a general scheme: Precursor peptides are first modified and then proteolytically activated; the latter may occur prior to, concomitantly with or after export from the cell . The genes for the biosynthetic machinery are organized in clusters and include information for the antibiotic prepeptide, the modification enzymes and accessory functions such as dedicated proteases and ABC transporters as well as immunity factors and regulatory proteins . These fundamental aspects are discussed along with the biotechnological potential of the peptides and of the biosynthesis enzymes, which could be used for construction of novel, peptide-based biomedical effector molecules.

J Biol Chem, 1999 Jan 22, 274(4), 2350 - 9
Association of phospholipase D activity with the detergent-insoluble cytoskeleton of U937 promonocytic leukocytes; Iyer SS et al.; Phospholipase D (PLD) regulates cytoskeletal-dependent antimicrobial responses of myeloid leukocytes, including phagocytosis and oxidant generation . However, the mechanisms responsible for this association between PLD activity and the actin cytoskeleton are unknown . We utilized a cell-free system from U937 promonocytes to test the hypothesis that stimulation of PLD results in stable association of the activated lipase with the detergent-insoluble membrane skeleton . Plasma membrane and cytosol were incubated +/- guanosine 5'-3-O-(thio)triphosphate (GTPgammaS), followed by re-isolation and extraction of the washed membranes with octyl glucoside . The detergent-insoluble fraction derived from membranes incubated with GTPgammaS (DIFGTPgammaS) exhibited 22-fold greater PLD activity than that derived from control membranes (DIF0), when both were assayed in the presence of GTPgammaS . The DIF contained PLD1, RhoA, and ARF, and the level of each was increased by GTPgammaS in a dose-dependent manner . The DIF also contained F-actin, vinculin, talin, paxillin, and alpha-actinin, consistent with its identification as the membrane skeleton . The physiologic relevance of these findings was demonstrated by a similar increase in DIF-associated PLD activity after stimulation of intact U937 cells with opsonized zymosan . These results indicate that stimulation of PLD1 is accompanied by stable association of the activated lipase, RhoA, and ADP-ribosylation factor with the actin-based membrane skeleton.

Biochem Pharmacol, 1999 Jan 15, 57(2), 121 - 34
Epithelial peptide antibiotics; Schroder JM; Surfaces of higher eukaryotes such as plants, invertebrates, and vertebrates, including humans, are normally covered with microorganisms but usually are not infected by them . The reason, apart from physical barriers, is the production of gene-encoded antimicrobial peptides by epithelial cells . Many novel antimicrobial peptides have been discovered recently in the epithelia of plants, insects, amphibians, and cattle, and, more recently, also in humans . In situ hybridization studies indicate a rather organ-specific expression of the genes for peptide antibiotics, which, due to their antimicrobial spectrum and conditions of expression, may also define the physiologic microflora . Some epithelial antimicrobial peptides are constitutively expressed; others are inducible, either by the presence of microorganisms via as of yet not well characterized elicitor receptors or by endogenous proinflammatory cytokines . Most antimicrobial peptides kill microorganisms by forming pores in the cell membrane, and the sensitivity of some peptide antibiotics towards cholesterol, a major mammalian cell membrane constituent, may indicate why these peptide antibiotics are not toxic for mammalian cells . Thus, it seems to be difficult for microorganisms to acquire resistance, making these peptides very attractive for therapeutic use as antibiotics . The first clinical studies are very promising, and after solving the problems of a large-scale biotechnical synthesis, which is more complicated due to the principally suicidal activity of these peptides, a number of new natural structure-based peptides may be developed . Furthermore, discovery of the inducibility of many antimicrobial peptides may also lead to the development of compounds that elicit epithelial defense reactions by stimulating the synthesis of endogenous peptide antibiotics.

J Clin Microbiol, 1999 Feb, 37(2), 304 - 9
Development of a firefly luciferase-based assay for determining antimicrobial susceptibility of Mycobacterium avium subsp . paratuberculosis; Williams SL et al.; Paratuberculosis (Johne's disease) is a fatal disease of ruminants for which no effective treatment is available . Presently, no drugs against Mycobacterium avium subsp . paratuberculosis (M . paratuberculosis), the causative agent of Johne's disease, are approved for use in livestock . Additionally, M . paratuberculosis has been linked to a human chronic granulomatous ileitis (Crohn's disease) . To assist in the evaluation of antimicrobial agents with potential activity against M . paratuberculosis, we have developed a firefly luciferase-based assay for the determination of drug susceptibilities . The microorganism used was M . paratuberculosis K-10(pYUB180), a clinical isolate carrying a plasmid with the firefly luciferase gene . The MICs determined by the broth macrodilution method were as follows: amikacin, 2 microg/ml; Bay y 3118, 0.015 microg/ml; clarithromycin, 1.25 microg/ml; D-cycloserine, 25 microg/ml; ethambutol, 20 microg/ml; and rifabutin, 0.5 microg/ml . The strain was resistant to isoniazid and kanamycin . The results obtained by the luciferase assay were identical or fell within 1 doubling dilution . These results suggest that a combination of amikacin, clarithromycin, and rifabutin may be the most efficacious therapy for the treatment of M . paratuberculosis infections and that the use of fluoroquinolone class of antibiotics deserves further consideration . We demonstrate that the luciferase drug susceptibility assay is reliable for M . paratuberculosis and gives results within 7 days, whereas the broth macrodilution method requires 14 days.

J Clin Microbiol, 1999 Feb, 37(2), 290 - 5
Quantitative analysis of mRNA as a marker for viability of Mycobacterium tuberculosis; Hellyer TJ et al.; Numerous assays which use conserved DNA or rRNA sequences as targets for amplification have been described for the diagnosis of tuberculosis . However, these techniques have not been applied successfully to the monitoring of therapeutic efficacy owing to the persistence of amplifiable nucleic acid beyond the point at which smears and cultures become negative . Semiquantitative analysis of rRNA has been used to reduce the time required for antimicrobial susceptibility testing of Mycobacterium tuberculosis, although growth for up to 5 days in the presence of some drugs is still required to discriminate resistant strains . The purpose of the present study was to determine whether quantitative analysis of M . tuberculosis mRNA could be used to assess bacterial viability and to illustrate the application of this technique to rapid determination of drug susceptibility . Levels of mRNA encoding the 85B protein (alpha-antigen), IS6110 DNA, and 16S rRNA were compared in parallel cultures of M . tuberculosis that were treated with either no drug, 0 . 2 microg of isoniazid per ml, or 1 microg of rifampin per ml . Exposure of sensitive strains to isoniazid or rifampin for 24 h reduced the levels of 85B mRNA to <4 and <0.01%, respectively, of those present in control cultures without drug . In contrast, the levels of IS6110 DNA and 16S rRNA did not diminish over the same period . Strains which were resistant to either isoniazid or rifampin demonstrated no reduction in 85B mRNA in the presence of the drug to which they were nonresponsive . Quantitative analysis of 85B mRNA offers a potentially useful tool for the rapid determination of M . tuberculosis drug susceptibility and for the monitoring of therapeutic efficacy.

Biochemistry, 1999 Jan 12, 38(2), 705 - 14
Conformational studies by NMR of the antimicrobial peptide, drosocin, and its non-glycosylated derivative: effects of glycosylation on solution conformation; McManus AM et al.; Drosocin is a cationic 19 amino acid peptide secreted by Drosophila in response to septic injury . The sequence (GKPRPYSPRPTSHPRPIRV) contains six Pro and four Arg residues which are incorporated into three repeated triplet sequences Pro-Arg-Pro . The peptide is glycosylated at Thr11 and has potent antimicrobial activity . This activity is markedly reduced on deglycosylation, but a structural basis for this has not been previously established . In the current study, the solution conformations of drosocin and its non-glycosylated derivative were determined by NMR spectroscopy and structure calculations . The NMR and structure studies showed that the peptides have significant populations of essentially random coil conformations in aqueous solution . Addition of 50% trifluoroethanol causes the development of small populations of folded conformations, mainly in the form of turns . In particular, turn elements occur near residues 4-7, 10-13, 17, and 18 . No substantial difference was detected in the predominantly random coil conformation of the glycosylated and non-glycosylated forms, but there are subtle differences in the small populations of folded conformers . In particular, the turn at residues 10-13 tends toward a more extended structure on glycosylation, while there is some tightening of the downstream turn at residues 17 and 18 . There are a significant number of nuclear Overhauser enhancement contacts between the sugar moiety and the peptide near the glycosylation site, consistent with a close association between them . Despite this close association, the pKa of H13, which is proximate to the glycosylation site, was found to be unaffected by glycosylation.

Wien Med Wochenschr, 1998, 148(18), 427 - 32
{Possibilities and limits of ambulatory supportive measures in oncology exemplified by antibiotic therapy of febrile neutropenia}; Karthaus M et al.; Neutropenia is common after intensive chemotherapy . Hospitalization and intravenous broad-spectrum antibiotics are the standard of care for febrile neutropenic patients because of the risk of serious complications and associated mortality . Short neutropenic periods (< 7 days) are considered to be at a low-risk in cases when fever occurs in clinically stable patients . Recent work suggests that such a low-risk population of febrile neutropenic patients might benefit from alternatives to inpatient care . The agents that best qualify for outpatient treatment include quinolones i.v./p.o., glycopeptides, ceftriaxone and aminoglycosides, particularly if the latter are given once daily . Response rates to antimicrobial therapy range from 80 to 95% in low-risk febrile neutropenia episodes . Treating these patients in an outpatient setting avoids hospitalization in 75 to 95% . There is no doubt that outpatient therapy may have several advantages, including lower costs and an improved quality of live . Outpatient antibiotic therapy for febrile low-risk neutropenia should be considered as an acceptable alternative to inpatient treatment.

Klin Monatsbl Augenheilkd, 1998 Nov, 213(5), 284 - 92
{Clearance of liposome-incorporated ciprofloxacin after intravitreal injection in rabbit eyes}; Wiechens B et al.; BACKGROUND: Ciprofloxacin (CIP) is a fluoroquinolone-antibiotic with a high antimicrobial activity against all pathogens causing bacterial endophthalmitis . After intravitreal injection, however, elimination half-life of this antibiotic is only 2.2 hours . To prolong intraocular bioavailability this study was performed to incorporate CIP into liposomes and to determine its clearance from the vitreous after intravitreal injection . MATERIALS AND METHODS: CIP was incorporated into multilamellar vesicles by mechanical dispersion . 0.1 ml of this suspension (equiv . 273.6 micrograms CIP) was injected into the midvitreous of pigmented rabbit eyes (Chinchilla-bastards) . One day, 3 and 14 days after the injection intravitreal concentration of CIP was determined by means of high-pressure-liquid-chromatography after dissolution of the liposomes by ultrasound . At the same intervals serum concentration of the antibiotic was examined as well . RESULTS: Within 24 hours intravitreal concentration fell to 18.0 micrograms/ml . Three days after the injection the concentration of CIP was 6.9 micrograms/ml . This is still above the minimal inhibitory concentration (MIC90) of the most common ocular pathogens . At 14 days CIP was not detectable in the vitreous any more . The serum concentration was between 0.04 microgram/ml and 0.07 microgram/ml . 3 and 14 days after injection no CIP could be detected . CONCLUSIONS: This study shows that the incorporation of CIP into liposomes can be achieved in sufficient doses by mechanical dispersion method . After intravitreal application the bioavailability of the antibiotic can be markedly improved . Even after 3 days the intravitreal levels were above the MIC90 of the most common endophthalmitis pathogens.

J Cardiovasc Nurs, 1999 Jan, 13(2), 66 - 9
Pharmacology department . Antimicrobial resistance; Gylys KH; Patients with cardiovascular disease are often predisposed to multiple infections . The degree of resistance to antibiotics that has developed in the last decade makes a significant contribution to the severity of infections in this patient population . Mechanisms for development and spread of resistance between organisms are described and related to a clinical example.

J Cardiovasc Nurs, 1999 Jan, 13(2), 23 - 30
Use of antimicrobial agents in patients with cardiovascular disease; Guglielmo BJ; Antimicrobial agents are widely utilized in the prevention and treatment of infection in patients with cardiovascular diseases . Knowledge of spectrum of activity, pharmacology, adverse effect and toxicity profile, and emergence of resistant pathogens is critical to the appropriate use of these agents . The following review will emphasize the safe, effective use of antimicrobial drugs in the cardiovascular patient.

J Cardiovasc Nurs, 1999 Jan, 13(2), 1 - 22
Pathogens, old and new: an update for cardiovascular nurses; Jackson MM et al.; Infectious diseases remain the major cause of death throughout the world, and this is not likely to change in the foreseeable future . However, there are steps that can be taken to combat them, including both the recognition of and interventions against emerging infectious diseases . This article will provide general information about emerging infectious organisms, mechanisms of resistance to antimicrobial agents, and comments on a variety of prevention strategies . In addition, the reader is directed to a number of comprehensive references for additional information.

Infect Dis Clin North Am, 1998 Dec, 12(4), 963 - 77, viii
Outpatient parenteral antibiotic therapy for fever and neutropenia; Tice AD; The treatment of fever and neutropenia following chemotherapy lends itself well to outpatient parenteral antimicrobial therapy (OPAT) . Patients prefer to be at home rather than hospitalized again . There is a clear cost advantage of outpatient therapy . With a quality program and careful patient selection, OPAT can be provided effectively and safely . The chances of an infection due to resistant bacteria also appear to be reduced . There are an increasing number of studies that support the use of empiric antibiotic therapy for the first fever in neutropenic patients . The choice of antimicrobial, dose, as well as vascular access and infusion devices must be tailored to the individual patient needs and circumstances.

Infect Dis Clin North Am, 1998 Dec, 12(4), 903 - 19
Outpatient parenteral antimicrobial therapy for osteomyelitis; Tice AD; OPAT for osteomyelitis is effective, safe, and well-established . There are particular considerations with osteomyelitis, however, that relate to patient selection and the plans of therapy . Orthopedic infections may impose physical considerations that need to be considered . Concomitant medical problems, such as diabetes, must be considered and may be good reasons for hospital care aside from the infection . Further investigations of treatment of osteomyelitis are clearly needed, with OPAT patients being good subjects to study.

Infect Dis Clin North Am, 1998 Dec, 12(4), 861 - 78, vi
Outpatient parenteral antimicrobial therapy technology; Mortlock NJ et al.; Health care costs are continuing to spiral upward despite government and public insistence on cost containment . To meet the challenge, medical professionals and organizations are seeking opportunities for cost reduction and alternatives for delivery health care . This article discusses the tools that allow the effective delivery of care using the outpatient parenteral antimicrobial therapy (OPAT) model.

Infect Dis Clin North Am, 1998 Dec, 12(4), 849 - 60, vi
Pharmacokinetics and pharmacodynamics of outpatient intravenous antimicrobial therapy; Andes D et al.; Outpatient intravenous antimicrobial therapy has been widely accepted over the past decade . Knowledge of both the pharmacokinetics of antimicrobials and the pharmacodynamics predictive of antimicrobial efficacy enables one to design reasonable outpatient intravenous regimens for most agents . This article summarizes current knowledge of the pharmacokinetics and pharmacodynamics of agents commonly used in outpatient intravenous treatment regimens.

Infect Dis Clin North Am, 1998 Dec, 12(4), 835 - 47, v-vi
Patient selection in outpatient parenteral antimicrobial therapy; Nolet BR; Outcome data as well as reported anecdotal experience over the past 20 years indicate that any infection can be safely treated with parenteral antimicrobials outside the hospital setting . However, outpatient parenteral antimicrobial therapy (OPAT) is a reasonable option only when the final decision for patient selection is based on the judgment of a knowledgeable, experienced physician, and when an experienced qualified provider is available . Criteria to be considered include clinical status, patient acceptance, ability to comply with the plan of treatment, home environment, support systems, and reimbursement . Physician direction and participation in appropriate patient selection will become increasingly important as the growth of managed care increases the importance of cost-savings.

Infect Dis Clin North Am, 1998 Dec, 12(4), 827 - 34
Evolution of outpatient parenteral antibiotic therapy; Poretz DM; The future will no doubt continue to promote safe, cost-effective therapies such as outpatient intravenous therapy . It is imperative that physicians trained and knowledgeable in the administration of outpatient intravenous antimicrobial drug administration continue to assume responsibility and leadership roles.

Rev Med Liege, 1998 Nov, 53(11), 680 - 4
{Cat-scratch disease}; Rigo F et al.; Cat-scratch disease is a subacute, regional lymphadenitis syndrome that occurs mainly in children . The causative agent is Bartonella henselae . After an incubation period ranging usually between 1 and 2 weeks, red papules develop at the site of cutaneous inoculation and persist until the development of lymphadenopathy with some malaise . Cases with complications have been observed including Parinaud oculoglandular syndrome, encephalopathy, a variety of exanthems and granumatous hepatitis . Diagnosis is based on serologic tests and, when necessary, antimicrobial treatment can be considered . Incision and drainage should not be done.

Arch Esp Urol, 1998 Nov, 51(9), 897 - 900
{A simple kidney cyst in childhood}; Morales Concepcion J et al.; OBJECTIVE: To report on a 6-year-old patient with an infected simple renal cyst . METHODS/RESULTS: A 6-year-old girl was admitted on three occasions for acute infectious syndrome and right lumboabdominal pain . The ultrasound scans showed a simple cyst in the right kidney which contained cellular elements . The patient was treated with antimicrobials on each occasion and the symptoms disappeared a few days later . On her third admission surgery was decided due to the recurrent clinical symptoms, a persistently high erythrocyte sedimentation rate and the presence of intracystic cellular elements, which raised the suspicion of intracystic abscess or tumor . The patient was submitted to surgery; the cyst was drained, resected and the internal wall marsupialized . The postoperative period was unremarkable and the patient is asymptomatic 10 months after surgery . CONCLUSION: The case described herein is uncommon; to our knowledge, a similar case has not been reported in the literature.

Arch Med Res, 1998 Winter, 29(4), 331 - 5
Empirical antimicrobial therapy in pediatric patients with neutropenia and fever . Risk factors for treatment failure; Miranda-Novales MG et al.; BACKGROUND: The use of combinations of antibiotics has been the cornerstone of therapy for febrile patients with cancer and severe neutropenia . Each empirical regimen should be selected according to the epidemiology and susceptibility patterns in each center . We describe here the experience with empirical antimicrobial treatments in pediatric patients with cancer, fever and severe neutropenia, and identify the risk factors associated with treatment failure . METHODS: This is a prospective study including 145 patients with cancer, and 171 episodes of neutropenia and fever . Blood cultures were taken before initiating empirical treatment: a) carbenicillin (400 mg/kg/day) plus amikacin (21 mg/kg/day) (Cb/ak), and b) ceftazidime (100 mg/kg/day), plus amikacin at the same dosage (Cz/ak) . RESULTS: The overall response rate was 54.9% and 56.3% for Cb/ak and Cz/ak, respectively . Fifty-seven episodes (33.3%) were microbiologically documented, gram-positive isolated in 38% and gram-negative in 49% . Risk factors associated significantly with treatment failure were acute myelocytic leukemia (AML) (RR 2.59, CI 95% 1.42-4.7, p = 0.003); bacteriological identification (RR = 4.41, CI 95% 2.21-8.8, p < 0.001), and the presence of two or more sites of infection (RR = 2.89, CI 95% 1.03-8.11, p = 0.03) . CONCLUSIONS: The rates of response are similar to the combinations used in the hospital (Cb/ak, Cz/ak) . The risk factors associated with treatment failure were AML diagnosis, bacteriological identification, and the presence of two or more sites of infection.

Ophthalmologica, 1999, 213(2), 120 - 8
Experimental intravitreal application of ciprofloxacin in rabbits; Wiechens B et al.; BACKGROUND: Ciprofloxacin (CFLX) is a fluoroquinolone antibiotic with a broad antimicrobial spectrum . This study was performed to examine the retinal toxicity of free and liposome-incorporated CFLX in rabbit eyes after intravitreal injection . MATERIALS AND METHODS: Free CFLX in doses of 100, 250, 500, 1,000 and 2,000 microg was injected into the midvitreous of rabbit eyes (n = 28) . To prolong the intravitreal antibacterial level, CFLX was incorporated into multilamellar liposomes: 0.1 ml of this suspension ( wedge 273.6 microg CFLX) was injected into the midvitreous of a second group of rabbit eyes (n = 6) . The other eye served as a control and received normal saline solution or empty liposomes, respectively . Before injection and at the end of follow-up an electroretinogram (ERG) was obtained . After a follow-up of 1, 14 and 28 days the animals were perfused with glutaraldehyde and the eyes were examined by light and transmission electron microscopy . RESULTS: Significant reduction of the ERG was observed after 2,000 microg free CFLX in 4 out of 6 eyes after 14 days . Fourteen days after injection of 2,000 microg CFLX the central retina showed pigmentary changes in 4 out of 6 eyes . In the second group the ERG as well as the histologic studies did not reveal any pathologic changes after injection of liposome-incorporated CFLX compared to the control eyes . CONCLUSION: In therapeutic doses of 100-500 microg, free CFLX does not have retinal toxicity in rabbit eyes . No retinal toxicity was observed after intravitreal injection of liposome-incorporated CFLX.

J Vet Pharmacol Ther, 1998 Dec, 21(6), 421 - 7
Effect of cephapirin and mecillinam on the phagocytic and respiratory burst activity of neutrophil leukocytes isolated from bovine blood; Dosogne H et al.; Antimicrobial therapy is the most commonly used treatment of bacterial infections in dairy cows . Polymorphonuclear neutrophil leukocytes (PMN) play an important role in the first line defence against invading bacteria and it is important that the function of PMN is not compromised by antibiotics . We investigated the in vitro effect of cephapirin, a first generation cephalosporin, and mecillinam, an amidinopenicillin with activity against mainly Gram-negative bacteria, on phagocytosis and respiratory burst activity of PMN isolated from bovine blood . After in vitro incubation of PMN with different concentrations of the antibiotics, phagocytosis was evaluated by flow cytometry and respiratory burst activity was evaluated by registration of chemiluminescence (CL) with a luminometer . None of the investigated concentrations of cephapirin and mecillinam had an effect in vitro on phagocytosis of Escherichia coli by PMN . At high concentrations (100 and 1000 microg/mL), cephapirin and mecillinam reduced the respiratory burst activity of PMN . Part of these suppressive effects could be ascribed to oxidant scavenging . Inhibitory effects of cephapirin were stronger than mecillinam . In conclusion, cephapirin and mecillinam did not seem to affect antibacterial activity of PMN isolated from bovine blood in vitro at therapeutic concentrations.

Nucl Med Commun, 1998 Dec, 19(12), 1117 - 21
Radiolabelled antimicrobial peptides for imaging of infections: a review; Nibbering PH et al.; At present, it is difficult to distinguish between bacterial infections and sterile inflammatory processes using radiopharmaceuticals . This is so for a variety of reasons, including binding to bacteria with low affinity (e.g . infection) and binding to a specific micro-organism (e.g . radiolabelled monoclonal antibodies or F(ab)2 fragments thereof against micro-organisms) . In this review, we propose that radiolabelled antimicrobial peptides should be the first choice in the development of new radiopharmaceuticals for imaging of bacterial infections . Antimicrobial peptides are a recently discovered component of the innate defence system of plants, animals and humans . These peptides, which now number more than 100, with proven microbicidal activity against a variety of micro-organisms, share certain properties, such as their small size and cationic charge . The latter allows them to bind preferentially to a broad spectrum of micro-organisms . We have recently demonstrated that radiolabelled human defensins allow the rapid visualization of bacterial infections in mice . Furthermore, binding of this antimicrobial peptide to bacteria is the major factor contributing to the accumulation of this tracer in bacterial infections . Based on these considerations, we believe that radiolabelled antimicrobial peptides will be an important asset in the imaging of infections in patients.

Mol Plant Microbe Interact, 1999 Jan, 12(1), 16 - 23
Snakin-1, a peptide from potato that is active against plant pathogens; Segura A et al.; A new type of antimicrobial peptide, snakin-1 (SN1), has been isolated from potato tubers and found to be active, at concentrations < 10 microM, against bacterial and fungal pathogens from potato and other plant species . The action of SN1 and potato defensin PTH1 was synergistic against the bacterium Clavibacter michiganensis subsp . sepedonicus and additive against the fungus Botrytis cinerea . Snakin-1 causes aggregation of both gram-positive and gram-negative bacteria . The peptide has 63 amino acid residues (M(r) 6,922), 12 of which are cysteines, and is unrelated to any previously isolated protein, although it is homologous to amino acid sequences deduced from cloned cDNAs that encode gibberellin-inducible mRNAs and has some sequence motifs in common with kistrin and other hemotoxic snake venoms . A degenerate oligonucleotide probe based on the internal sequence CCEECKC has been used to clone an SN1 cDNA . With the cDNA used as probe, one copy of the StSN1 gene per haploid genome has been estimated and expression of the gene has been detected in tubers, stems, axillary buds, and young floral buds . Expression levels in petals and carpels from fully developed flowers were much higher than in sepals and stamens . The expression pattern of gene StSN1 suggests that protein SN1 may be a component of constitutive defense barriers, especially those of storage and reproductive plant organs.

Z Kardiol, 1998 Nov, 87(11), 851 - 64
The role of reactive oxygen species in atherosclerosis; Mugge A; Reactive oxygen species (ROS) are probably not only unintended, toxic side-products of oxygen metabolism in mammalian cells, they also have several important physiologic functions including antimicrobial killing, regulation of cellular proliferation and growth, and regulation of vascular tone . ROS are generated within the vessel wall by several mechanisms, including a vascular type of a NAD(P)H oxidase . ROS formation can be stimulated by mechanical stress, environmental factors, the peptide angiotensin II, cytokines, native low-density lipoproteins (LDL), and in the presence of catalytic metal ions . Their ability to modify LDL, react with endothelial-derived nitric oxide subsequently forming peroxynitrite, and amplify the expression of various genes important for leukocyte recruitment within the arterial wall are the basis of the oxidant injury theory of atherosclerosis . In animal studies, antioxidant therapy (probucol, butylated hydroxytoluene, N', N'-diphenylenediamide, vitamin E, superoxide dismutase) have been successfully used to prevent fatty streak formation, and to restore impaired nitric oxide-dependent vasorelaxation . In man, antioxidant therapy (e.g., supplementation with vitamin E) clearly increased the resistance of LDL to oxidative modification . Case-controlled and prospective clinical studies suggest a relation between baseline antioxidant plasma levels and/or antioxidant supplementation and risk of cardiovascular events . In one secondary prevention trial (randomized, blinded, placebo-controlled), vitamin E supplementation reduced significantly the risk for non-fatal myocardial infarctions . Before general recommendations can be made, results of further large-scale trials should be awaited.

J UOEH, 1998 Dec 1, 20(4), 361 - 8
{Emergence of new-risk factors associated with nosocominal infection}; Udou T; During the last several decades, we have experienced the emerging and reemerging of infectious pathogens and diseases . The outbreaks of infection due to these pathogens sometimes occur via the sources and/or routes which have not been recognized during previous studies on epidemiology and pathogenesis of the diseases . There are many factors contributing to the increase in infectious diseases . Namely, medical progress often results in an increasing number of immunocompromised patients . Common, usually avirulent, commensal and environmental organisms become pathogens to these patients . The evolution of organisms acquiring resistance to antimicrobial agents, disinfectants, and environmental stimuli also relates to the high incidence of nosocominal (hospital-acquired) infections as well as to the clinical situation of the patients . Because of these tendencies, as risks of nosocominal infections, are characteristic especially in major health care centers such as large teaching hospitals, most health care workers are obliged to participate actively in control and preventive efforts in addition to their traditional roles . In this review I discuss the recent characteristics of nosocominal pathogens and the environments surrounding the hospitalized patients to design effective strategies for and to facilitate the infection control activities.

Drugs Aging, 1998 Dec, 13(6), 443 - 65
Streptogramins and their potential role in geriatric medicine; Lomaestro BM et al.; Despite advances in antimicrobial chemotherapy over recent decades, morbidity and mortality secondary to infection continues to rise . In addition, the incidence of infection caused by resistant organisms has also increased . Concurrently, the elderly are living longer than prior generations, often with disabling chronic diseases . The more debilitated of the geriatric population are at greater risk for infection, and more likely to acquire or develop antimicrobial resistant organisms . Gram-positive organisms are a source of resistance and commonly cause infection in older patients . Whereas resistance is a concern in all patients, in the elderly this is magnified by limitations in treatment options because of differences in pharmacokinetics and tolerance as compared with younger counterparts . Pharmacokinetic differences include changes in drug distribution and may arise as a result of diminished end organ function . Age-related decreases in renal function often impact on commonly prescribed antimicrobials . In addition, the elderly are more susceptible to drug-drug interactions because polypharmacy is common in this patient population . Streptogramins may offer a useful alternative in the treatment of infections in the elderly due to their coverage of organisms commonly causing infections in this population and because of their favourable pharmacokinetic profiles . While published experience is limited, streptogramins are not appreciably eliminated by the kidney and, therefore, they are less subject to age-related changes in renal elimination . What is required is multi-dose pharmacokinetic analysis of streptogramins in geriatric populations and subset analysis of patient use data on file . The following will provide the reader with the most recently presented data on streptogramin use and their potential . While focusing on potential use in the elderly, we have cited data and issues which we believe will be relevant in the geriatric population.

Arch Biochem Biophys, 1999 Jan 1, 361(1), 127 - 34
Conformation and antimicrobial activity of linear derivatives of tachyplesin lacking disulfide bonds; Rao AG; Tachyplesin is a potent antimicrobial peptide isolated from the hemocytes of the horseshoe crab, Tachypleus tridentatus . Previous studies have shown that the 17-residue peptide has an intrinsic amphipathic structure conferred by two antiparallel beta-sheets held rigidly by two disulfide bonds . Taking its short length into account and the potential of such a small polypeptide to take on multiple conformational states, one may assume that the disulfide bonds are relevant determinants of function . However, in order to gain a global perspective on the tolerance of cysteine residues in tachyplesin to amino acid substitutions, a series of linear peptides have been synthesized and their physicochemical properties analyzed . In these linear peptides, the cysteines have been replaced with amino acids possessing different side-chain properties, i.e., aliphatic hydrophobic (Ala, Leu, Ile, Val, and Met), aromatic hydrophobic (Phe and Tyr), and acidic (Asp) . Activity assays using natural and synthetic membranes, and conformational measurements, highlight the subtle influence and variability of the amino acid side-chain properties on peptide structure . While an unequivocal interpretation of the results will have to await more refined structural measurements, our results indicate that a rigidly held disulfide-bonded beta-pleated sheet structure may not be absolutely essential for antimicrobial activity . Furthermore, the results challenge the accepted dogma of structure-activity relationships among antimicrobial peptides and suggest that the maintenance of peptide hydrophobic-hydrophilic balance may be a critical parameter, in addition to structure, in the design of peptides with pharmaceutical relevance .

Burns, 1998 Nov, 24(7), 604 - 8
Antimicrobial mixtures used by tissue banks for harvested skin: comparative in vitro activity; Holder IA et al.; The activities of antimicrobial combinations from three geographically diverse skin/tissue banks used in the processing of skin/ tissue were compared using bacteria and yeast isolated from burn patients . All formulations showed 90% or more effectiveness against bacteria generally susceptible to antibiotics but were less effective (60-80%) when tested against bacteria resistant to specific antimicrobials . Anti-yeast activity was present when an appropriate antifungal agent was included in the combination . All formulations were stable for at least six weeks . Results of this study raise certain questions about the use of these antimicrobial combinations in contemporary skin/tissue banking and point the way toward areas for future study.

Aliment Pharmacol Ther, 1998 Dec, 12(12), 1175 - 84
Review article: factors influencing antibiotic transfer across the gastric mucosa; Goddard AF; The delivery of antimicrobial drugs to Helicobacter pylori within the stomach is poorly understood . The gastric environment represents a unique pharmacokinetic compartment, into which drug can be delivered directly following oral administration, or indirectly following intestinal absorption and transfer from the blood into the stomach across the gastric mucosa . Several methods have been used to study drug disposition across the gastric mucosa, including endoscopic biopsy studies, nasogastric intubation studies and animal models . Direct, or topical, delivery is limited by luminal drug degradation, drug formulation and the permeability of the mucus layer . Indirect, or systemic, delivery is limited by factors affecting the concentration gradient across the gastric mucosa and the permeability of the mucosa . These factors include intragastric pH, plasma protein binding, drug lipophilicity, the presence of active transport mechanisms, drugs that damage the gastric mucosa and inflammation secondary to H . pylori infection . Little is known about the last of these, and further research in this area should help in the rational approach to development of treatments against H . pylori.

Acta Ophthalmol Scand, 1998 Dec, 76(6), 683 - 5
Penetration of oral and topical ciprofloxacin into human aqueous humor; Celebi S et al.; PURPOSE: This study was planned to investigate the penetration of ciprofloxacin into aqueous humor following oral and topical application as a prophylactic antimicrobial agent . METHODS: Forty-six patients undergoing cataract surgery were randomly divided into two groups . In the first group, the patients received 500 mg oral ciprofloxacin eight hours before surgery and in the second, 5 drops of 0.3% ciprofloxacin were applied to the patients every twenty minutes, starting 100 minutes before the surgery . By paracentesis, aqueous samples were taken just before the operation so the interval between the first topical application and paracentesis was 100 minutes . RESULTS: The mean concentration of ciprofloxacin in aqueous humor was 0.63+/-0.29 microg/ml in the first group . The concentration was 0.69+/-0.30 microg/ml in the second group . Both of these mean concentrations were higher than the levels of MIC90 of S.aureus , S . epidermidis, P . aeruginosa and Gram (-) bacteriae . CONCLUSION: As a result, both topically and orally applied ciprofloxacin achieved a significant aqueous concentration . Each route studied might be suitable for surgical prophylaxis or treatment of infections.

Dig Dis Sci, 1998 Dec, 43(12), 2750 - 6
Antibiotic properties of bovine lactoferrin on Helicobacter pylori; Dial EJ et al.; To investigate a potential new treatment for gastric Helicobacter pylori infection, we have examined the use of the natural antibiotic lactoferrin, found in bovine milk, for activity against Helicobacter species both in vitro and in vivo . Lactoferrin was bacteriostatic to H . pylori when cultured at concentrations > or =0.5 mg/ml . Growth of H . pylori was not inhibited by another milk constituent, lysozyme, or by a metabolite of lactoferrin, lactoferricin B, but growth was inhibited by the iron chelator deferoxamine mesylate . Lactoferrin inhibition of growth could be reversed by addition of excess iron to the medium . Lactoferrin in retail dairy milk was found to be more stable intragastrically than unbuffered, purified lactoferrin . Treatment of H . felis-infected mice with lactoferrin partially reversed mucosal disease manifestations . It is concluded that bovine lactoferrin has significant antimicrobial activity against Helicobacter species in vitro and in vivo . Bovine lactoferrin should be further investigated for possible use in H . pylori infections in man.

Zentralbl Chir, 1998, 123 Suppl 4, 82 - 4
{Antibiotic prophylaxis in appendectomy . Often neglected--but necessary!}; Hell K; For several decades it has been proven that adequate antimicrobial prophylaxis is effective in reducing postoperative septic complications also in appendectomy . The rational for this approach--including laparoscopic procedures--is discussed and national and international recommendations for antibiotic prophylaxis in appendectomy are cited . Unfortunately, in spite of all the evidence, less than 50% of all appendectomies in 1996 in Germany had been carried out under antibiotic cover--with serious consequences for many patients and increased costs for prolonged hospital stay and treatment due to the higher incidence of infectious postoperative complications . Surgeons are encouraged not to neglect facts and benefits concerning the use of appropriate prophylactic antimicrobials in all appendectomies.

Clin Microbiol Rev, 1999 Jan, 12(1), 147 - 79
Antiseptics and disinfectants: activity, action, and resistance; McDonnell G et al.; Antiseptics and disinfectants are extensively used in hospitals and other health care settings for a variety of topical and hard-surface applications . A wide variety of active chemical agents (biocides) are found in these products, many of which have been used for hundreds of years, including alcohols, phenols, iodine, and chlorine . Most of these active agents demonstrate broad-spectrum antimicrobial activity; however, little is known about the mode of action of these agents in comparison to antibiotics . This review considers what is known about the mode of action and spectrum of activity of antiseptics and disinfectants . The widespread use of these products has prompted some speculation on the development of microbial resistance, in particular whether antibiotic resistance is induced by antiseptics or disinfectants . Known mechanisms of microbial resistance (both intrinsic and acquired) to biocides are reviewed, with emphasis on the clinical implications of these reports.

Peptides, 1998, 19(10), 1653 - 8
Antimicrobial activity and conformation of gaegurin-6 amide and its analogs; Lee KH et al.; A function of the intra-disulfide bridge located at the C-terminal of Rana peptides has not been extensively studied . To investigate the function of the disulfide bridge related to the activity and the structure, we chose Gaegurin-6, isolated from Rana rugosa as a model peptide and synthesized linear analogs . The reduction of the disulfide bridge resulted in the complete loss of antimicrobial activity while replacements of cysteines by serines retained antimicrobial activity . Circular dichroism spectra from a titration of the peptides in sodium dodecyl sulfate indicated that the disulfide bridge of Gaegurin-6 might stabilize the induction of an alpha helical structure in lipid membranes and the alpha helical forming propensity of the peptides correlated with antimicrobial activity.

Eur J Cardiothorac Surg, 1998 Dec, 14(6), 572 - 4
War injuries to the thoracic esophagus; Ilic N et al.; OBJECTIVE: Presentation of our experience in the treatment of war injuries to the thoracic esophagus at the Split University Hospital, Croatia, during the 1991-1995 wars in Croatia and Bosnia-Herzegovina . METHODS: Retrospective analysis of clinical and surgical data on patients with war injuries to the esophagus . RESULTS: Of 2494 treated injured persons, 5 patients (0.2%) had injuries to the esophagus . We performed temporary double-exclusion of the esophagus in all our patients, followed by gastric interposition after partial esophagegtomy in three patients and simple suturing with pericardial protection of the esophagus in one patient . One of our patients died after double-exclusion due to septic complications in spite of antimicrobial chemoprophylaxis regularly performed in all injured persons . Final surgical outcome and mortality rate (20%) in our patients were quite satisfactory . CONCLUSION: Prompt transportation, appropriate diagnostic methods and an adequate surgical treatment can markedly reduce mortality and complications rate in war injuries to the thoracic esophagus.

Pharmazie, 1998 Dec, 53(12), 839 - 43
Synthesis and antimicrobial activity of pyrazolo{3',4':4,3}pyrido{6,5-c}pyridazine and thieno{2,3-c}pyridazine derivatives; el-Dean AM et al.; 4-Acetyl-5,6-diphenyl-2(H)pyridazine-3-one (1) was allowed to react with phenyl hydrazine to afford the corresponding hydrazone 2 . Hydrazone 2 upon treatment with Vilsmeier's reagent gave pyrazolylpyridazine derivative 3, which was allowed to react with thiosemicarbazide and hydroxyl amine to give the corresponding thiosemicarbazone and oxime 4 and 5, respectively . Treatment of oxime 5 with Ac2O gave the pyrazolylpyridazine carbonitrile derivative 6 . Compound 5 reacts with POCl3 to give the corresponding chloro compound 7 . The chloro compound 7 was reacted with hydrazine hydrate or aniline to afford pyrazolopyridazodiazepine 9 or pyrazolopyridazopyridazine 10 . When compound 1 was allowed to react with POCl3 the chloro derivative 11 resulted . This compound reacts with thiourea, piperidine or hydrazine hydrate to give compounds 12, 14 and 15, respectively . Compound 12 reacted with alpha-haloester or alpha-haloketone to give the thienopyridazines 13a and b, respectively . Most of the newly synthesized compounds were screened for fungicidal and bactericidal activity.

N Engl J Med, 1999 Jan 7, 340(1), 1 - 8
A comparison of two antimicrobial-impregnated central venous catheters . Catheter Study Group; Darouiche RO et al.; BACKGROUND: The use of central venous catheters impregnated with either minocycline and rifampin or chlorhexidine and silver sulfadiazine reduces the rates of catheter colonization and catheter-related bloodstream infection as compared with the use of unimpregnated catheters . We compared the rates of catheter colonization and catheter-related bloodstream infection associated with these two kinds of antiinfective catheters . METHODS: We conducted a prospective, randomized clinical trial in 12 university-affiliated hospitals . High-risk adult patients in whom central venous catheters were expected to remain in place for three or more days were randomly assigned to undergo insertion of polyurethane, triple-lumen catheters impregnated with either minocycline and rifampin (on both the luminal and external surfaces) or chlorhexidine and silver sulfadiazine (on only the external surface) . After their removal, the tips and subcutaneous segments of the catheters were cultured by both the roll-plate and the sonication methods . Peripheral-blood cultures were obtained if clinically indicated . RESULTS: Of 865 catheters inserted, 738 (85 percent) produced culture results that could be evaluated . The clinical characteristics of the patients and the risk factors for infection were similar in the two groups . Catheters impregnated with minocycline and rifampin were 1/3 as likely to be colonized as catheters impregnated with chlorhexidine and silver sulfadiazine (28 of 356 catheters {7.9 percent} vs . 87 of 382 {22.8 percent}, P<0.001), and catheter-related bloodstream infection was 1/12 as likely in catheters impregnated with minocycline and rifampin (1 of 356 {0.3 percent}, vs . 13 of 382 {3.4 percent} for those impregnated with chlorhexidine and silver sulfadiazine; P<0.002) . CONCLUSIONS: The use of central venous catheters impregnated with minocycline and rifampin is associated with a lower rate of infection than the use of catheters impregnated with chlorhexidine and silver sulfadiazine.

Chemotherapy, 1999 Jan-Feb, 45(1), 8 - 14
Prevalence of antimicrobial resistance in eighty clinical isolates of Helicobacter pylori; Iovene MR et al.; We studied the in vitro susceptibility of 80 Helicobacter pylori clinical isolates to several antimicrobials commonly used to treat the infection, using the Epsilometer test (E-test) . We also compared E-test and disk diffusion test in determining H . pylori susceptibility to the same antibiotics . We found a high prevalence of H . pylori strains resistant to metronidazole (23.7%), whereas the prevalence of H . pylori strains resistant to clarithromycin was 10% . Also, a significant correlation was found between MICs obtained with the disk diffusion test and E-test for metronidazole and clarithromycin . In conclusion, our study confirms a high prevalence of metronidazole- or clarithromycin-resistant H . pylori strains . Also, our data suggest that the E-test is a single, reliable, and cost-effective method to assess in vitro susceptibility of H . pylori to antimicrobial agents commonly used to eradicate the infection.

Avian Dis, 1998 Oct-Dec, 42(4), 738 - 45
In vitro and in vivo comparisons of valnemulin, tiamulin, tylosin, enrofloxacin, and lincomycin/spectinomycin against Mycoplasma gallisepticum; Jordan FT et al.; The minimum inhibitory concentrations (MICs) for valnemulin, tiamulin, enrofloxacin, tylosin, and lincomycin/spectinomycin were determined for a virulent strain of Mycoplasma gallispeticum (MG) . At the initial reading, the lowest MICs were seen with valnemulin and tiamulin, followed by tylosin, enrofloxacin, and a relatively high MIC for lincomycin/spectinomycin . At the final reading, at 14 days, a similar pattern was obtained, with valnemulin giving the lowest MIC (< 0.008 mg/ml) . The same strain of MG was used to infect groups of 20 2-day-old chicks in two separate experiments . In both, several concentrations of valnemulin and tiamulin and one each of tylosin and enrofloxacin were administered to separate groups in the drinking water . In the second experiment, one group of chicks was given lincomycin/spectinomycin . Each experiment had one infected unmedicated group and an uninfected unmedicated group . Mortality, clinical signs, and gross lesions, in both experiments, were significantly less (P < 0.001) in the uninfected and infected medicated groups (except for the two lowest dosages of valnemulin, lincomycin, and spectinomycin) than in the infected unmedicated groups . Also, the mean body weight gain was greater in the uninfected and infected medicated groups . Among the infected birds, MG was recovered from fewer chicks in the infected medicated groups except for the lowest two dosages of valnemulin . Serologic results were negative for the uninfected groups, and there were fewer positive reactors for the infected medicated groups except for the group treated with lincomycin/spectinomycin . Valnemulin should prove to be a useful addition to the antimicrobials in the control of MG infection in chickens.

Ann Pharmacother, 1998 Dec, 32(12), 1310 - 6
Infection and atherosclerosis--focus on cytomegalovirus and Chlamydia pneumoniae; Cheng JW et al.; BACKGROUND AND OBJECTIVE: Numerous studies have reported an association of coronary atherosclerosis and restenosis with certain bacterial and viral infections . This article reviews the pathophysiology of atherosclerosis, the role of infectious agents (i.e, cytomegalovirus and Chlamydia pneumoniae) in atherogenesis, and studies supporting the potential beneficial effects of antibiotics or antiviral agents in the management of atherosclerotic disease . DATA SOURCES: English-language clinical studies, abstracts, and review articles pertaining to infectious agents and coronary atherosclerosis . STUDY SELECTION AND DATA EXTRACTION: Relevant seroepidemiologic and pathologic studies and animal models evaluating the role of cytomegalovirus or C . pneumoniae in coronary atherosclerosis . DATA SYNTHESIS: Studies evaluating the possible role of cytomegalovirus and C . pneumoniae in the pathogenesis of atherosclerosis, as well as studies examining the use of antimicrobial and antiviral agents for reduction of cardiovascular events, are reviewed and critiqued . CONCLUSIONS: Current data do not allow us to determine whether infection is a cause or a cofactor of atherosclerosis . These uncertainties can be resolved by larger scale seroepidemiologic, pathologic, and interventional studies . Such efforts will contribute to identifying populations that are appropriate for particular surveillance or specific interventions, such as antibiotics or antiviral therapy.

Anaesth Intensive Care, 1998 Dec, 26(6), 648 - 53
The use of antimicrobials in ten Australian and New Zealand intensive care units . The Australian and New Zealand Intensive Care Multicentre Studies Group Investigators; Bellomo R et al.; A prospective standardized collection of clinical, microbiological and pharmaceutical information on antibiotic use was conducted in Australia and New Zealand intensive care units (ICUs) involving 481 consecutive critically ill patients who were receiving antibiotics for any reason while in ICU . Patients had a mean SAPS II score of 34.1 +/- 17.8 with an expected mortality of 15.6% (actual mortality 12%) . Of these, 292 (60.8%) were admitted to the ICU within 72 hours of surgery . Among such surgical patients, 233 (79.9%) received antibiotics for "surgical prophylaxis" while in ICU (48% of sample population) . The second largest group of patients treated with antibiotics in ICU included those with systemic inflammatory response syndrome and clinical suspicion of infection (38%) . Antibiotics were prescribed for the treatment of clinically diagnosed infection in 268 patients . Clinical response was apparent in 62.6% and in most (71%) was achieved in the first 72 hours of treatment . The incidence of antimicrobial-related side-effects was 4%, mostly in the form of diarrhoea or rash (75% of all side-effects) . The most commonly prescribed antimicrobials were gentamicin (n = 146), ceftriaxone (n = 98), vancomycin (n = 94) and metronidazole (n = 111) . Three times daily prescription of aminoglycosides was uncommon (< 1%) . Forty-one patients had a documented infection (positive culture) with a gram-negative organism . Of these, 17 received therapy with a single antibiotic and 24 received therapy with two antibiotics . Despite similar illness severity, there were six deaths in the former group and only two in the latter.

Drug Dev Ind Pharm, 1998 Sep, 24(9), 879 - 82
Preparation and evaluation of erythromycin fumarate--a new derivative of erythromycin; Manna PK et al.; Erythromycin fumarate, a new water-soluble derivative of erythromycin, was prepared and its physicochemical and biological properties were evaluated . The derivative also has considerable solubility in organic solvents . Its partition coefficient data in different organic solvent-water systems may indicate that it is well-distributed in various tissues in vivo . Antimicrobial potency in vitro of the derivative, 725 micrograms/mg, is much higher than that of the existing derivatives and its antimicrobial spectrum is comparable to that of the parent antibiotic . The LD50 value of the new derivative in mice intraperitoneally is 402.7 mg/kg . Results of this and the previous investigation on pharmacokinetics and protein binding indicate that erythromycin fumarate has high potential for possible clinical application and further investigation may be undertaken.

J Pathol, 1998 Sep, 186(1), 99 - 103
Localization of expression of human beta defensin-1 in the pancreas and kidney; Schnapp D et al.; Defensins are antimicrobial peptides which play a key role in innate immunity . High levels of human beta defensin-1 (hBD-1) have previously been detected in the kidney and pancreas, but the cell-specific location of hBD-1 mRNA has not been determined . The expression of hBD-1 mRNA has been examined in fetal and adult pancreas and kidney by mRNA in situ hybridization . In fetal pancreas, hBD-1 expression was detected in the developing acini and in adult pancreas in the acini, but not in the pancreatic ducts . In both fetal and adult kidney, hBD-1 expression was detected in the collecting ducts and in the loops of Henle in adult kidney . Expression of hBD-1 mRNA in the pancreas and kidney from early development and in the acini of the adult pancreas, rather than in the pancreatic ducts, may indicate that in these tissues, hBD-1 fulfils physiological functions in addition to host defence.

J Chemother, 1998 Dec, 10(6), 427 - 48
Antibiotic-induced release of bacterial cell wall components in the pathogenesis of sepsis and septic shock: a review; Periti P et al.; This article reviews the new criteria for selecting the proper antimicrobial agent and dosage regimen for standard treatment of severe sepsis, with the intention of preventing septic shock . After introducing new concepts on the pathogenesis of sepsis and septic shock, the authors analyze the parameters of betalactam antibacterial activity, the antibiotic-induced release of bacterial endotoxin and the interrelationships between pharmacokinetics and pharmacodynamics of antibiotics in the search for an optimum dosage regimen of antimicrobial mono- or polytherapy for severely ill septic patients admitted to the intensive care unit.

AIDS, 1998 Dec 24, 12(18), 2439 - 46
A phase II/III trial of antimicrobial therapy with or without amikacin in the treatment of disseminated Mycobacterium avium infection in HIV-infected individuals . AIDS Clinical Trials Group Protocol 135 Study Team; Parenti DM et al.; OBJECTIVE: To determine the clinical and microbiologic benefit of adding amikacin to a four-drug oral regimen for treatment of disseminated Mycobacterium avium infection in HIV-infected patients . DESIGN: A randomized, open-labeled, comparative trial . SETTING: Outpatient clinics . PATIENTS: Seventy-four patients with HIV and symptomatic bacteremic M . avium infection . INTERVENTIONS: Rifampin 10 mg/kg daily, ciprofloxacin 500 mg twice daily, clofazimine 100 mg every day, and ethambutol 15 mg/kg orally daily for 24 weeks, with or without amikacin 10 mg/kg intravenously or intramuscularly 5 days weekly for the first 4 weeks . MAIN OUTCOME MEASURE: Clinical and microbiologic response at 4 weeks; quantitative level of bacteremia with M . avium . RESULTS: No difference in clinical response was noted with the addition of amikacin to the four-drug oral regimen, and only 25% in either group had a complete or partial response at 4 weeks . A comparable quantitative decrease in bacteremia was noted in both treatment groups, with 16% of patients being culture-negative at 4 weeks and 38% at 12 weeks . Toxicities were mainly gastrointestinal . Amikacin was well tolerated . Median survival was 30 weeks in both groups . CONCLUSIONS: The addition of amikacin to a four-drug oral regimen of rifampin, ciprofloxacin, clofazimine, and ethambutol did not provide clinical or microbiologic benefit.

Arch Pharm Res, 1998 Oct, 21(5), 591 - 4
Structural analogues of cumambrin B from the flower of Chrysanthemum boreale; Jang DS et al.; The structural analogues of cumambrin B (1, 2, 3, 4) were isolated from the flower of Chrysanthemum boreale Makino . The structures of compounds were determined by two-dimensional 1H-1H COSY and 13C-1H COSY spectra with the aid of homonuclear and heteronuclear double resonance experiment . The stereochemistry of compounds has been verified from single crystal X-ray diffraction of cumambrin A (2) . The antimicrobial activities of these guaianolides have been studied.

Arch Pharm Res, 1998 Jun, 21(3), 278 - 85
Screening of new bioactive materials from microbial extracts of soil microorganism (I) . Antimicrobial activity from 200 samples using microdilution assay; Jung SO et al.; The microdilution assay recommended by NCCLS (National Committee for Clinical Laboratory Standards) is one of the standardized methods of antibiotic susceptibility test . This method has been widely used clinically to obtain MIC values of antibiotics on pathogenic microorganisms . It is more convenient, rapid and simple to test many samples than other test methods such as agar diffusion assay and broth macrodilution assay . The screening of antimicrobial agents from microbial extracts is too laborious in its process . Therefore, a number of screening methods having more simple procedure have been developed . In our laboratory, we applied microdilution assay for screening the antimicrobial agents . This assay showed dose-response results and was more sensitive than disc diffusion assay in our system . We tested 200 samples of microbial extracts originated from 100 microbial strains and selected several samples as potential candidates . In this report, we show that the microdilution assay is more convenient method in screening of antibiotic susceptibility than those previously reported.

J Food Prot, 1998 Dec, 61(12), 1597 - 601
Occurrence and survival of verocytotoxin-producing Escherichia coli O157 in raw cow's milk in The Netherlands; Heuvelink AE et al.; From May through November 1997, 1,011 samples of raw milk from bulk storage tanks were examined for the presence of verocytotoxin-producing Escherichia coli of serogroup O157 (O157 VTEC) by immunomagnetic separation following selective enrichment . The samples originated from 1,011 different dairy herds located throughout the Netherlands . O157 VTEC was not isolated from any of the milk samples examined . Additionally, survival of O157 VTEC in raw and UHT-sterilized cow's milk at 7 and 15 degrees C was studied, both in the absence and presence of an activated lactoperoxidase-thiocyanate-hydrogen peroxide system (LPS) . Results indicated that the O157 VTEC strain tested was able to grow in raw milk at 7 degrees C as well as at 15 degrees C . Naturally occurring amounts of thiocyanate and hydrogen peroxide in the raw milk tested were not sufficient to activate the LPS . Although the LPS exhibited an antimicrobial activity against O157 VTEC in LPS-activated sterilized milk, O157 VTEC populations were not (or not as obviously) reduced in LPS-activated raw milk . Possibly background microflora were more sensitive to the LPS than the O157 VTEC test strain . It was concluded that raw milk contaminated with O157 VTEC will remain a hazard if kept at 7 or 15 degrees C . Effective pasteurization and avoiding postpasteurization contamination are necessary to ensure the safety of milk.

Front Biosci, 1999 Jan 01, 4, D43 - 62
Bacterial plasmids: replication of extrachromosomal genetic elements encoding resistance to antimicrobial compounds; Actis LA et al.; Plasmids are self-replicating extrachromosomal DNA molecules found in Gram-negative and Gram-positive bacteria as well as in some yeast and other fungi . Although most of them are covalently closed circular double-stranded DNA molecules, recently linear plasmids have been isolated from different bacteria . In general, plasmids are not essential for the survival of bacteria, but they may nevertheless encode a wide variety of genetic determinants, which permit their bacterial hosts to survive better in an adverse environment or to compete better with other microorganisms occupying the same ecological niche . The medical importance of plasmids that encode for antibiotic resistance, as well as specific virulence traits has been well documented and demonstrated the important role these bacterial genetic elements play in nature . Although they encode specific molecules required for initiation of their replication, plasmids rely on host-encoded factors for their replication . Plasmid replication initiates in a predetermined cis-site called ori and can proceed either by a rolling circle or a theta replication mechanism . Some of the plasmid-encoded elements required for their replication, such antisense RNA molecules and DNA repeated sequences located close to ori, determine plasmid attributes like copy number and incompatibility.

J Clin Gastroenterol, 1998, 27 Suppl 1, S163 - 9
Helicobacter pylori infection, chronic gastritis, and proton pump inhibitors; Dattilo M et al.; The proton pump inhibitors (PPIs) omeprazole, lansoprazole, and pantoprazole are widely used as antisecretory drugs and, in association with antibiotics, for the treatment of Helicobacter pylori infections . PPIs possess antibacterial activity against H . pylori in vitro, and may also exert an anti-inflammatory effect by interfering with the cellular immune response to infection . Their antimicrobial activity is selective for H . pylori . Lansoprazole is the most effective, although its bactericidal activity is similar to that of omeprazole . Pantoprazole is the least effective . The mechanisms that account for the antibacterial effects of PPIs may depend on a structural similarity of PPIs to antibiotics which are active against H . pylori, on the inhibition of bacterial urease exerted by PPIs, or on the possible interaction of PPIs with bacterial ATPases that regulate the transmembrane ion flux . Recent studies have shown that PPIs have anti-inflammatory actions and can interfere with the host-bacteria interactions . Lansoprazole can bind to polymorphonuclear leukocytes that infiltrate the gastric mucosa colonized by H . pylori and can thus inhibit the oxidative burst of activated inflammatory cells . In an in vivo study, lansoprazole reduced the degree of activity of histologic gastritis independently of the presence of H . pylori . In another study, omeprazole was capable of inhibiting the cytotoxic activity of NK T cells . Investigation of PPI interactions with H . pylori activities and the cellular immune response to the infection may help us to understand the pathogenic mechanisms of H . pylori-associated diseases and enable clinicians to better treat them.

Bioorg Med Chem Lett, 1998 Jun 2, 8(11), 1307 - 12
Anti-Helicobacter pylori agents . 2 . Structure activity relationships in a new series of 2-alkylguanidino-4-furylthiazoles; Katsura Y et al.; SAR for antimicrobial activity against H . pylori was investigated in a new series of 2-alkylguanidino-4-furylthiazoles . Of the compounds obtained, cyclohexylmethyl and ethoxyethyl derivatives were identified as a novel class of anti-H . pylori agents which possessed potent and selective antimicrobial activity against H . pylori . These compounds also showed gastric antisecretory activity.

Bioorg Med Chem Lett, 1998 Apr 21, 8(8), 945 - 50
Peptide inhibitors of N-succinyl diaminopimelic acid aminotransferase (DAP-AT): a novel class of antimicrobial compounds; Cox RJ et al.; Dipeptide substrates of N-Succinyl Diaminopimelic Acid Aminotransferase (DAP-AT) were converted to hydrazines by treatment with hydrazine and cyanoborohydride . These compounds were tested in vitro as inhibitors of DAP-AT from E . coli and in vivo as antibiotics . The hydrazino-dipeptides showed potent slow binding slow binding inhibition of DAP-AT as well as antimicrobial activity.

Biomaterials, 1998 Nov, 19(22), 2065 - 74
Investigation of a rifampin, fusidic-acid and mupirocin releasing silicone catheter; Schierholz JM et al.; After strict hygienical measures have been exhausted the use of plastic materials with antibacterial activity may reduce catheter related-bacterial colonization . An antimicrobial silicone catheter was investigated by HPLC-measurement, SEM, antimicrobial assays and standard biocompatibility tests . The modified catheter was highly biocompatible and the antimicrobial leaching non-toxic . The initially release rate was governed by the drug solubility in the 'sink' and surface loading ('burst effect') . The second continuous period depended on the drug velocity in the silicone matrix and was extended up to 100 days with a proportionality to square root of t for each drug . Diffusion exponents were in range of 2 x 10(-8) to 1 x 10(-9) (cm2 sec(-1)) . The lower diffusion exponent of mupirocin was explained by its higher cohesion energy and lower physico-chemical compatibility with the embedding silicone . The antimicrobial drugs were in a molecular-dispersed state with the silicone-matrix, whereas superficially located crystals of the antibiotics covering the catheter surface could be demonstrated by SEM.

J Heart Valve Dis, 1998 Nov, 7(6), 633 - 8
Evaluation of a novel bioprosthetic heart valve incorporating anticalcification and antimicrobial technology in a sheep model; Langanki D et al.; BACKGROUND AND AIM OF THE STUDY: The St . Jude Medical (SJM) Epic valve has been designed to diminish the risk of prosthetic valve endocarditis by the use of silver-coated polyester fabric, and to inhibit dystrophic calcification by the use of ethanol pretreatment . METHODS: A 20-week juvenile sheep mitral valve implant model was used to determine safety and efficacy of the device, as well as the rate of silver release and degree of dystrophic calcification . The SJM Epic valves were compared with SJM Biocor porcine valves (not ethanol-pretreated, not silver-modified polyester fabric) and Baxter Carpentier-EdwardsR standard valves . RESULTS: Blood concentrations of silver reached a maximum of 40 p.p.b . within 10 days of SJM Epic valve implantation, and were well below toxic levels (300 p.p.b.) . Blood silver concentrations returned to baseline within 30 days after surgery . Maximal silver accumulation occurred in the liver (16.75 mg/g dry weight); concentrations in the brain, spleen, kidney and lung were similar to those reported for other silver-modified prosthetic valves . No statistically significant difference was found in calcium content between SJM Epic and Biocor valves . The fibrous response to the sewing cuff was similar among the three valve types . CONCLUSIONS: At all times tested, silver release from the SJM Epic valve led to blood concentrations well below toxic levels . Although calcification in the two SJM valve groups was extremely low, the 20-week sheep model may be insufficiently sensitive to detect differences in calcium accumulation in modern bioprosthetic valves.

J Hosp Infect, 1998 Dec, 40(4), 257 - 62
Efficacy of silver-coated medical devices; Schierholz JM et al.; Silver coating of medical devices is believed to prevent device-associated infection . Several in-vitro and in-vivo studies, as well as clinical observations on silver-nylon, silver-intramedullary pins, silver oxide Foley catheters and silver-coated vascular prostheses have been performed during the past 30 years . Nevertheless, randomized clinical studies showing efficacy of such coated medical devices in high-risk patient populations are rare, have dealt with very small numbers of patients or are controversial . Physico-chemical, pharmacological and microbiological data explaining the antimicrobial efficacy of silver in prophylaxis of implants are presented here, as well as the scientific background for the established clinical benefits of silver-preparations in burns.

Arch Pharm Res, 1998 Dec, 21(6), 723 - 8
A novel synthesis of heterocyclic compounds containing coumarin moiety of potential antimicrobial activity; el-Fattah ME; The chemical behaviours of 4-methyl-2-oxo-2H-benzopyran-7-yl oxoacetyl hydrazine (2) towards some different reagents such as anhydride compounds, aromatic aldehydes, carbon disulphide, and nitrous acid yielded the corresponding pathalazine derivatives (3, 4, 5), hydrazone derivative (6), 1,3,4-oxadiazole derivative (7, 8, 9) and acid azide (10) respectively . Treatment of 10 with absolute alcohols, amines and ethyl amino acid ester gave the corresponding carbamate derivative (11), substituted urea derivative (12) and ethyl substituted alkyl acetate (13) respectively . The biological activity of some synthesized compounds was evaluated.

Autoimmunity, 1998, 28(3), 157 - 61
Dapsone at onset of diabetes lowers glycated hemoglobin and delays death in NOD mice; Peterson CM et al.; Dapsone (4,4'-diaminodiphenyl sulfone) is a compound that has a large clinical experience due to its antimicrobial effects against mycobacterium leprae, the causative agent of leprosy . It is increasingly used in a number of clinical situations where inflammation may play an ancillary role . An inhibitory effect of the drug or lack thereof in the cumulative incidence or propagation of diabetes mellitus in the NOD mouse has mechanistic as well as therapeutic implications . We previously showed that dapsone administered continuously as a percentage of food to NOD mice inhibits the cumulative incidence of diabetes in a dose dependent fashion . In the present experiment, female NOD litter mates were randomized to receive dapsone (0.001% w/w as a percentage of food) at onset of diabetes . There were no differences in weight, blood glucose, or glycated hemoglobin at 10 weeks of age among the animals that were ultimately to receive dapsone (n = 10), mouse chow alone (n = 9), or those who did not develop diabetes (n = 3) . The mean time to onset of diabetes, mean blood glucose at onset, and mean glycated hemoglobin at onset did not differ between animals who did or did not receive dapsone . Animals receiving dapsone had significantly (p < or = 0.03) lower glycated hemoglobin at weeks 2, 3, and 4 following the onset of diabetes and lived significantly longer following diagnosis of diabetes (7 vs . 4 weeks, p < 0.05) . In conclusion, dapsone modulates the progression of autoimmune diabetes in the NOD mouse even when administered after the initiation of hyperglycemia.

J Fam Pract, 1998 Dec, 47(6), 429 - 33
Mupirocin cream is as effective as oral cephalexin in the treatment of secondarily infected wounds; Kraus SJ et al.; BACKGROUND: Topical antimicrobials have been considered for treatment of secondarily infected wounds because of the potential for reduced risk of adverse effects and greater patient convenience . We compared mupirocin cream with oral cephalexin in the treatment of wounds such as small lacerations, abrasions, or sutured wounds . METHODS: In 2 identical randomized double-blind studies, 706 patients with secondarily infected wounds (small lacerations, abrasions, or sutured wounds) received either mupirocin cream topically 3 times daily or cephalexin orally 4 times daily for 10 days . RESULTS: Clinical success at follow-up was equivalent in the two groups: 95.1% and 95.3% in the mupirocin cream and the cephalexin groups, respectively (95% confidence interval {CI}, -4.0% to 3.6%; P = .89) . The intention-to-treat success rate was 83% in both groups . Bacteriologic success at follow-up was also comparable: 96.9% in the mupirocin cream and 98.9% in the cephalexin groups (95% CI, -6.0% to 2.0%; P = .22) . The occurrence of adverse experiences related to study treatment was similar for the 2 groups, with fewer patients in the mupirocin cream group reporting diarrhea (1.1% vs 2.3% for cephalexin) . CONCLUSIONS: Mupirocin cream applied topically 3 times daily is as effective as oral cephalexin given 4 times daily for the treatment of secondarily infected wounds and was well tolerated.

Appl Microbiol Biotechnol, 1998 Nov, 50(5), 530 - 7
Production and structure elucidation of di- and oligosaccharide lipids (biosurfactants) from Tsukamurella sp . nov; Vollbrecht E et al.; The bacterium Tsukamurella sp . nov., isolated from soil, was found to produce novel glycolipids when grown on sunflower oil as the sole carbon source . The glycolipids were isolated by chromatography on silica columns and their structures elucidated using a combination of multidimensional NMR and MS techniques . The three main components are 2,3-di-O-acyl-alpha-D-glucopyranosyl-(1-1)-alpha-D-glucopyranose, 2,3-di-O-acyl-beta-D-glucopyranosyl-(1-2)-4,6-di-O-acyl-alpha-D- glucopyranosyl-(1-1)-alpha-D-glucopyranose and 2,3-di-O-acyl-beta-D-glucopyranosyl-(1-2)-beta-D-galactopyranosyl- (1-6)-4,6-di-O-acyl-alpha-D-glucopyranosyl-(1-1)-alpha-D- glucopyranosyl which are linked to fatty acids varying in chain length from C4 to C18 . The glycolipids are mainly extracellular but are also found attached to the cell walls . During the cultivation the composition of the glycolipids changed from disaccharide- to tri- and tetrasaccharide lipids . The glycolipids show good surface-active behaviour and have antimicrobial properties.

Contraception, 1998 Oct, 58(4), 251 - 5
Women's preferences for vaginal antimicrobial contraceptives . IV . Attributes of a formulation that would protect from STD/AIDS; Hardy E et al.; Vaginal formulations may have "dual" protective activity, against sexually transmitted diseases/AIDS and unplanned pregnancy . The attributes that women find acceptable or unacceptable for such dual protective methods were investigated . More than 50% of the women would not accept messiness, but it was more accepted for dual protective methods than for contraceptives . Very few women would use a dual protective method if it caused vaginal irritation, itching, swelling, or burning, problems associated with presently marketed methods . More than half of the women would use it if it appeared on the penis of their partner or required refrigeration . Use of an applicator to insert the formulation was generally preferred over a manual method . Most women preferred the formulation to be colorless or white, about 16% liked light colors, and about 10% liked darker colors . Almost half of the women were willing to pay up to $5.00 per application of a dual protective formulation, about 15% $3.00, and 30% $1.00 . Dual protective methods seem highly acceptable and women would pay much more for them than for condoms . However, these methods should be free of problems usually associated with presently marketed formulations.

Contraception, 1998 Oct, 58(4), 245 - 9
Women's preferences for vaginal antimicrobial contraceptives . III . Choice of a formulation, applicator, and packaging; Hardy E et al.; Novel vaginal formulations are under development to combat the increasing incidence of sexually transmitted diseases, including AIDS, and also unplanned pregnancies . A study was performed to determine women's preferences for different dosage forms (gel, cream, ovule/suppository, film, foam, tablet), width, length, and color of an applicator, and various types of packages . The study was conducted in Campinas, Brazil . A total of 635 women were interviewed, including both adolescents and adults and low and middle-high socioeconomic groups . The large majority of the women preferred a gel over a cream; both were preferred over the other methods . When asked which method they would not use, the film was most frequently identified, followed by the tablet and ovule . The primary reasons for selecting a particular dosage form were ease of use, absence of odor or the presence of a pleasant one, absence of color, and insertion with an applicator . The major reasons for not using a method were discomfort, "plastic" appearance, distrust of effectiveness, difficulty with insertion, messiness, and rigidity/hardness . The majority of the women liked the applicator shown . The prefilled single dose applicator was by far the preferred packaging . This information should aid in the development of consumer-friendly, vaginal formulations.

Contraception, 1998 Oct, 58(4), 239 - 44
Women's preferences for vaginal antimicrobial contraceptives . II . Preferred characteristics according to women's age and socioeconomic status; Hardy E et al.; A study was carried out to identify characteristics that women would want for an idealized vaginal contraceptive, and the possible association of these characteristics with age and socioeconomic status . The study was done in Campinas, Sao Paulo State, Brazil . A total of 635 women were selected by age and socioeconomic status, using the "social network" technique . Almost half were adolescents (15-19 years old) and the rest were adults (20-45 years old) . Half were of low socioeconomic status and the rest of medium-high status . The data were analyzed with SPSS-PC and EPI-INFO 6.0 . Logistic regression and chi 2 were used for the analysis . Despite some differences found between age and socioeconomic status in regard to the characteristics desired for the idealized method, most of the participants expressed the same preferences . The results indicate that women would like the idealized method to be a cream, rather than a suppository, with no odor or flavor, to be colorless, to be placed in the vagina with an applicator well before coitus, and to offer protection against sexually transmitted diseases including AIDS.

Contraception, 1998 Oct, 58(4), 233 - 8
Women's preferences for vaginal antimicrobial contraceptives . I . Methodology; Hardy E et al.; Sexually transmitted diseases, including AIDS, and unplanned pregnancies continue to be a serious worldwide problem . A number of organizations are developing woman-controlled vaginal formulations to prevent these problems . However, little information is available regarding the types of products women prefer even though such knowledge is essential to obtain widespread use . This is the first of several articles that describe the results of a consumer preference study for such vaginal formulations performed in Campinas, Sao Paulo State, Brazil . Because no published methodology was available, the instruments and interview techniques were developed first and procedures established for the identification and participation of research subjects . After preparation of a questionnaire, a pilot study was performed to evaluate it, to establish the interview technique, and to determine the optimal method for subject recruitment . Based on the results, the approach was selected and applied to 635 subjects from different age and socioeconomic groups . The developed methodology and questionnaire, the advantages and the problems encountered, are presented.

Arch Surg, 1998 Dec, 133(12), 1275 - 80
Comparison of wound culture and bronchial lavage in the severely burned child: implications for antimicrobial therapy; Ramzy PI et al.; BACKGROUND: The relationship of the burn wound flora to microbial pathogens in the tracheobronchial tree has important implications for antimicrobial therapy in the severely burned patient . Management of septic complications is bolstered by surveillance quantitative wound cultures (QWC) and bronchial lavage fluid (BLF) cultures . OBJECTIVES: To compare the organisms present in BLF with those found in QWC and to determine if QWC can predict BLF results . DESIGN: Results of BLF cultures from all patients who underwent bronchial lavage from January 1, 1996, to December 31, 1996, at our institution were compared with QWC data from the same date . Criteria for a positive match included an identical antibiotic susceptibility pattern and biotype . Match rates were calculated qualitatively and quantitatively . RESULTS: In 30 (48%) of the 62 BLF cultures, there was a match between the organism identified in the BLF and the QWC . When strict quantitative criteria were applied, the match rate was only 9 (14%) of 62 . Burn size and inhalation injury had no significant effect on match rate . CONCLUSIONS: Whereas the microbial pathogens were similar in the QWC and BLF, linear regression showed no value of QWC in predicting BLF culture results . The difference between qualitative and quantitative match rates suggests cross-colonization between the burn wound and tracheobronchial tree, but little to no cross-infection . The QWC and BLF cultures must be performed independently in determining antimicrobial specificity in the burned patient.

Biol Chem, 1998 Nov, 379(11), 1371 - 5
Cystatin and cystatin-derived peptides have antibacterial activity against the pathogen Porphyromonas gingivalis; Blankenvoorde MF et al.; We investigated whether cystatins and cystatin-derived peptides, encompassing sequences of secondary structures of cystatin S and papain binding domains of cystatin C, display antimicrobial properties . Of the different microorganisms tested, only the growth of P . gingivalis was inhibited by chicken cystatin and cystatin C . Cystatin S, cystatin S:1-14, cystatin S:61-73 and cystatin S:108-121 also inhibited its growth, whereas cystatin S:21-38, cystatin S:39-55, cystatin S:81-95, cystatin S:94-109, and cystatin C: 9-12/55-60/106-107 did not . No inhibition of the cysteine proteinase activity of P . gingivalis was observed for all cystatin-derived peptides . On the other hand, leupeptin and antipain inhibited P . gingivalis proteinase activity, but had no effect on the growth . These data suggest that cystatins contain antibacterial sequences active against P . gingivalis and that the growth inhibition does not depend on the inhibition of P . gingivalis cysteine proteinases.

J Eukaryot Microbiol, 1998 Nov-Dec, 45(6), 612 - 8
Efficacy of novel antimicrobials against clinical isolates of opportunistic amebas; Schuster FL et al.; We examined the effects of the macrolide antimicrobial agent azithromycin and phenothiazine compounds against clinical isolates of Acanthamoeba spp . and Balamuthia mandrillaris, opportunistic pathogens of human beings and other animals . Acanthamoeba growth was inhibited in vitro at 1, 5, and 10 micrograms/ml of azithromycin, but not the macrolides, erythromycin, and clarithromycin . In experiments attempting to simulate in vivo conditions, azithromycin protected monolayers of rat glioma cells from destruction by Acanthamoeba at a concentration of 0.1 microgram/ml, and delayed destruction at concentrations of 0.001 and 0.01 microgram/ml . We concluded that the minimal inhibitory concentration of azithromycin was 0.1 microgram/ml . Our results, however, suggested that the drug was amebastatic but not amebicidal, since ameba growth eventually resumed after drug removal . The phenothiazines (chlorpromazine, chlorprothixene, and triflupromazine) inhibited Acanthamoeba growth by 70-90% at 5 and 10 micrograms/ml, but some of these compounds were toxic for rat glioma cells at 10 micrograms/ml . Azithromycin was not very effective against B . mandrillaris in an in vitro setting, but was amebastatic in tissue culture monolayers at concentrations of 0.1 microgram/ml and higher . Balamuthia amebas showed in vitro sensitivity to phenothiazines . Ameba growth was inhibited 30-45% at 5 micrograms/ml in vitro, but completely at 5 micrograms/ml in the rat glioma model . In spite of their potential as antiamebic drugs in Balamuthia infections, toxicity of phenothiazines limits their use in clinical settings.

Infect Immun, 1999 Jan, 67(1), 439 - 42
Cathelicidin gene expression in porcine tissues: roles in ontogeny and tissue specificity; Wu H et al.; Cathelicidins constitute a family of mammalian antimicrobial peptides that are synthesized in the bone marrow as prepropeptides, stored in neutrophil granules as propeptides, and released as active, mature peptides upon neutrophil degranulation . We investigated the developmental expression of two porcine cathelicidins, PR-39 and protegrin . Both cathelicidins were expressed constitutively in the bone marrow of all pigs at all of the ages tested . Peripheral blood neutrophils from young pigs expressed PR-39 and protegrin mRNA, which were not detectable at 42 days of age . At earlier ages, expression of PR-39 mRNA was detected in the kidney and liver and several lymphoid organs, including the thymus, spleen, and mesenteric lymph nodes, but disappeared at 4 weeks of age . These data provide the first evidence of cathelicidin gene expression in peripheral leukocytes and may indicate a role for these antimicrobial peptides in the development of host defense mechanisms.

Wei Sheng Wu Xue Bao, 1997 Jun, 37(3), 232 - 3
{Using lyophilization to the preparation of drug paper disks for antimicrobial susceptibility test}; Huang Y et al.; It was found that the paper disks used in the antimicrobial susceptibility test could be prepared by natural drying at 37 degrees C, but the drug distribution between these disks is not so enen as determined by antimicrobial inhibitory test, thus it was difficult to fit the needs of the national standards . Alternatively, we applied the lyophilization technique to the disks preparation and 12 batches, of different antibiotic disks were made out and found that the difference between disks is reduced, and all are meet to the national requirement . It is supposed that the capillary action may play a role in the variation of drug distribution in the natural drying process, and the lyophilization process avoided the capillary action, hence the more even distributed antibiotic disks are produced . The preparation of lyophilized disks is a simple and practical method that could be used in the antimicrobial susceptibility tests in hospital.

Acta Clin Belg, 1998 Oct, 53(5), 303 - 10
Surgical site infections; Lauwers S et al.; The New CDC-definitions for surveillance of surgical site infections (1992) take into account 3 classes of surgical site infections (SSI): superficial and deep incisional SSI, and organ/space SSI . The most important host-related risk factors for development of SSI are advanced age, morbid obesity, disease severity, an ASA score > 2, prolonged preoperative hospital stay, and infection at distal sites . Microbial contamination of the surgical site occurs mainly during the surgical intervention . Although exogenous contamination may be of concern, especially in clean operations, most surgical site infections are caused by microorganisms of the patient's own commensal flora . SSI rates vary according to the type and duration of the surgical procedure and the skill of the surgeon . Proper surgical technique is the most important factor in the prevention of SSI . Modification of host risk factors should be attempted whenever possible . In addition, adequate protocols for antimicrobial prophylaxis with antibiotics should be followed . Surveillance of surgical site infections is probably beneficial for SSI prevention.

Can Vet J, 1998 Dec, 39(12), 757 - 63
Cutaneous antimicrobial preparation prior to intravenous catheterization in healthy dogs: clinical, microbiological, and histopathological evaluation; Coolman BR et al.; The purpose of this study was to determine the effects of a one-minute chlorhexidine gluconate skin preparation protocol prior to cephalic vein catheterization . Twenty-three healthy beagle dogs had one leg aseptically prepared and the opposite leg served as a control . Twenty-six- and 77-hour time groups were studied . Chlorhexidine-treated legs had significantly lower cutaneous bacterial counts than the control legs prior to catheter insertion and prior to catheter withdrawal for both time groups . Control legs developed significantly more dermatitis than the treated legs after 77 h . A one-minute preparation with 4% chlorhexidine gluconate was an effective method for sustained reduction of cutaneous bacterial counts at peripheral intravenous catheter insertion points in dogs . Increased cutaneous bacterial counts were associated with significantly more microscopic dermatitis in untreated legs after 77 h of catheterization.

Proc Natl Acad Sci U S A, 1998 Dec 22, 95(26), 15769 - 74
Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia; Yrjanheikki J et al.; Ischemic stroke is the most common life-threatening neurological disease and has limited therapeutic options . One component of ischemic neuronal death is inflammation . Here we show that doxycycline and minocycline, which are broad-spectrum antibiotics and have antiinflammatory effects independent of their antimicrobial activity, protect hippocampal neurons against global ischemia in gerbils . Minocycline increased the survival of CA1 pyramidal neurons from 10.5% to 77% when the treatment was started 12 h before ischemia and to 71% when the treatment was started 30 min after ischemia . The survival with corresponding pre- and posttreatment with doxycycline was 57% and 47%, respectively . Minocycline prevented completely the ischemia-induced activation of microglia and the appearance of NADPH-diaphorase reactive cells, but did not affect induction of glial acidic fibrillary protein, a marker of astrogliosis . Minocycline treatment for 4 days resulted in a 70% reduction in mRNA induction of interleukin-1beta-converting enzyme, a caspase that is induced in microglia after ischemia . Likewise, expression of inducible nitric oxide synthase mRNA was attenuated by 30% in minocycline-treated animals . Our results suggest that lipid-soluble tetracyclines, doxycycline and minocycline, inhibit inflammation and are neuroprotective against ischemic stroke, even when administered after the insult . Tetracycline derivatives may have a potential use also as antiischemic compounds in humans.

Biochemistry, 1998 Dec 8, 37(49), 17331 - 8
Multiple states of beta-sheet peptide protegrin in lipid bilayers; Heller WT et al.; Protegrin-1 (PG-1), a beta-sheet antimicrobial peptide, was studied in aligned lipid bilayers by oriented circular dichroism (OCD) . All of its spectra measured in a variety of lipid compositions were linear superpositions of two primary basis spectra, indicating that PG-1 existed in two different states in membranes . We designated these as state S and state I . The state assumed by PG-1 was strongly influenced by lipid composition, peptide concentration, and hydration condition . We have previously reported that the helical peptides, alamethicin and magainin, also exhibit two distinct OCD basis spectra-one corresponding to surface adsorption with the helix parallel to the bilayer and the other with perpendicular transbilayer insertion . States S and I of PG-1 may correspond to the surface state and the insertion state of alamethicin, since they show a similar dependence on lipid composition, peptide concentration, and hydration condition . Nonoriented CD spectra obtained from vesicle, micelle, and solution preparations are not linear superpositions of the basis spectra of the states S and I . This indicates that a molecular orientation change alone is insufficient to describe the S left and right arrow I transition . Rather, a more complicated process is taking place, perhaps involving a change in the hydrogen bonding pattern of the backbone . Although the structural basis of the OCD spectra remains to be determined, the discovery of two distinct states can provide information about dynamic changes of PG-1 in membranelike environments, properties undoubtedly related to its antimicrobial and cytotoxic effects.

Acta Odontol Scand, 1998 Oct, 56(5), 250 - 6
Antimicrobial function of human saliva--how important is it for oral health?
Tenovuo J.
Human saliva contains a number of physical physicochemical, and chemical agents that protect oral tissues against noxious compounds, in particular those produced by various microorganisms . Among such protective factors, the flushing effect of saliva flow is the most important one, not only because it so effectively removes exogenous and endogenous microorganisms and their products into the gut but also because a steady supply of saliva guarantees continuous presence of both non-immune and immune factors in the mouth . A great number of studies with controversial results have been published regarding various individual agents and their possible association to oral health, particularly to dental caries . It appears that no single chemical agent is far more important than the others . For example, patients with selective IgA deficiency have normal levels of non-immune defense factors and often display a compensatory increase in the other immunoglobulin isotypes . The concerted action of all agents in whole saliva, both saliva- and serum-derived, provides a multifunctional protective network that is collapsed only if salivary flow rate is substantially reduced . In this mixture of defense factors, many show additive or even synergistic interactions against oral pathogens . Increased knowledge of the molecular functions of various agents has made it possible to prepare oral hygiene product that include host-derived antimicrobial agents instead of synthetic agents . Although the clinical efficacy of such products is still unsatisfactory and poorly described, new technologies, for example in the production of specific antibodies against oral pathogens, may considerably improve the antimicrobial power of these products.

Biochim Biophys Acta, 1998 Dec 9, 1415(1), 235 - 45
Cecropins induce the hyperosmotic stress response in Escherichia coli; Oh JT et al.; Cecropin A and B, below or near their minimum inhibitory concentrations in viable Escherichia coli, interfered with the rapid NaCl-induced hyperosmotic shrinkage of the cytoplasmic volume (plasmolysis), and also activated the promoter of the hyperosmotic stress gene osmY . The same promoter was also expressed by hyperosmolar NaCl or sucrose, two of the most commonly used antimicrobial food preservatives . Stress responses were monitored during the logarithmic growth phase of E . coli strains that contain specific promoters fused to a luxCDABE operon on a plasmid . The luminescence assay, developed to monitor the transcriptional response to stresses, is based on the premise that organisms often respond and adapt to sublethal environmental adversities by increased expression of stress proteins to restore homeostasis . The luminescence response from these fusion strains to a specific stress occurs as the transcription at the promoter site is activated . Cecropins induced luminescence response only from the osmY-luxCDABE fusion, but not the corresponding stress promoter activation associated with macromolecular or oxidative damage, or leakage of the cytoplasmic content including the proton gradient . The inhibitory effect of cecropins on plasmolysis is interpreted to suggest that the primary locus of action of these antimicrobial peptides in the periplasmic space is on the coupling between the inner and outer membrane.

Microbiol Immunol, 1998, 42(10), 677 - 81
Analysis of genetic relationships and antimicrobial susceptibility of verotoxin-producing Escherichia coli strains isolated in Nagasaki Prefecture, Japan in 1996; Izumikawa K et al.; A total of 19 Escherichia coli O157 isolates were obtained in Nagasaki Prefecture, in the south-western part of Japan, between 1990 and 1996 . Pulsed-field gel electrophoresis (PFGE) and computer-assisted analysis were applied to determine genetic relationships among these strains . Fragment patterns of the isolates in Nagasaki, as determined by PFGE, were compared with those of isolates in other areas where large outbreaks and sporadic cases of E . coli O157 infection occurred . Similarity values of all the strains isolated in Nagasaki Prefecture were over 0.65 except for E . coli O26 . Some strains were identical to the strains isolated from the areas where large outbreaks occurred . All strains were susceptible to ampicillin, fosfomycin, minocycline, amikacin, ofloxacin and sulfamethoxazole-trimethoprim.

Postepy Hig Med Dosw, 1998, 52(5), 489 - 506
{Biological properties and clinical significance of interleukins 12 (IL-12)}; Maranda E et al.; IL-12 is a heterodimeric cytokine composed of 2 disulfide-linked subunits with molecular masses of 40 and 35 kDa, respectively . The cytokine is produced by phagocytic cells, professional antigen-presenting cells such as dendritic cells, skin Langerhans cells and B cells . IL-12 production is induced by bacteria, intracellular pathogens, fungi, viruses, or their products in a T-cell-independent pathway or a T-cell-dependent pathway, the latter mediated through CD40 ligand-CD40 interaction . Interleukin 12 induces interferon gamma secretion by T cells and natural killer cells, enhances the proliferation of activated T cells and natural killer cells, augments the cytolytic activity of cytotoxic T lymphocytes and natural killer cells, and supports the differentiation of Th1 helper effector cells . The therapeutic potential of these activities is suggested by studies in tumor and microbial models . IL-12 has suppressed tumor growth in all murine models examined . Antimicrobial activity has been demonstrated in bacterial, parasitic, and viral models of infection . The cytokine also stimulates in vitro antitumor activity of lymphocytes from patients with cancer . Current data indicate that CD4 T cells, CD8 T cells, natural killer cells and interferon-gamma may contribute to the antitumor effects of interleukin-12 therapy . Clinical trials are being initiated to evaluate the possible therapeutic uses of IL-12 in the treatment of neoplastic diseases and some infections.

J Med Microbiol, 1998 Dec, 47(12), 1115 - 22
Comparative susceptibilities of various AIDS-associated and human urogenital tract mycoplasmas and strains of Mycoplasma pneumoniae to 10 classes of antimicrobial agent in vitro; Hannan PC; The susceptibilities of 40 strains of various Mycoplasma species to 10 classes of antimicrobial agents were compared in vitro by a broth microdilution method . The strains tested comprised 20 strains of four AIDS-associated species--M . penetrans (1 strain), M . fermentas (5 strains), M . pirum (6 strains) and M . genitalium (8 strains)--nine strains of the urogenital tract species M . hominis and 11 strains of M . pneumoniae . The results demonstrated wide variation in the susceptibilities of the different Mycoplasma spp . to different classes of antimicrobial agent . All the mycoplasmas were susceptible or highly susceptible to the fluoroquinolones, with sparfloxacin the most active, and to the diterpine antibiotic tiamulin . M . pneumoniae and M . genitalium strains were also highly susceptible to the macrolides, particularly azithromycin and had similar antibiotic susceptibility patterns to most other antimicrobial agents . However, all strains of M . genitalium were resistant to streptomycin (MIC 250->500 mg/L) whereas all M . pneumoniae isolates, except the MAC strain, were susceptible (MICs 1.25-12.5 mg/L) . M . pirum isolates varied considerably in their susceptibility to macrolides (MIC range versus azithromycin 0.0025->100 mg/L) . M . fermentans strains were susceptible to the tetracyclines, lincosamides and mupirocin, but varied in susceptibility to aminoglycosides . Most M . hominis strains were susceptible to the tetracyclines and all were susceptible to clindamycin and mupirocin . M . penetrans GTU 54 was susceptible to azithromycin, the tetracyclines and lincosamides as well as to the fluoroquinolones and tiamulin.

Ned Tijdschr Geneeskd, 1998 Sep 5, 142(36), 2006 - 9
{Rat bite fever after a bite from a tame pet rat}; Schuurman B et al.; A 43-year-old woman presented with a generalized febrile illness, an exanthema with mixed maculopapulous and pustulous eruptions on the lower halves of the extremities, elbows, knees, palms and soles . There was also severe arthralgia and asymmetric arthritis . The diagnosis was rat bite fever . The disease became manifest eight days after she was bitten by a pet rat . Rat bite fever can easily be missed, even after adequate anamnesis and physical examination, while the differential diagnostic considerations are numerous . Our patient was cured completely after intravenous administration of penicillin G . Antimicrobial therapy was completed by an oral course of doxycycline.

J Clin Nurs, 1998 Sep, 7(5), 392 - 400
Are we facing a 'post-antibiotic era'?--a review of the literature regarding antimicrobial drug resistance; Trnobranski PH; Since the introduction of antibiotics in the 1940s, antibiotic resistance has become an increasing problem . Today, multiple-antibiotic resistance is commonly associated with a number of clinically important pathogens and is therefore an important issue in clinical nursing practice . Epidemiological studies identify a number of important factors associated with increases in antimicrobial resistance . These include patterns of antimicrobial use, changes in medical and veterinary care and social practices affecting the transmission of microbes . Bacterial mechanisms of antibiotic resistance and the genetics of resistance-gene transfer are explored, with the intention of developing nurses' knowledge and understanding of control measures.

Eur J Gastroenterol Hepatol, 1998 Jul, 10(7), 579 - 82
Eradication of Helicobacter pylori by a 1-week course of famotidine, amoxicillin and clarithromycin; Gschwantler M et al.; OBJECTIVES: The combination of a proton pump inhibitor (PPI) such as omeprazole with amoxicillin and clarithromycin constitutes one of the most effective treatments for the eradication of Helicobacter pylori . Nevertheless, the mechanisms of interaction between these drugs remain unclear . It has been shown that minimal inhibitory concentration values of both antibiotics are considerably lower at neutral pH levels than in an acid environment . Further, omeprazole possesses bacteriostatic activity . To evaluate the significance of these mechanisms we replaced omeprazole with famotidine, a drug which only suppresses acid production, but has no intrinsic antimicrobial activity . METHODS: We evaluated the efficacy of a 1-week course of famotidine 80 mg b.i.d., amoxicillin 1000 mg b.i.d . and clarithromycin 500 mg b.i.d . in a pilot study (20 patients), and then confirmed our results in a larger replication study (87 patients) . A total of 107 patients with H . pylori-associated duodenal ulcer (n = 54), gastric ulcer (n = 14) or non-ulcer dyspepsia (n = 39) were included . Endoscopy was performed at baseline and 4-6 weeks after discontinuation of treatment . H . pylori status was assessed by the urease test and histology . RESULTS: H . pylori was successfully eradicated in 94 of 104 patients who completed the study (90.4%; CI 95%, 83.0-95.3%) . By intention-to-treat analysis, the eradication rate was 87.9% (CI 95%, 80.1-93.4%) . Ulcer healing was observed in 98.1% of duodenal ulcers and 92.9% of gastric ulcers (based on per-protocol analysis) . Mild side effects that did not require termination of treatment were reported by seven patients (6.7%) . CONCLUSION: A 1-week course of famotidine, amoxicillin and clarithromycin is a highly effective, simple and safe eradication regimen . Our data indicate that acid suppression is the crucial mechanism by which the activity of amoxicillin and clarithromycin against H . pylori is enhanced, whereas additional antimicrobial activity or other specific effects of PPIs seem to be less important.

J Urban Health, 1998 Dec, 75(4), 896 - 902
The pharmacoeconomic impact of antimicrobial therapy for peptic ulcer disease in a large urban jail; Shuter J et al.; PURPOSE: To determine the pharmacoeconomic impact of antimicrobial treatment of peptic ulcer disease (PUD) in a large urban jail . PATIENTS AND METHODS: Retrospective comparison of PUD-related pharmacy and laboratory expenditures over a 2-year period before and after the institution of a PUD treatment protocol with the priority of Helicobacter pylori eradication for inmates in Rikers Island Correctional Facility . RESULTS: After the protocol was adopted, total pharmacy-related and laboratory-related expenses for PUD care decreased by 40.2%, and expenditures for ranitidine declined by 52.2% . There was an increase in spending for antimicrobial agents and H . pylori antibody testing, but this was insignificant compared to the savings generated by decreased ranitidine usage . Annual savings in our facility as a result of this intervention were $123,449 . CONCLUSIONS: Modern therapeutic strategies for PUD aimed at eradicating H . pylori can result in significant savings in the institutional setting; these savings are largely attributable to the decreased usage of histamine-2 receptor antagonists.

J Clin Microbiol, 1999 Jan, 37(1), 270 - 3
Improvement of immunoglobulin M capture immunoassay specificity: toxoplasma antibody detection method as a model; Tuuminen T et al.; In the Toxoplasma gondii immunoglobulin M (IgM) capture fluorometric enzyme immunoassay used as a model, nonspecific responses due to the binding of human IgM to horseradish peroxidase (HRP) conjugates were observed despite the removal of the Fc portion of the immunoglobulin . This interaction may be mediated through the binding of human IgM to the HRP moiety of the conjugate . Addition of polymerized HRP into the reaction mixture reduced nonspecific signals in the majority of low false-positive serum reactions . Other plausible sites of interaction are conserved epitopes of mouse immunoglobulins presenting antigenic similarities with the allotopes of other species . Fragmentation of mouse antimicrobial IgG to Fab' and selection of proper conjugation procedure improved assay specificity.

J Clin Microbiol, 1999 Jan, 37(1), 45 - 8
Multicenter evaluation of the mycobacteria growth indicator tube for testing susceptibility of Mycobacterium tuberculosis to first-line drugs; Rusch-Gerdes S et al.; In a multicenter study involving three reference centers for mycobacteria, the reliability of the Mycobacteria Growth Indicator Tube (MGIT) for rapid antimicrobial susceptibility testing (AST) of Mycobacterium tuberculosis was evaluated and compared to the radiometric method (BACTEC 460TB) . Test cultures for which the results of the MGIT and BACTEC 460TB tests were discordant were checked by the conventional proportion method on solid medium . Four hundred forty-one isolates have been tested for susceptibility to isoniazid (INH), rifampin (RMP), ethambutol (EMB), and streptomycin (SM) . Discrepant results were obtained for three isolates (0.7%) with INH (susceptible by MGIT, resistant by BACTEC 460TB), for four isolates (0.9%) with RMP (susceptible by MGIT, resistant by BACTEC 460TB), for six isolates (1.9%) with EMB (four susceptible by MGIT, resistant by BACTEC 460TB; two resistant by MGIT, susceptible by BACTEC 460TB), and for four isolates (0.9%) with SM (two susceptible by MGIT, resistant by BACTEC 460TB; two resistant by MGIT, susceptible by BACTEC 460TB) . When cultures with discordant results were tested by the conventional proportion method, about half of the cultures yielded results similar to the BACTEC 460TB results, while the other half yielded results similar to the MGIT results . Turnaround times were 3 to 14 days (median, 8.8 days) for MGIT and 3 to 15 days (median, 7.8 days) for BACTEC 460TB . There was no statistically significant difference between the susceptibility testing results of the two methods (P > 0.05) . These data demonstrate that the MGIT system is an accurate, nonradiometric alternative to the BACTEC 460TB method for rapid susceptibility testing of M . tuberculosis.

Ther Drug Monit, 1998 Dec, 20(6), 697 - 705
High-performance liquid chromatography-electrospray tandem mass spectrometry for the measurement of 1-(3,4-dichlorobenzyl)-5-octylbiguanide in human serum; Kudo S et al.; 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB-2045) is a new biguanide antimicrobial agent currently in clinical use as a topical bactericidal antiseptic . A method combining high-performance liquid chromatography (HPLC) with electrospray ionization (triple and quadruple stage) tandem mass spectrometry (ESI-MS/MS) was developed to quantify OPB-2045 in human serum . Solid phase extraction was performed on 0.2 ml of sample to ensure a high level of sensitivity before HPLC-ESI-MS/MS analysis . The limit of quantitation for the method was set at 0.05 ng/ml . Intra-assay and interassay precision were less than 13.7%, with a deviation from the expected value of no greater than 10.5% at a concentration range of 0.05 ng/ml to 5 ng/ml . Decomposition of OPB-2045 in human serum did not occur after storage for 15 months at -20 degrees C, even after three repetitions of freezing and thawing . Application of this method was demonstrated in a pharmacokinetic study of OPB-2045 in healthy patient subjects after a single topical application of 5 g/L preparation of its liquid formulation.

Pharmazie, 1998 Nov, 53(11), 748 - 51
A novel synthesis of fused pyrazole systems as antimicrobial agents; Erian AW et al.; The pyrazolo{3,4-b}pyridine derivatives 3 could be prepared by condensing compounds 1 with the 3-aminopyrazolone derivative 2 . The pyrazolo{5,2-b}-1,3-oxazine derivative 11 and polyfunctionally substituted 1,4-dihydropyridines 15, 18 were also synthesized . Some of the obtained compounds were tested for their antimicrobial activity.

Dent Update, 1998 Jul-Aug, 25(6), 230 - 4
An update on antimicrobial chemotherapy: 3 . Antimicrobial resistance and the oral cavity; Smith A et al.; As mentioned in the preceding articles, the widespread appearance of antimicrobial resistance has become a major threat to the effective treatment of infectious disease . However, does this have any relevance to the dental profession? This article relates current knowledge to everyday dental practice.

Dent Update, 1998 May, 25(4), 147 - 50
An update on antimicrobial chemotherapy: 1 . The mechanisms of action of antibiotics; Smith A et al.; This three-part series will provide an update on the modes of action of currently available antibiotics, review the mechanisms of antibiotic resistance and discuss the impact of antibiotic resistance on prescribing for oral infections.

Int J Mol Med, 1998 Jan, 1(1), 117 - 9
Experimental dermatophyte infection abated by povidone-iodine: assessment by computerized-assisted corneofungimetry; Pierard-Franchimont C et al.; The effect of antiseptics upon fungal growth inside human stratum corneum is poorly documented . Therefore the present study was undertaken to assess the anti-dermatophyte activity of a diluted povidone-iodine wash solution using the corneofungimetry bioassay . When compared to a non-medicated cleansing product, regular applications of the antimicrobial for two weeks significantly abated the fungal invasiveness inside human stratum corneum . The present findings are most likely relevant for the clinical practice.

J Bacteriol, 1998 Dec, 180(24), 6565 - 70
The lantibiotic nisin induces transmembrane movement of a fluorescent phospholipid; Moll GN et al.; Nisin is a pore-forming antimicrobial peptide . The capacity of nisin to induce transmembrane movement of a fluorescent phospholipid in lipid vesicles was investigated . Unilamellar phospholipid vesicles that contained a fluorescent phospholipid (1-acyl-2-(6-{(7-nitro-2-1, 3-benzoxadiazol-4-yl)amino}caproyl)-sn-glycero-3-phosphocholine) in the inner leaflet of the bilayer were used . Nisin-induced movement of the fluorescent phospholipid from the inner leaflet to the outer leaflet of the membrane reached stable levels, which were dependent on the concentration of nisin added . The rate constant k of this nisin-induced transmembrane movement increased with the nisin concentration but was not dependent on temperature within the range of 5 to 30 degrees C . In contrast, the rate constant of movement of fluorescent phospholipid from vesicle to vesicle strongly depended on temperature . The data indicate that nisin transiently disturbs the phospholipid organization of the target membrane.

Arch Biochem Biophys, 1998 Dec 15, 360(2), 179 - 86
Interaction of the wheat endosperm lipid-binding protein puroindoline-a with phospholipids; Le Guerneve C et al.; Puroindoline-a is the main component of a new family of proteins that has been suggested to exert an antimicrobial activity in plant seeds through an interaction with lipid membranes . Here the interaction of puroindoline-a with model phospholipid membranes and micelles has been studied using intrinsic tryptophan fluorescence, fluorescence polarization of diphenyl hexatriene, and proteolysis experiments . The protein appears to interact with both zwitterionic and negative phospholipids . The interaction with phosphatidylcholine is characterized by low-affinity surface binding with very limited penetration into the hydrophobic membrane interior . On the other hand, the interaction with phosphatidylglycerol displays a high affinity and involves a partial penetration of the protein into the bilayer interior that disrupts acyl chain packing . The specificity appears to be due to the presence of a stretch of positively charged residues in the protein sequence . In all, the lipid-binding properties of puroindoline-a resemble those of cardiotoxins, another family of proteins for which a disruptive effect on the membrane structure has been involved to explain their biological function .

Pediatr Infect Dis J, 1998 Nov, 17(11), 1090 - 8; discussion 1099-100
Role of surgery for otitis media in the era of resistant bacteria; Bluestone CD; Otitis media is currently the most common diagnosis made by clinicians, and its prevalence has an impact on managed health care . With the emergence of bacterial pathogens resistant to many antimicrobial agents, an urgent need exists to reassess the indications for surgical management of this more prevalent disease . In an effort to determine the causative bacterial etiology of acute otitis media, which may be resistant to commonly prescribed antimicrobial agents, tympanocentesis is indicated today more than ever, especially when patients fail to improve or worsen while receiving antibiotics (i.e . treatment failures) . In an effort to reduce the use of antimicrobial agents, prophylactic administration of these drugs for prevention of recurrent otitis media should only be prescribed on an individualized basis, with myringotomy and tympanostomy tube insertion being a more reasonable alternative . Adenoidectomy should be also considered when moderate to severe nasal obstruction is present or when repeat tympanostomy tube placement is needed . Likewise when chronic otitis media with effusion is unresponsive to a trial of antimicrobial therapy, tympanostomy tube insertion, adenoidectomy or both procedures should be considered, as opposed to re-treating with a variety of antibiotics . The role of these surgical procedures has become more important today in this era of antibiotic-resistant bacteria . Also in our cost-conscious environment, it is uncertain which method of management is more expensive, surgery or prolonged medical management.

J Ethnopharmacol, 1998 Oct, 62(3), 251 - 4
Antimicrobial study of the resinous exudate and of diterpenoids isolated from Eupatorium salvia (Asteraceae); Urzua A et al.; The antimicrobial properties of the resinous exudate from twigs and leaves of Eupatorium salvia were tested against five gram-negative and five gram-positive bacteria . Comparison of the antimicrobial activities of 7-hydroxy-8(17)-labden-15-oic acid (salvic acid) and of its acetate, both compounds isolated from the plant, with that of the crude extract suggested that the latter ester derivative was the major active component in the exudate . These results validate the vernacular medicinal use of Eupatorium salvia as an antiseptic agent.

J Antimicrob Chemother, 1998 Nov, 42(5), 657 - 60
In-vitro evaluation of nitrofurantoin as an alternative agent for metronidazole in combination antimicrobial therapy against Helicobacter pylori; Coudron PE et al.; Increasing metronidazole resistance suggests the need for alternative antibiotics for combination therapy of Helicobacter pylori infections . We evaluated a metronidazole-resistant and a clarithromycin-resistant strain of H . pylori under stationary growth phase conditions that favoured physiological conditions in order to determine if nitrofurantoin might be a suitable alternative for metronidazole in combination therapy . The results demonstrated that the triple combination of bismuth, tetracycline and nitrofurantoin achieved greater bactericidal activity against these two strains than did the combination of bismuth, tetracycline and metronidazole . These results suggest that further evaluation is warranted.

J Burn Care Rehabil, 1998 Nov-Dec, 19(6), 531 - 7
A matched-pair, randomized study evaluating the efficacy and safety of Acticoat silver-coated dressing for the treatment of burn wounds; Tredget EE et al.; A new silver-coating technology was developed to prevent wound adhesion, limit nosocomial infection, control bacterial growth, and facilitate burn wound care through a silver-coated dressing material . For the purposes of this article, Acticoat (Westaim Biomedical Inc, Fort Saskatchawan, Alberta, Canada) silver-coated dressing was used . After in vitro and in vivo studies, a randomized, prospective clinical study was performed to assess the efficacy and ease of use of Acticoat dressing as compared with the efficacy and ease of our institution's standard burn wound care . Thirty burn patients with symmetric wounds were randomized to be treated with either 0.5% silver nitrate solution or Acticoat silver-coated dressing . The dressing was evaluated on the basis of overall patient comfort, ease of use for the wound care provider, and level of antimicrobial effectiveness . Wound pain was rated by the patient using a visual analog scale during dressing removal, application, and 2 hours after application . Ease of use was rated by the nurse providing wound care . Antimicrobial effectiveness was evaluated by quantitative burn wound biopsies performed before and at the end of treatment . Patients found dressing removal less painful with Acticoat than with silver nitrate, but they found the pain to be comparable during application and 2 hours after application . According to the nurses, there was no statistically significant difference in the ease of use . The frequency of burn wound sepsis (> 10(5) organisms per gram of tissue) was less in Acticoat-treated wounds than in those treated with silver nitrate (5 vs 16) . Secondary bacteremias arising from infected burn wounds were also less frequent with Acticoat than with silver nitrate-treated wounds (1 vs 5) . Acticoat dressing offers a new form of dressing for the burn wound, but it requires further investigation with greater numbers of patients in a larger number of centers and in different phases of burn wound care.

J Indiana Dent Assoc, 1996 Spring, 75(1), 37 - 42; quiz 43
Practitioner and student latex exposure and allergy; Amin A et al.; Greater application of universal precautions has increased practitioner exposure to chemicals present in personal protective equipment . Of prime concern is the latex present in examination and surgical gloves . A survey concerning latex exposure, allergies, and handwashing was administered to three advanced classes of dental students and was sent to 300 private practitioners in Central Indiana . Results indicate that adverse skin reactions to latex start while in dental school . Problems due to latex gloves were reported by 18.6 percent of the students . Student handwashing materials and methods were adequate, except for inadequate washing time . Adverse skin reactions were reported by 24.1 percent of practitioners wearing latex gloves . Two handwashing problems were noted--inadequate washing time and the common use of water instead of an antimicrobial soap after glove removal . Both students and practitioners reported relatively high levels of personal and family histories of allergy to a variety of sources.

Trends Microbiol, 1998 Nov, 6(11), 441 - 3
How important is Nramp1 in tuberculosis?
North RJ, Medina E.
The assumption that the antimicrobial resistance gene Nramp1 is a major determinant of resistance of mice to infection with virulent Mycobacterium tuberculosis can now be challenged on the basis of published evidence to the contrary . It is likely that, with tuberculosis, Nramp1-determined defenses are subordinate to other defenses.

Proc Natl Acad Sci U S A, 1998 Dec 8, 95(25), 15107 - 11
Separate jasmonate-dependent and salicylate-dependent defense-response pathways in arabidopsis are essential for resistance to distinct microbial pathogens
Thomma BPHJ, Eggermont K, Penninckx IAMA, Mauch-Mani B, Vogelsang R, Cammue BPA, Broekaert WF.
The endogenous plant hormones salicylic acid (SA) and jasmonic acid (JA), whose levels increase on pathogen infection, activate separate sets of genes encoding antimicrobial proteins in Arabidopsis thaliana . The pathogen-inducible genes PR-1, PR-2, and PR-5 require SA signaling for activation, whereas the plant defensin gene PDF1.2, along with a PR-3 and PR-4 gene, are induced by pathogens via an SA-independent and JA-dependent pathway . An Arabidopsis mutant, coi1, that is affected in the JA-response pathway shows enhanced susceptibility to infection by the fungal pathogens Alternaria brassicicola and Botrytis cinerea but not to Peronospora parasitica, and vice versa for two Arabidopsis genotypes (npr1 and NahG) with a defect in their SA response . Resistance to P . parasitica was boosted by external application of the SA-mimicking compound 2, 6-dichloroisonicotinic acid {Delaney, T., et al . (1994) Science 266, 1247-1250} but not by methyl jasmonate (MeJA), whereas treatment with MeJA but not 2,6-dichloroisonicotinic acid elevated resistance to Alternaria brassicicola . The protective effect of MeJA against A . brassicicola was the result of an endogenous defense response activated in planta and not a direct effect of MeJA on the pathogen, as no protection to A . brassicicola was observed in the coi1 mutant treated with MeJA . These data point to the existence of at least two separate hormone-dependent defense pathways in Arabidopsis that contribute to resistance against distinct microbial pathogens.

Proc Natl Acad Sci U S A, 1998 Dec 8, 95(25), 14961 - 6
Production of beta-defensins by human airway epithelia; Singh PK et al.; Human beta-defensins (HBDs) are antimicrobial peptides that may play a role in mucosal defense . Diminished activity of these peptides has been implicated in the pathogenesis of cystic fibrosis (CF) lung disease . We show that HBD-1 and HBD-2 mRNAs are expressed in excised surface and submucosal gland epithelia from non-CF and CF patients . The pro-inflammatory cytokine interleukin-1beta stimulated the expression of HBD-2 but not HBD-1 mRNA and peptide in primary cultures of airway epithelia . HBD-1 was found in bronchoalveolar lavage (BAL) fluid from normal volunteers, CF patients, and patients with inflammatory lung diseases, whereas HBD-2 was detected in BAL fluid from patients with CF or inflammatory lung diseases, but not in normal volunteers . Both HBD-1 and HBD-2 were found in BAL fluid in concentrations of several ng/ml, and both recombinant peptides showed salt-sensitive bactericidal activity . These data suggest that in the lung HBD-2 expression is induced by inflammation, whereas HBD-1 may serve as a defense in the absence of inflammation.

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