Antimicrobial

Pediatr Infect Dis J, 1999 Dec, 18(12), 1081 - 5
Bacteremia-associated pneumococcal pneumonia and the benefit of initial parenteral antimicrobial therapy; Chumpa A et al.; OBJECTIVES: To describe clinical characteristics of patients with bacteremia-associated pneumococcal pneumonia (BAPP) and evaluate features that may distinguish these patients from those with uncomplicated pneumococcal bacteremia . To determine the impact of the route of initial antibiotic therapy on the clinical course of patients with BAPP . DESIGN/METHODS: Retrospective review of children with pneumococcal bacteremia comparing those with pneumonia to those without focal infections . RESULTS: We identified 110 patients with BAPP and 112 patients with pneumococcal bacteremia alone . Patients with pneumonia were significantly older (mean age, 34 vs . 19 months; P = 0.002) and more likely to present with cough/congestion (28% vs . 14%; P = 0.01) or difficulty breathing (12% vs . 4%; P = 0.047) . There was no difference in mean temperature (39.5 vs . 39.7 degrees C; P = 0.3), mean white blood cell count WBC (21.9 vs . 22.6 x 1000/mm,3 P = 0.5) or presence of tachypnea (23% vs . 22%, P = 0.8) . Sixty-one patients (55%) with pneumonia were discharged home from the initial visit in the emergency department . Those who received a parenteral antibiotic before discharge, when compared with the group who received an oral antibiotic alone, were more likely to have an improved condition (95% vs . 67%, P = 0.03) and were less likely to be admitted to the hospital (0% vs . 24%; P = 0.007) at follow-up . CONCLUSIONS: Children with bacteremia-associated pneumococcal pneumonia are older and more likely to complain of cough/congestion or difficulty breathing than those with uncomplicated pneumococcal bacteremia . The use of a parenteral antibiotic at the initial visit for children with bacteremia-associated pneumococcal pneumonia resulted in a lower admission rate and more likely parental report of improved condition at follow-up than those for children treated only with an oral antibiotic.

Pediatr Infect Dis J, 1999 Dec, 18(12), 1078 - 80
Antimicrobial use in febrile children diagnosed with respiratory tract illness in an emergency department; Le Saux N et al.; BACKGROUND: In an era of increasing antibiotic resistance, the prevalence of antibiotic usage and associated factors should be ascertained to optimize their use . We set out to determine the prevalence of antibiotic use in febrile children diagnosed with respiratory tract illnesses at a children's hospital emergency department; to determine how often viral studies were conducted; and to identify patient characteristics associated with antibiotic use . METHODS: We conducted a retrospective study of antibiotic use in febrile children 3 months to 10 years old presenting with respiratory illnesses during two 1-month periods . Patient charts and laboratory tests were reviewed . Antibiotic use was related to diagnosis by logistic regression . RESULTS: A total of 836 patient visits were selected . Antibiotics were prescribed for otitis media in 96% of patients, for pneumonia in 100%, for pharyngitis in 66%, for bronchiolitis in 38%, for reactive airway disease in 24% and for viral or "upper respiratory tract illness" in 14% . For viral illness or upper respiratory tract infection, antibiotic use was associated with a fever duration of >48 h {odds ratio (OR), 3.2; 95% confidence interval (CI) 1.7, 5.9} and having a chest radiograph performed (OR 2.1; 95% CI 1.02, 4.37) . Patients with pharyngitis who had a throat swab were less likely to receive an antibiotic (OR 0.08; 95% CI 0.02, 0.4) than those who did not have a swab . In this emergency department antibiotic use for these indications decreased by 11% during the 1997 to 1998 study interval (P < 0.001) . CONCLUSION: Antibiotics were commonly prescribed for pharyngitis, bronchiolitis and reactive airway disease, which are conditions principally caused by viruses . Addressing reasons why there is a difference between guidelines and antibiotic use in these conditions may be important.

Curr Opin Hematol, 2000 Jan, 7(1), 26 - 31
Leishmania parasites and their ploys to disrupt macrophage activation; Kane MM et al.; Leishmania are intracellular protozoan parasites of macrophages . At the cellular level, the disease leishmaniasis involves the invasion of tissue macrophages by the parasite, the avoidance of cellular killing mechanisms, and the subsequent intracellular replication of parasites, with the eventual spread of the organisms to adjacent macrophages . This paper describes the process by which Leishmania organisms invade macrophages, with an overview of some of the molecules involved in this process; the mechanisms available to macrophages that have the potential to restrict the growth of Leishmania within them; and the ways that Leishmania and Leishmania-derived molecules can modulate macrophage functions and circumvent leukocyte antimicrobial responses.

Curr Opin Pulm Med, 2000 Jan, 6(1), 21 - 5
Nitric oxide and asthma: a review; Ashutosh K; Nitric oxide (NO) is synthesized from the amino acid arginine by enzymes called nitric oxide synthases . NO has an important physiologic role in the regulation of vascular tone, response to vascular injury, and hemostasis . It also acts as a neurotransmitter for the nonadrenergic noncholinergic nerves and has important antimicrobial, immunologic, and proinflammatory activities . The lung is rich in nitric oxide synthases, and NO is normally present in the exhaled air . Use of NO in the treatment of asthma has not withstood the test of time and is not recommended . With the advent of analyzers capable of measuring NO rapidly and reliably, however, the analysis of NO in exhaled air is being increasingly recognized as a potential noninvasive test for the evaluation of the inflammatory component of the pathology of patients with asthma . An increase in the exhaled NO has been shown to accompany eosinophilic inflammation and to correlate with other indices of inflammation in asthma . Exhaled NO increases during exacerbation and decreases with recovery in patients with asthma . As exhaled NO is not increased during bronchospasm in the absence of coexisting inflammation, it could serve to differentiate between the inflammatory and bronchospastic components in asthma, thereby guiding therapy with steroids and other anti-inflammatory medications . Levels of NO also can be increased in certain other conditions, for example, allergic rhinitis and adult respiratory distress syndrome, but these can be clinically differentiated from asthma and do not lessen the diagnostic value of exhaled NO . Measurements of exhaled NO are influenced by several physiologic and technical variables, which results in a wide variation in the levels reported from the different laboratories . Standardization of technique, a better understanding of the confounding effects of physiologic and environmental variables, and establishment of the normal range and variability of exhaled NO are needed before its measurement could gain wide acceptance as a clinically useful test . Development of less expensive NO analyzers is also an important consideration.

Recenti Prog Med, 1999 Nov, 90(11), 613 - 8
{Enterohemorrhagic Escherichia coli O157:H7 infection}; Rocchi G et al.; Infections in the digestive tract are due to multiple organism, which cause different syndromes . Escherichia coli O157:H7, already identified as a human pathogen in 1982, has been recognised as a major public health issue, being responsible for sporadic and epidemic cases of haemorrhagic colitis, often associated, in children and elderly, with the haemolytic uraemic syndrome . E . coli O157:H7 infection may occur everywhere, but is more frequent in North Europe, Canada, USA, Argentina and Japan, with annual incidence rates of 8 per 100,000 population . In Italy until 1997 the Italian National Institute of Health has identified 196 cases of haemolytic uraemic syndrome, in addition, an outbreak caused by E . coli O157:H7 occurred in 1993 . In Italy the incidence of the haemolytic uraemic syndrome is 4-5 times lower than in Great Britain, Germany and other European countries . E . coli infection is more frequently associated with the ingestion of food from bovine and sheep origin and with infected water . The clinical spectrum includes an asymptomatic infection, non bloody diarrhoea, haemorrhagic colitis, haemolytic uraemic syndrome . When the E . coli infection is suspected, it is necessary to isolate the bacterium in a specialised laboratory . Treatment is essentially supportive in order to control anaemia and to maintain an adequate fluid and electrolyte balance, if necessary with the use of dialysis . The use of antimicrobial agents is currently under debate as there are controversial data on the risk of developing haemolytic uraemic syndrome.

Cell Immunol, 1999 Nov 1, 197(2), 145 - 50
Adjuvant effect of a 14-member macrolide antibiotic on DNA vaccine; Sato Y et al.; Macrolide antibiotics have unique immunomodulatory actions apart from their antimicrobial properties . We examined the effect of erythromycin (EM), a 14-member macrolide, on the immune response to a DNA vaccine that induces a T-helper-1 (Th1)-biased immune response through a Th1-promoting adjuvant effect of unmethylated CpG motifs within plasmid DNA . EM enhanced Th1 responses in plasmid DNA-immunized mice as measured by antigen-specific IgG2a antibody production, interferon-gamma production by antigen-specific CD4(+) T cells, and cytotoxic T lymphocyte responses . EM augmented the accessory cell activity of unmethylated CpG DNA-stimulated antigen-presenting cells (APCs), suggesting that EM enhances Th1 responses to a DNA vaccine, possibly through augmentation of accessory cell activity of APCs stimulated with CpG motifs within plasmid DNA .

J Agric Food Chem, 1999 Dec, 47(12), 5044 - 8
Fractional extraction of compounds from grape seeds by supercritical fluid extraction and analysis for antimicrobial and agrochemical activities; Palma M et al.; White grape seeds were subjected to sequential supercritical fluid extraction . By increasing the polarity of the supercritical fluid using methanol as a modifier of CO(2), it was possible to fractionate the extracted compounds . Two fractions were obtained; the first, which was obtained with pure CO(2), contained mainly fatty acids, aliphatic aldehydes, and sterols . The second fraction, obtained with methanol-modified CO(2), had phenolic compounds, mainly catechin, epicatechin, and gallic acid . The fractions were bioassayed . Antimicrobial activities were checked on human pathogens, and a high degree of activity was obtained with the lipophilic fraction . Agrochemical activities on phytopathogenic fungi and activities on the etiolated wheat coleoptile bioassay were also checked . The more polar fraction was active in the latter bioassay.

J Rheumatol, 1999 Dec, 26(12), 2701 - 2
Beaver fever--a rare cause of reactive arthritis; Tupchong M et al.; Giardia lamblia infection is rarely associated with adult reactive arthritis . We report the first North American case and review the pediatric and adult literature to date . Antimicrobial treatment is essential to eradicate the parasite and control the arthritis.

Chemotherapy, 2000 Jan-Feb, 46(1), 43 - 8
In vitro investigation of the antimicrobial activities of novel tetramethylpiperidine-substituted phenazines against Mycobacterium tuberculosis; van Rensburg CE et al.; The intra- and extracellular activities of 5 novel tetramethylpiperidine (TMP)-substituted phenazines against Mycobacterium tuberculosis H37Rv (ATCC 27294) were determined and compared with those of clofazimine and rifampicin . Two of these agents, together with clofazimine, were also tested for their activities against drug-resistant strains of M . tuberculosis . Three of the TMP-substituted phenazine compounds were significantly more active than clofazimine against M . tuberculosis, including multidrug-resistant clinical strains of this microbial pathogen, demonstrating a lack of cross-resistance between the riminophenazines and standard anti-tuberculous drugs . Using M . tuberculosis-infected monocyte-derived macrophages, all of the TMP-substituted phenazines were found to possess intracellular activity which was superior to that of both clofazimine and rifampicin . In this model of intracellular bioactivity, the experimental compounds inhibited bacterial growth at concentrations which were approximately 10-fold lower than the corresponding minimal inhibitory concentration values obtained using conventional in vitro sensitivity testing procedures . These results demonstrate that the novel TMP phenazines are active against multidrug-resistant M . tuberculosis strains, and particularly effective intracellularly .

Pharmacotherapy, 1999 Dec, 19(12), 1369 - 77
A randomized, prospective study measuring outcomes after antibiotic therapy intervention by a multidisciplinary consult team; Gums JG et al.; Our aim was to identify financial and outcome benefits of therapeutic intervention by a multidisciplinary antimicrobial treatment team composed of pharmacists, a clinical microbiologist, and an infectious disease specialist . Of 252 consecutive inpatients receiving suboptimal intravenous antibiotics identified by the clinical pharmacist, 127 were prospectively randomized to intervention and 125 to a control group . The groups were similar with regard to severity of illness, infection type, and time from admission to randomization . Physicians received timely, detailed reviews of relevant microbiologic and clinical data with recommendations of possible optimal antibiotic choices, dosages, and rationales . Median length of stay after randomization for control and intervention groups was 9.0 days and 5.7 days, respectively (3.3-day difference, p=0.0001) . Fifteen (12.0%) and eight patients (6.3%), respectively, died, although the time-specific mortality risk was not significantly different when length of postrandomization follow-up and time to death were taken into account . Physician acceptance of suggestions was 89% . Median patient charges for radiology, laboratory, pharmacy, and room were reduced by $4404/intervention, and median hospital costs were reduced by $2642/intervention . A multidisciplinary antimicrobial therapy team can be a useful information source for physicians, improve outcomes in hospitalized patients receiving intravenous antimicrobials, and result in substantial cost savings.

Biochemistry, 1999 Dec 21, 38(51), 16963 - 73
Structure and organization of hemolytic and nonhemolytic diastereomers of antimicrobial peptides in membranes; Hong J et al.; Recently, we reported on a new group of diastereomers of short-model peptides (12 amino acids long) composed of leucine and lysine with varying ratios, possessing several properties that make them potentially better than native or de novo-designed all L-amino acid antimicrobial peptides . Preliminary studies have revealed that modulating the hydrophobicity and positive charges of these diastereomers is sufficient to confer antibacterial activity and cell selectivity . However, the relationship between their biological function, structure, and mode of action was not investigated . Here we synthesized and investigated three types of linear model diastereomers (12 amino acids long) with varying lysine:leucine (or tryptophan) ratios (i.e., K(3)L(8)W, K(5)L(6)W, and K(7)L(4)W), which confer different levels of lytic activities . For each K:L ratio, tryptophan was introduced in the middle or the N- or C-terminus of the peptides, as an intrinsic fluorescent probe . Only the hemolytic peptide K(3)L(8)W binds to both negatively charged and zwitterionic phospholipid membranes . K(5)L(6)W and K(7)L(4)W bind similarly, but only to negatively charged membranes, despite the fact that K(5)L(6)W is substantially more lytic to bacteria than K(7)L(4)W . Interestingly, although K(3)L(8)W contains 33% D-amino acids, ATR-FTIR spectroscopy revealed a structure of approximately 90% alpha-helix in both types of membranes . In addition, K(5)L(6)W contains approximately 40% 3(10)-helix and K(7)L(4)W is predominantly a random coil in membranes . Polarized ATR-FTIR and tryptophan-quenching experiments, using brominated phospholipids, revealed a similar depth of penetration and an orientation that was parallel to the membrane surface for all the peptides, but with K(3)L(8)W affecting the lipid order more than the others . The results provide insight into the mode of action of this group of diastereomeric peptides, and the effect of hydrophobicity and positive charges on their membrane structure, function, and cell selectivity . Moreover, this research should assist in the development of suitable diastereomeric peptide antibiotics for therapeutic use that would overcome the problem the increasing resistance of bacteria to conventional antibiotics.

Biochemistry, 1999 Dec 21, 38(51), 16749 - 55
Structure of the antimicrobial peptide tritrpticin bound to micelles: a distinct membrane-bound peptide fold; Schibli DJ et al.; Tritrpticin is a member of the cathelicidin family, a group of diverse antimicrobial peptides found in neutrophil granules . The three Trp and four Arg residues in the sequence VRRFPWWWPFLRR make this a Trp-rich cationic peptide . The structure of tritrpticin bound to membrane-mimetic sodium dodecyl sulfate micelles has been determined using conventional two-dimensional NMR methods . It forms two adjacent turns around the two Pro residues, a distinct fold for peptide-membrane interaction . The first turn involves residues 4-7, followed immediately by a second well-defined 3(10)-helical turn involving residues 8-11 . The hydrophobic residues are clustered together and are clearly separated from the basic Arg residues, resulting in an amphipathic structure . Favorable interactions between the unusual amphipathic fold and the micelle surface are probably key to determining the peptide structure . NMR studies of the peptide in the micelle in the presence of the spin-label 5-doxylstearic acid determined that tritrpticin lies near the surface of the micelle, where its many aromatic side chains appear to be equally partitioned into the hydrophilic-hydrophobic interface . Additional fluorescence studies confirmed that the tryptophan residues are inserted into the micelle and are partially protected from the effects of the soluble fluorescence quencher acrylamide.

Enferm Infecc Microbiol Clin, 1999, 17 Suppl 2, 86 - 94
{Evidence-based medicine, health costs and treatment of intra-abdominal infection}; Badia X et al.; BACKGROUND: Anti-infectious drugs are among the most-prescribed medications in the community, in 1997 being more than 9% of all drugs prescribed by the Spanish National Health System . In the particular case of the treatment of patients with moderate or severe intra-abdominal infection, economic aspects are important . Antimicrobial therapy is responsible for as much as 50% of the drug budget in some Spanish hospitals . On the other hand, as more options become available for the treatment of intra-abdominal infection, it is important to know their clinical and economic consequences . Imipenem/cilastatin (IC) is a broad-spectrum beta-lactam antibiotic that has demonstrated its effectiveness in the treatment of nosocomial and community-acquired bacterial infections . OBJECTIVE: The objective of this study was to determine if IC has a favorable cost-effectiveness relation compared to other antibiotic therapies for the treatment of intra-abdominal infections . METHODS: A cost-effectiveness analysis was made based on retrospective information on the treatment of patients over 18 with clinical suspicion of moderate-to-severe intra-abdominal infection . Health-care results were measured in natural health units (percentage of clinically favorable cases) in a systematic review of the literature . Direct health-care costs associated with the treatments compared were calculated . The other options studied, apart from IC, included the most common and least expensive option (a combination of an aminoglycoside and an anaerobicide {AA}) and an antibiotic from the same family as IC, meropenem (M) . RESULTS: The results, in terms of the percentage of patients with clinically favorable results, showed that the effectiveness of IC was equivalent to that of M (95.2% vs . 96.4%) and the AA association (88.0% vs . 86.6%) . Analysis of cost minimization showed that the total cost per patient treated with the IC and M options was similar, but that the lower price of IC slightly reduced the total cost per patient treated (ptas . 455,320 IC and ptas . 483,404 M) . In the comparison of IC and AA, the higher price of IC was compensated for by the lower cost associated with the duration of hospitalization in patients treated with IC (total cost per patients treated ptas . 844,678 IC and ptas . 1,009,180 AA) . CONCLUSIONS: The results of the meta-analysis showed that imipenem/cilastatin was highly effective (more than 90% clinically favorable results) and that it can be considered a minimum equivalent to meropenem and to the combination of an aminoglycoside and anaerobicide for the treatment of patients with moderate or severe intra-abdominal infection . Given the equivalence in effectiveness of the options studied, analysis of cost minimization was used to study their relative effectiveness . This analysis showed that IC was accompanied by lower costs per patient than M and AA . The most relevant variables in the study of the efficiency of the treatment of intra-abdominal infections were, in conditions of equivalent effectiveness, days of hospitalization (and associated costs) and drug price.

Enferm Infecc Microbiol Clin, 1999, 17 Suppl 2, 32 - 58
{Evidence-based medicine in antimicrobial surgical prophylaxis}; Vega D et al.; INTRODUCTION: The main objective of antibiotic prophylaxis in surgery is to reduce morbidity and mortality associated with wound infection, which has a favorable impact on quality of care and overall health-care costs . The bases of antibiotic prophylaxis have been known for decades, but the appearance of new pharmacological agents, alternative routes of administration, modern surgical procedures, and previously unknown antimicrobial resistances involve the need for reviewing these bases . OBJECTIVE: To re-evaluate some of the general principles of the use of antibiotic prophylaxis in surgery and highlight the quality of the evidence supporting our clinical decisions found in the literature . METHOD: Review of the literature with special attention to prospective, randomized, evidence-based clinical trials on the need for antibiotic prophylaxis in surgery, mainly general surgery . RESULTS: The method for demonstrating the effectiveness of an antibiotic in prophylaxis continues to be the prospective, randomized clinical trial . Evidence of the need for antibiotic prophylaxis in clean-contaminated surgery and when prosthetic materials are used is good . CONCLUSIONS: Most studies on the general principles of prophylaxis have been carried out in general surgery and it is difficult to extrapolate their results to other fields or surgical specialties . Therefore, new clinical trials in each specialty are needed to establish specific recommendations . However, the standardization of aseptic, antiseptic, and technical procedures in surgery has produced a notable decrease in the wound infection rate compared to historical controls, so now it is difficult to demonstrate significant differences in the results of clinical trials . Finally, the response to the fundamental question of "What do we propose to prevent and to what degree?" with which the antibiotic era began is either difficult to formulate or described ambiguously when referring to advanced procedures, such as endoprostheses, endoscopic retrograde cholangiography, or dental implants.

Enferm Infecc Microbiol Clin, 1999, 17 Suppl 2, 9 - 14
{Scientific evidence and antimicrobial therapy: A perfect couple?}; Jovell AJ; BACKGROUND: The dynamics of infectious diseases at the end of the century claims for the use of evidence-based medicine in clinical and public health decision-making . METHODS: Description of the methodological process of a systematic review of the evidence . RESULTS: Description of the stages of a systematic review of the evidence taking as case-study an example of the prevention of respiratory infection in acute care unit patients . CONCLUSION: The case-study described allows us to make recommendations based on the value of evidence to make clinical decisions on the use of antimicrobial therapy.

J Antibiot (Tokyo), 1999 Oct, 52(10), 873 - 9
Vinylamycin, a new depsipeptide antibiotic, from Streptomyces sp; Igarashi M et al.; A new depsipeptide antibiotic, vinylamycin, was isolated from the culture broth of an actinomycete strain . The producing organism, designated MI982-63F1, was identified as a member of Streptomyces . Vinylamycin was isolated from the culture broth by extraction with EtOAc and purified by crystallization from EtOAc . The structure of vinylamycin was determined by spectroscopic analysis and degradation studies . Vinylamycin showed antimicrobial activities against Gram-positive bacteria including MRSA.

Clin Nephrol, 1999 Dec, 52(6), 357 - 62
Effect of early fosfomycin treatment on prevention of hemolytic uremic syndrome accompanying Escherichia coli O157:H7 infection; Ikeda K et al.; OBJECTIVE: To clarify the effect of early fosfomycin treatment, an antimicrobial agent in common use in Japan, on children with E . coli O157 with the aim of preventing hemolytic uremic syndrome (HUS) . PATIENTS AND METHODS: Design: Non-randomized prospective study for development of HUS among inpatients with E . coli O157 . Setting: The hospitals where the 292 inpatients were treated . Cases: A total of 292 inpatients aged six to eleven years with E . coli O157 infection, 36 (12.3%) of whom were HUS cases . RESULTS: Most of the HUS inpatients (91.7%) developed this complication between the sixth and ninth day of illness . We therefore analyzed the effects of antimicrobial therapy, especially that of fosfomycin, on prevention of HUS within the first five days of illness, because fosfomycin was the most frequently used (88.0%) . To clarify the effect of fosfomycin alone on prevention of HUS, we carried out an analysis using the data for 130 inpatients who received fosfomycin alone or did not receive any antimicrobial agents, within the first five days of illness . multivariate analysis, controlled for age, gender and presence of fever, showed that all adjusted odds ratios for the development of HUS with the use of fosfomycin within the first three days of illness were less than 1.0, with the use of fosfomycin on the second day of illness achieving statistical significance (adjusted OR, 0.09; 95% CI, 0.01-0.79) . Furthermore, inpatients who took fosfomycin within the first two days of illness developed HUS significantly less often than those who did not (adjusted OR, 0.15; 95% CI, 0.03-0.78) . On the other hand, fosfomycin therapy on and after the third day of illness was not associated with the prevention of HUS . CONCLUSION: The early use of fosfomycin within the first two days of illness might prevent the development of HUS.

J Pept Res, 1999 Dec, 54(6), 522 - 7
Peptides with antimicrobial activity of the brevinin-1 family isolated from skin secretions of the southern leopard frog, Rana sphenocephala; Conlon JM et al.; Three peptides with growth-inhibitory activity towards the gram-negative bacterium Eschericia coli were isolated from electrically stimulated secretions from the skin of the southern leopard frog, Rana sphenocephala . Structural characterization demonstrated that the peptides {brevinin-1Sa, minimum inhibitory concentration (MIC) = 55 microM; brevinin-1Sb, MIC = 17 microM; brevinin-1Sc, MIC = 14 microM} represent new members of the brevinin-1 family of antimicrobial peptides, previously isolated from several other species of frogs of the genus Rana . Their high concentration in skin secretions and extreme variability in amino acid sequence suggest that the brevinin family of peptides may be of value as molecular markers for the identification and taxonomic classification of Ranid frogs.

Pharmazie, 1999 Nov, 54(11), 808 - 13
Quinoxaline derivatives . Part II: Synthesis and antimicrobial testing of 1,2,4-triazolo{4,3-a}quinoxalines, 1,2,4-triazino{4,3-a}quinoxalines and 2-pyrazolylquinoxalines; el-Hawash SA et al.; Three main classes of quinoxaline derivatives have been synthesized . The first class comprises the synthesis of three novel series of 1,2,4-triazolo{4,3-a}quinoxalines; namely 1-substituted-1,2,4-triazolo{4,3-a}quinoxalines 3a-f, 1-substituted aminomethyl-1,2,4-triazolo{4,3-a}quinoxalines 14a-d and 1-cyano or ethoxycarbonylmethyl-1,2,4-triazolo{4,3-a}quinoxalines 6, 12 . The second class involves the synthesis of 2-substituted-1 H-1,2,4-triazino{4,3-a}quinoxalines 4a-d . The third class deals with the synthesis of a variety of 2-pyrazolylquinoxalines, namely 2-(5-amino-3-arylpyrazol-1-yl)-3-phenylquinoxalines 5a-d, 2-{5-hydroxy-3-phenyl-4-(4-substituted sulfamoylphenyl)azopyrazol-1-yl}-3-phenylquinoxalines 15a, b, and 2-(5-hydroxy-4-nitroso-3-phenylpyrazol-1-yl)-3-phenylquinoxalin e (16) . The prepared compounds were tested in vitro for their antimicrobial activity . Compounds 13 and 14b exhibited promising antifungal activity against C . albicans (MIC 25, 50 mu/ml respectively) . Compound 13 was as active as the antibiotic nystatin.

Infect Immun, 2000 Jan, 68(1), 257 - 63
Effects of opsonization and gamma interferon on growth of Brucella melitensis 16M in mouse peritoneal macrophages in vitro; Eze MO et al.; Entry of opsonized pathogens into phagocytes may benefit or, paradoxically, harm the host . Opsonization may trigger antimicrobial mechanisms such as reactive oxygen or nitric oxide (NO) production but may also provide a safe haven for intracellular replication . Brucellae are natural intramacrophage pathogens of rodents, ruminants, dogs, marine mammals, and humans . We evaluated the role of opsonins in Brucella-macrophage interactions by challenging cultured murine peritoneal macrophages with Brucella melitensis 16M treated with complement- and/or antibody-rich serum . Mouse serum rich in antibody against Brucella lipopolysaccharide (LPS) (aLPS) and human complement-rich serum (HCS) each enhanced the macrophage uptake of brucellae . Combinations of suboptimal levels of aLPS (0 . 01%) and HCS (2%) synergistically enhanced uptake . The intracellular fate of ingested bacteria was evaluated with an optimal concentration of gentamicin (2 microg/ml) to control extracellular growth but not kill intracellular bacteria . Bacteria opsonized with aLPS and/or HCS grew equally well inside macrophages in the absence of gamma interferon (IFN-gamma) . Macrophage activation with IFN-gamma inhibited replication of both opsonized and nonopsonized brucellae but was less effective in inhibiting replication of nonopsonized bacteria . IFN-gamma treatment of macrophages with opsonized or nonopsonized bacteria enhanced NO production, which was blocked by N(G)-monomethyl L-arginine (MMLA), an NO synthesis inhibitor . MMLA also partially blocked IFN-gamma-mediated bacterial growth inhibition . These studies suggest that primary murine macrophages have limited ability to control infection with B . melitensis, even when activated by IFN-gamma in the presence of highly opsonic concentrations of antibody and complement . Additional cellular immune responses, e.g., those mediated by cytotoxic T cells, may play more important roles in the control of murine brucellosis.

Infect Immun, 2000 Jan, 68(1), 113 - 9
Transcriptional regulation of beta-defensin gene expression in tracheal epithelial cells; Diamond G et al.; Innate immunity provides an ever-present or rapidly inducible initial defense against microbial infection . Among the effector molecules of this defense in many species are broad-spectrum antimicrobial peptides . Tracheal antimicrobial peptide (TAP) was the first discovered member of the beta-defensin family of mammalian antimicrobial peptides . TAP is expressed in the ciliated epithelium of the bovine trachea, and its mRNA levels are dramatically increased upon stimulation with bacteria or bacterial lipopolysaccharide (LPS) . We report here that this induction by LPS is regulated at the level of transcription . Furthermore, the transfection of reporter gene constructs into tracheal epithelial cells indicates that DNA sequences in the 5' flanking region of the TAP gene, within 324 nucleotides of the transcription start site, are responsible in part for mediating gene induction . This region includes consensus binding sites for NF-kappaB and nuclear factor interleukin-6 (NF IL-6) transcription factors . Gel mobility shift assays indicate that LPS induces NF-kappaB binding activity in the nuclei of these cells, while NF IL-6 binding activity is constitutively present . The gene encoding human beta-defensin 2, a human homologue of TAP with similar inducible expression patterns in the airway, was cloned and found to have conserved NF-kappaB and NF IL-6 consensus binding sites in its 5' flanking region . Previous studies of antimicrobial peptides from insects indicated that their induction by infectious microbes and microbial products also occurs via activation of NF-kappaB-like and NF IL-6-like transcription factors . Together, these observations indicate that a strategy for the induction of peptide-based antimicrobial innate immunity is conserved among evolutionarily diverse organisms.

Pediatr Nephrol, 1999 Nov, 13(9), 838 - 9
A case of Fournier gangrene complicating idiopathic nephrotic syndrome of childhood; Wright AJ et al.; A 10-year-old boy presenting with steroid resistant nephrotic syndrome developed Fournier gangrene of the scrotum . Antimicrobial drug therapy, intravenous albumin, excision of necrotic scrotum and left orchidectomy followed by skin grafting 3 weeks later led to an excellent cosmetic and medical result . Six months later he remains nephrotic on diuretic and angiotensin converting enzyme inhibitor medication.

Antimicrob Agents Chemother, 2000 Jan, 44(1), 181 - 2
In vitro susceptibilities of rapidly growing mycobacteria to telithromycin (HMR 3647) and seven other antimicrobials; Fernandez-Roblas R et al.; The antimicrobial activities of telithromycin (HMR 3647) and seven other antimicrobials against 94 strains of rapidly growing mycobacteria were determined . Telithromycin at a concentration of 1 microg/ml inhibited Mycobacterium peregrinum (100%), Mycobacterium chelonae (80%), Mycobacterium abscessus-Mycobacterium mucogenicum (44.4%), and Mycobacterium fortuitum (2.1%) . All or most strains of M . peregrinum, M . fortuitum, and M . mucogenicum were inhibited by 2 microg of quinolones per ml.

Curr Opin Chem Biol, 1999 Dec, 3(6), 672 - 80
Synergy and duality in peptide antibiotic mechanisms; McCafferty DG et al.; The molecular mechanisms by which peptide antibiotics disrupt bacterial DNA synthesis, protein biosynthesis, cell wall biosynthesis, and membrane integrity are diverse, yet historically have been understood to follow a theme of one antibiotic, one inhibitory mechanism . In the past year, mechanistic and structural studies have shown a rich diversity in peptide antibiotic mechanism . Novel secondary targeting mechanisms for peptide antibiotics have recently been discovered, and the mechanisms of peptide antibiotics involved in synergistic relationships with antibiotics and proteins have been more clearly defined . In apparent response to selective pressures, antibiotic-producing organisms have elegantly integrated multiple functions and cooperative interactions into peptide antibiotic design for the purpose of improving antimicrobial success.

J Clin Periodontol, 1999 Dec, 26(12), 847 - 54
Combined systemic and local antimicrobial therapy of periodontal disease in Papillon-Lefèvre syndrome . A report of 4 cases; Rudiger S et al.; 4 patients, 2 pairs of siblings, suffering from Papillon-Lefevre syndrome were treated for periodontal disease . Following extraction of hopeless teeth, the children received scaling and adjunctive systemic antibiotics (metronidazole and amoxicillin for 7 to 10 days) . In addition, they performed supragingival pulsated jet irrigation with 0.06% chlorhexidine digluconate 1 x daily . In 2 siblings, A . actinomycetemcomitans was suppressed subgingivally below detectable levels, pocket probing depths were reduced to 4 mm or less, and plaque and bleeding indices were low . No further disease progression was seen over a 3-year-period . Another female patient also showed clinical improvement and suppression of subgingival A . actinomycetemcomitans and B . forsythus up to the 9-month-follow-up, while her sister showed further attachment loss over the course of 4 years . The present case reports indicated that in some patients suffering from Papillon-Lefevre syndrome periodontal disease may be arrested by means of (i) oral hygiene instruction, (ii) extraction of severely diseased teeth, (iii) scaling, (iv) systemic antibiotics and (v) long-term antimicrobial irrigation.

Adv Exp Med Biol, 1999, 455, 397 - 406
Newer concepts in antimicrobial therapy; Parish LC; Antimicrobial agents continue to play a significant role in clinical practice not only due to their active role in the treatment of bacterially induced infections . The accompanying anti-inflammatory characteristics and their antagonism against superantigens add to their importance . The practitioner must also be aware of both overt and covert unwanted effects . During the past decade, the new quinolones, advanced macrolides, and better cephalosporins have been introduced . The staid penicillins have been up-graded with the addition of a beta-lactamase inhibitor . Many antibiotics have been available for several decades but new uses for them and their derivatives permit the dermatologist to have a more versatile armamentarium . Rifamycin has been shown to be effective in the treatment of leishmaniasis . The new macrolide, clarithromycin, will reduce the lesions of acne vulgaris and acne rosacea . Although phototoxicity was well recognised in the sulfonomides, several quinolones can create similar light-induced problems . Bullous diseases are known to be instigated by the penicillins, while vasculitis may be caused by a quinolone . Even porphyria has been reported to be induced by a tetracycline . Antimicrobial therapy has been an integral part of dermatologic practice since the introduction of the sulfa drugs six decades ago . Whether skin is affronted by more pathogenic bacteria than any other organ or whether the percentage of infectious etiologies is greater for cutaneous maladies than for other organ afflictions is not germane to this presentation . The facts remain that signs and symptoms of many dermatitides are diminished or even eliminated by antimicrobials {1, 2, 3, 4}.

APMIS, 1999 Nov, 107(11), 971 - 81
Lactoferrin: a multifunctional glycoprotein; Vorland LH; Lactoferrin is an iron-binding glycoprotein found in milk, exocrine secretions of mammals, and in secondary granules from polymorphonuclear neutrophils . This review describes the wide spectrum of functions ascribed to lactoferrin, with special emphasis on the antimicrobial properties of this protein, and its derived peptides.

Xenobiotica, 1999 Nov, 29(11), 1157 - 69
Metabolism of furazolidone: alternative pathways and modes of toxicity in different cell lines; De Angelis I et al.; 1 . The metabolism and cytotoxicity of the antimicrobial nitrofuran drug furazolidone have been studied in Caco-2, HEp-2 and V79 cell lines . Free radical production, metabolite pattern, formation of bound residues, inhibition of cellular replication and protection by the antioxidant glutathione were compared for the three cell lines . 2 . All three cell lines produced the same nitro-anion radical with similar kinetics . Little further metabolic breakdown was observed in V79 cells, whereas Caco-2 and HEp-2 cells showed extensive degradation of furazolidone, but with different end patterns . 3 . Under hypoxic conditions, the colony-forming ability was extensively impaired in HEp-2 cells whereas the other two cell lines were less affected, suggesting that irreversible damage to DNA occurred prevalently in HEp-2 cells . In V79 cells the absence of oxygen caused a 25-fold increase in the formation of protein-bound residues . 4 . Brief exposure to furazolidone caused a 50% loss of endogenous glutathione in Caco-2 cells, but no loss could be detected in V79 and HEp-2 cells . Consistently, when glutathione was depleted by buthionine-{S,R}-sulphoximine (BSO) and diethylmaleate (DEM) treatment, the viability of V79 and HEp-2 cells was minimally affected by furazolidone, whereas that of Caco-2 cells was substantially reduced . 5 . It is concluded that the cytotoxicity of furazolidone in these cell lines can be exerted by a number of different mechanisms, possibly related to different metabolic pathways . The cytotoxicity of nitrofuran drugs, therefore, cannot be ascribed to a single toxic intermediate, but in Caco-2 cells furazolidone is extensively metabolized and detoxified by GSH, in V79 is only partially activated and then bound to proteins, whereas in HEp-2, once activated, may react with DNA.

Berl Munch Tierarztl Wochenschr, 1999 Oct-Nov, 112(10-11), 370 - 9
{Antibiotic growth promoters for the view of animal nutrition}; Kamphues J; From 01 . 07./09 . 1999 on six further antibiotic growth promoters have been banned--with only four substances remaining in this group of feed additives . Therefore, the discussion on a possible induction of bacterial resistance by antibiotic growth promoters, especially in potentially pathogenic bacteria, will sooner or later come to an end which is not least in the interest of the reputation of animal husbandry and food of animal origin . Unfortunately, no short-term solution for health problems by legislation--especially in the gastrointestinal tract--during rearing and the beginning of the fattening period is possible as experiences in Sweden have distinctively shown . Anyway, growth promoting feed additives were not a cure-all of rearing problems, in spite of their use considerable amounts of antibiotics were prescribed during this period . But growth promoters (especially chinoxalines) were most suitable for the prophylaxis of a microbial imbalance in the gastrointestinal tract . Therefore, after the ban of these effective representatives of feed additives the amount of prescribed antimicrobial drugs for metaphylaxis and therapy should be critically observed . The questions of practicable alternatives will be primarily addressed to the fields of animal nutrition, veterinary medicine and feed industry . To answer these questions and to evolve new solutions (as well as to check their suitability in practice) is considerably more intricate than simply to ban these substances which is more attractive for the media, however . It is no progressive solution to give up antimicrobial growth promoters as feed additives and to use the same substances (for example olaquindox) as therapeutics now (prescribed by veterinarians) or to switch to zincoxide or copper (in a dosage high above all nutrient requirements) in order to prevent postweaning problems due to E . coli . But one has to take into consideration the reasons for the use of antibiotics (growth promoters and therapeutics) or other "aids" (e.g . ZnO, Cu) in food producing animals (especially in beef-cattle, pigs and poultry) in "modern" production systems . The matter for conflict is the contrast between a minimised use of antimicrobial substances, as science as well as general public demand, and the requirements of "modern" livestock industry (rationalisation, increase in performance, specialisation, concentration) and general economy (save of resources, lowering of production costs) . These well-known and expected problems arise in an almost exemplary manner in the case of antibiotic growth promoting feed additives . Therefore it is most difficult to impart suggestions to the persons involved as well as to the public.

Boll Chim Farm, 1999 Jul-Aug, 138(7), 369 - 73
Preliminary report on antimicrobial activity of Helichrysum litoreum Guss; Guida M et al.; The authors present the preliminary results regarding the antibacterial action of extracts of Helichrysum litoreum Guss . The leaves and the young stems of this species, gathered on the slopes of Mt Vesuvius, in the Campania region, were ground and four extracts were made as follows: with dichloromethane, ethanol and water (70:30 v/v), water and methanol . The antibacterial activity of each of the samples was tested in order to determine which of the extracts was more antibacterial . The results of the test showed that the extract with the ethanol/water (70/30 v/v) was the most active one . This will allow us to advance in the research, purifying the extract and hopefully identifying the active principles.

Helicobacter, 1999 Dec, 4(4), 218 - 21
Pretreatment antimicrobial susceptibilities of paired gastric Helicobacter pylori isolates: antrum versus corpus; Ikezawa K et al.; BACKGROUND: Antimicrobial susceptibility testing of Helicobacter pylori isolates is the most useful tool for guiding specific therapy, especially when primary resistance is suspected . However, the most informative gastric biopsy site for detection of resistant H . pylori isolates is uncertain . We sought to determine whether susceptibilities to commonly used antimicrobials (amoxicillin, clarithromycin, minocycline, and metronidazole) were related to biopsy site . METHODS: H . pylori isolates were obtained from patients who had duodenal ulcer and had not received any therapy directed against H . pylori . Agar-dilution minimum inhibitory concentrations of each antimicrobial were compared between paired H . pylori isolates from the antrum and the proximal corpus . RESULTS: Differences in minimum inhibitory concentrations exceeding twofold were observed within the pairs of H . pylori isolates in 5 of the 40 patients tested . In three patients with clarithromycin-resistant isolates and two with metronidazole-resistant isolates, both antral and corporeal specimens revealed resistance . However, no patient had pairs of isolates categorized as resistant at one site and sensitive at the other . CONCLUSIONS: While we found that an individual may have a mixed H . pylori infection with respect to differing antimicrobial susceptibility in different parts of the stomach, a single biopsy specimen from either the antrum or the corpus should provide reliable detection of H . pylori isolates with primary resistance.

Am J Health Syst Pharm, 1999 Dec 1, 56(23 Suppl 4), S5 - 11
Use of proton-pump inhibitors in complicated ulcer disease and upper gastrointestinal tract bleeding; Howden CW; The use of proton-pump inhibitors in the management of complicated peptic ulcer disease and upper gastrointestinal bleeding is described . Treatment of peptic ulcers in patients who are Helicobacter pylori positive should include antimicrobial therapy to eradicate the infection; based on considerations of primary antimicrobial resistance and safety, one recommended regimen is the combination of a proton-pump inhibitor (lansoprazole 30 mg or omeprazole 20 mg), clarithromycin 500 mg, and amoxicillin 1 g, each twice daily for 14 days . The proportion of H . pylori-negative ulcers has increased in the United States, now accounting for 39% of patients with ulcers who report no intake of nonsteroidal anti-inflammatory drugs (NSAIDs) . Compared with H . pylori-positive ulcers, H . pylori-negative ulcers are more aggressive, characterized by high recurrence rates and increased risk of bleeding and perforation . Long-term therapy with a proton-pump inhibitor may be useful in these patients . Acid suppressants may also have a role in the initial treatment of patients who have a bleeding ulcer, including those associated with NSAID use . For patients who require continuous NSAID therapy, proton-pump inhibitors have been shown to heal a significantly higher percentage of peptic ulcers in eight weeks than histamine H2-receptor antagonists, and maintenance therapy with either lansoprazole or omeprazole reduces ulcer recurrence . Preliminary data suggest a role for proton-pump inhibitors in the prevention of stress ulcers among critically ill patients . Proton-pump inhibitors play an important role in the treatment of both H . pylori-negative and H . pylori-positive peptic ulcers, as well as in upper gastrointestinal tract bleeding . Further study is needed regarding their role in preventing stress ulcers in critically ill patients.

Vestn Otorinolaringol, 1999, (6), 24 - 7
{Clinical and therapeutic aspects of otogenic sepsis in the antibiotic era}; Gadzhimirzaev GA; 152 cases of otogenic thrombophlebitis of the sigmoid sinus (TSS) are analysed . 128 (84.2%) patients had thrombophlebitis and sepsis, 24 (15.8%) had thrombophlebitis without sepsis . TSS occurred more frequently in combination with other intracranial complications . In conditions of wide use of antibiotics and other drugs thromboembolic and toxicoinfectious otogenic complications may run with an atypical clinical picture: with reduced symptoms, without classic manifestations of sepsis . In diagnosis such investigations as computed tomography, MR-tomography, ultrasonography may be decisive . Major diagnostic criterium in diagnosis of otogenic sepsis is polyorganic insufficiency . Otogenic thrombophlebitis and sepsis is treated first of all surgically--the purulent focus in the ear should be cleansed . Postoperative treatment includes antimicrobial drugs, immunomodulators, anticoagulants, antihistaminic, detoxicating and antiedematic medicines, UV irradiation of autoblood and hyperbaric oxygenation.

Gac Med Mex, 1999 Sep-Oct, 135(5), 457 - 62
{The costs of hospital infections in a group of patients in a tertiary-care hospital}; Juarez-Munoz IE et al.; OBJECTIVE: To know the cost generated by nosocomial infections, to establish the proportion of the total hospital budget used in extra-days of stay, drugs, laboratory and others items used for the treatment . METHODS: We studied 131 nosocomial infections in 82 patients attended in hospital's departments from June to August 1995 . We evaluated days of stay, type of infection, episodes per patient, drugs, laboratory, and others items used in the treatment of nosocomial infections . We took percentage of cost of every point and the mean of the total cost generated by year cause nosocomial infections and a cost per infection in every department . RESULTS: The total overtime of stay was 970 days, mean per infection was 7.4 . Totals days of antimicrobials was 974, mean was 11.9 days per infection . The hospital processed 410 laboratory studies, 191 cabinet studies . The total cost generated by overtime stay was $3,415,860.00, and considering also drugs, laboratory and cabinet studies $3,516,421.00 . CONCLUSIONS: The cost of the nosocomial infections depends on the overtime stay, drugs, laboratory and cabinet studies needed for their treatment . Neonatology generated presented more than one infection generating higher cost . Total cost in 3 months was $3'516,421.00, nosocomial infections would take $14'065,684.00 in a year, involving 12.1% of the hospital total budget . Preventive measures must be taken trying to diminish these costs.

J Agric Food Chem, 1999 Mar, 47(3), 1208 - 16
Chitosan treatment of wheat seeds induces resistance to Fusarium graminearum and improves seed quality; Bhaskara Reddy MV et al.; Chitosan treatment (2-8 mg/mL) of wheat seeds significantly improved seed germination to recommended seed certification standards (>85%) and vigor at concentrations >4 mg/mL, in two cultivars of spring wheat (Norseman and Max), by controlling seed-borne Fusarium graminearum infection . The germination was <80% in the control and >85% in benomyl- and chitosan-treated seeds . Seed-borne F . graminearum was reduced to >50% at higher chitosan treatments compared to the control . Synthesis of phenolic acids was stimulated in primary leaves following chitosan treatment, and levels of these phenolic acids, especially ferulic acid, increased significantly with increasing chitosan concentration . Lignin content of primary leaves also showed a similar pattern . The synthesis of precursors of lignin such as p-coumaric, ferulic, and sinapic acids and phenolic acids having antimicrobial activity such as benzoic, p-coumaric, caffeic, protocatechuic, chlorogenic, ferulic, and gallic acids was also stimulated by chitosan treatment . The induction of phenolic acids and lignin was significantly lower in cv . Max compared to Norseman . Chitosan also inhibited fungal transmission to the primary roots of germinating seedlings . Results suggest that chitosan controlled seed-borne F . graminearum infection and increased the resistance in seedlings by stimulating the accumulation of phenolics and lignin . Thus, chitosan has a potential for improvement of seed quality and enhancement of crop yields as well as increased value of stored grains for food and feed.

Clin Pharmacokinet, 1999 Oct, 37(4), 289 - 304
Basis of anti-infective therapy: pharmacokinetic-pharmacodynamic criteria and methodology for dual dosage individualisation; Sanchez-Navarro A et al.; Antimicrobial therapy should be designed on the basis of microbiological, as well as pharmacokinetic, criteria; microbiological parameters provide information about the susceptibility of the pathogen responsible for the infectious process while pharmacokinetic parameters give information about the potential ability of the drug in question to reach and remain at the sites of infection in the body . Microbiological parameters such as the minimum inhibitory concentration, minimum bactericidal concentration, bacterial titre, bactericidal rate and 'post-antibiotic effect' (PAE) must be considered . Among the pharmacokinetic parameters, the maximum serum concentration at steady state (CmaxSS), area under the concentration-time curve (AUC) and length of time that the serum concentrations exceed a particular value are the most useful in this context . Different relationships between these parameters, known as efficacy indices, have been established to predict the potential efficacy of antibacterial therapy . Antimicrobial dosage individualisation should be based on the optimisation of the efficacy index that best correlates with patient response . It seems appropriate to establish the degree of correlation among the different efficacy indices and clinical response observed in patients by means of a correlation analysis . This type of analysis can be either retrospective or prospective and may be based on linear or maximum response models . Simulation of the plasma concentration curves obtained with the particular regimen administered offers a methodology which is easy to apply and provides the pharmacokinetic information necessary to calculate the different efficacy indices . Information about the susceptibility of the pathogen to the antibacterial in question and about the response to the treatment used is also necessary for the correlation analysis . This type of analysis determines which of the indices is best correlated with efficacy and, hence, is the index to be optimised when attempting to individualise antibacterial therapy for different situations.

Drugs, 1999, 58 Suppl 2, 103 - 6
Outcome of antibiotic therapy with ciprofloxacin in chronic bacterial prostatitis; Weidner W et al.; Chronic bacterial prostatitis (CBP) is a rare infection of the prostate with Escherichia coli being the predominant causative pathogen . Appropriate antimicrobial therapy is mandatory for cure . We report on our experience with a 4-week regimen of ciprofloxacin in 40 men suffering from CBP due to E . coli . Follow-up was conducted over a period of 12 to 24 months . The microbiological work-up included an analysis of expressed prostatic secretions (EPS) and semen . Eradication of the pathogen in EPS was achieved in 92% of patients 3 months after therapy and in about 70 to 80% of patients evaluated 12 and 24 months after treatment, respectively . Treatment failure was not associated with the presence of prostatic calculi, as assessed by transrectal ultrasonography . After successful therapy, mean EPS pH decreased significantly from 7.95 to 7.35 . Significant bacteriospermia with E . coli was detected in 21/22 (95.5%) patients before treatment and in 6/22 (27.3%) patients 6 months after therapy . Our data reconfirm ciprofloxacin as an excellent antimicrobial agent in the therapy of CBP . However, eradication of the pathogen is unpredictable and cannot be achieved in every case . Further studies should correlate microbiological treatment success with symptomatic relief, as assessed by standardised questionnaires.

Drugs, 1999, 58 Suppl 2, 49 - 51
Quinolones in the aged; Nicolle LE; Pharmacokinetic studies of fluoroquinolone antibacterials generally demonstrate some quantitative alterations in elderly compared with younger populations . The most common observations are an increased maximal plasma drug concentration and area under the concentration-time curve, which are primarily attributable to the 10 to 15% decrease in lean body mass in the elderly . For quinolones excreted primarily by the renal route, there is a prolongation in elimination half-life correlated with the aging-associated decline in creatinine clearance . Quinolones with major routes of nonrenal clearance will not usually show a prolongation in half-life because of compensatory relative increases in nonrenal mechanisms . Alterations directly attributable to aging alone, however, are minor, and vary between different quinolones . They do not justify a consistent need for dosage alterations on the basis of age alone . Agents with primarily renal excretion, such as ofloxacin or levofloxacin, may require dosage adjustment in the very elderly or the frail elderly, if significant decreases in creatinine clearance are present . No age-related differences in adverse effects of fluoroquinolones have been reported . Studies in both community-dwelling and institutionalised elderly populations have consistently shown quinolones to be as effective as comparative parenteral or oral therapy . While elderly populations may be at greater risk of adverse effects because of comorbidities and concurrent therapies, an increased occurrence of adverse events in elderly populations receiving quinolone antimicrobials relative to younger populations has not been reported.

J Antimicrob Chemother, 1999 Nov, 44(5), 709 - 15
Sequential antimicrobial therapy: treatment of severe lower respiratory tract infections in children; Al-Eidan FA et al.; Although there have been a number of studies in adults, to date there has been little research into sequential antimicrobial therapy (SAT) in paediatric populations . The present study evaluates the impact of a SAT protocol for the treatment of severe lower respiratory tract infection in paediatric patients . The study involved 89 paediatric patients (44 control and 45 SAT) . The SAT patients had a shorter length of hospital stay (4.0 versus 8.3 days), shorter duration of inpatient antimicrobial therapy (4.0 versus 7.9 days) with the period of iv therapy being reduced from a mean of 5.6 to 1.7 days . The total healthcare costs were reduced by 52% . The resolution of severe lower respiratory tract infection with a short course of iv antimicrobials, followed by conversion to oral therapy yielded clinical outcomes comparable to those achieved using longer term iv therapy . SAT proved to be an important cost-minimizing tool for realizing substantial healthcare costs savings.

J Antimicrob Chemother, 1999 Nov, 44(5), 653 - 9
In-vitro activity of rifabutin and albendazole singly and in combination with other clinically used antimicrobial agents against Pneumocystis carinii; Cirioni O et al.; The in-vitro activity of rifabutin and albendazole alone and in combination with clarithromycin, etoposide, minocycline and pyrimethamine was investigated against four clinical isolates of Pneumocystis carinii . The susceptibility tests were performed by inoculation of the isolates on to cell monolayers and by determining the parasite count after 72 h incubation at 37 degrees C . The culture medium was supplemented with serial dilutions of each agent . Albendazole tested alone was more active than rifabutin . Albendazole suppressed the growth of cysts and trophozoites by >50% at 4 mg/L . Rifabutin, at the same concentration, produced about 40% reduction in the mean cyst and trophozoite counts . Albendazole (4 mg/L) combined with etoposide 4 mg/L showed the highest anti-P . carinii activity, with a decrease of 86.3% and 90.1% in cyst and trophozoite counts, respectively . The greatest synergic interaction was detected when rifabutin (4 mg/L) was combined with clarithromycin (4 mg/L) . Our study suggests that clinically used antimicrobial agents may be effective in inhibiting P . carinii growth in vitro and that, above all, some of these agents possess a positive interaction upon combination with other clinically used compounds . These findings may be useful in the establishment of a prophylaxis regimen for multiple opportunistic pathogens.

Microbes Infect, 1999 Jan, 1(1), 29 - 38
Legal challenges posed by the use of antimicrobials in food animal production; Fidler DP; This review article provides a general analysis of the legal challenges presented by antimicrobial use in food animal production and the emerging public health responses to such use . The article stresses the importance of national and international law to the public health strategies and the interdependence between national and international law . The article argues that antimicrobial use in food animal production poses a challenge to the development of global health jurisprudence.

J Appl Microbiol, 1999 Nov, 87(5), 750 - 6
Antimicrobial activity of a 14-residue peptide against Escherichia coli O157:H7; Appendini P et al.; An amphiphilic, cationic peptide composed of eight leucines and six lysines was synthesized by solid phase peptide synthesis (SPPS) . The synthetic peptide was bactericidal within 10 min at concentrations as low as 3 microg ml - 1 against mid-exponential Escherichia coli O157:H7 suspended in buffer . Concentrations of 25 microg ml - 1 caused up to 7 log10 cfu ml - 1 reductions . When tested against E . coli O157:H7 grown in TSB, the peptide was bactericidal and bacteriostatic at concentrations of 50 and 25 microg ml - 1, respectively . An inhibitory effect was also observed against stationary phase cells . The synthetic peptide caused the release of u.v.-absorbing materials from the E . coli O157:H7 as well as an increase in its O.D.600 nm . Intracellular K+ and ATP depletion were also observed . These results suggest that the peptide increased the cell membrane permeability but it did not lyse the cells.

Curr Microbiol, 2000 Feb, 40(2), 96 - 100
Clarithromycin and amoxicillin susceptibility of Helicobacter pylori strains isolated from adult patients with gastric or duodenal ulcer in Italy; Franzin L et al.; Helicobacter pylori strains, isolated from 100 gastric biopsies from 49 previously untreated adult patients with endoscopy and histology-confirmed gastric or duodenal ulcer, were tested for in vitro antimicrobial susceptibility . Strains were isolated from biopsies of 75.5% (37 of 49) patients before therapy and of 13.5% after therapy . Clarithromycin and amoxicillin susceptibility testing was performed on pretreatment and posttreatment strains by using the agar disk diffusion method and E-test, a quantitative technique for the minimal inhibitory concentration (MIC) determination . All strains (n = 53) were susceptible to amoxicillin by the two methods . Three strains of 34 (8.8%) patients were resistant to clarithromycin: two by both methods and one by E-test (MIC > 2 microg/ml) . E-test, although more expensive than the disk diffusion method, is easy to perform and is a reliable method for testing H . pylori susceptibility to antimicrobial agents in the clinical microbiology laboratory.

Drugs, 1999 Nov, 58(5), 785 - 92
Helicobacter pylori eradication in patients with non-ulcer dyspepsia; Xia HH et al.; Epidemiological and pathophysiological studies, as well as clinical trials, attempting to identify a relationship between Helicobacter pylori infection and non-ulcer dyspepsia (NUD), or a subset of NUD, have produced inconsistent and confusing results . While it is possible that H . pylori eradication may be beneficial for symptom relief in a small proportion of patients, routine H . pylori testing and treatment in documented NUD is not currently widely accepted . Despite the lack of convincing evidence, the European Helicobacter pylori Study Group, an Asian Pacific Consensus Meeting, the American Digestive Health Foundation and the American Gastroenterology Association have all recommended considering H . pylori eradication in patients with NUD on a patient-by-patient basis . Recently, large prospective, randomised, double-blind, controlled clinical trials applying highly effective antimicrobial therapy have been conducted with 12 months follow-up . Although these well-designed studies have reached differing conclusions, the results have been largely negative . H . pylori eradication therapy in NUD will fail to relieve symptoms in most patients in the long term.

Int J Antimicrob Agents, 1999 Oct, 13(2), 127 - 30
Empiric antimicrobial therapy of febrile neutropenic patients undergoing haematopoietic stem cell transplantation; Antabli BA et al.; This study was conducted to assess the efficacy and toxicity of intravenous (i.v.) ceftazidime and ciprofloxacin in neutropenic febrile patients undergoing high dose myeloablative therapy and hematopoietic stem cell transplantation (HSCT) . All patients undergoing HSCT for leukaemia, lymphoma, multiple myeloma and solid tumours received open-label ceftazidime 2 g i.v . every 8 h and ciprofloxacin 400 mg i.v . every 12 h if they developed fever while they were neutropenic . Success with or without modification of this regimen was defined as survival through the neutropenic period; failure was defined as death secondary to infection . Of 106 patients treated with this regimen, the success rate was 99% . Sixty-one of the patients (57.5%) defervesced within 48-72 h and remained afebrile without regimen modification . In 41.5% of the cases (44/106), the regimen was modified because of persistent fever . One patient died secondary to sepsis . The combination of ceftazidime and ciprofloxacin as initial empiric antibacterial therapy in febrile neutropenic patients undergoing myeloablative therapy and HSCT is highly effective and is associated with minimal toxicity.

Protein Sci, 1999 Nov, 8(11), 2330 - 7
The complexed structure and antimicrobial activity of a non-beta-lactam inhibitor of AmpC beta-lactamase; Powers RA et al.; Beta-lactamases are the major resistance mechanism to beta-lactam antibiotics and pose a growing threat to public health . Recently, bacteria have become resistant to beta-lactamase inhibitors, making this problem pressing . In an effort to overcome this resistance, non-beta-lactam inhibitors of beta-lactamases were investigated for complementarity to the structure of AmpC beta-lactamase from Escherichia coli . This led to the discovery of an inhibitor, benzo(b)thiophene-2-boronic acid (BZBTH2B), which inhibited AmpC with a Ki of 27 nM . This inhibitor is chemically dissimilar to beta-lactams, raising the question of what specific interactions are responsible for its activity . To answer this question, the X-ray crystallographic structure of BZBTH2B in complex with AmpC was determined to 2.25 A resolution . The structure reveals several unexpected interactions . The inhibitor appears to complement the conserved, R1-amide binding region of AmpC, despite lacking an amide group . Interactions between one of the boronic acid oxygen atoms, Tyr150, and an ordered water molecule suggest a mechanism for acid/base catalysis and a direction for hydrolytic attack in the enzyme catalyzed reaction . To investigate how a non-beta-lactam inhibitor would perform against resistant bacteria, BZBTH2B was tested in antimicrobial assays . BZBTH2B significantly potentiated the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria . This inhibitor was unaffected by two common resistance mechanisms that often arise against beta-lactams in conjunction with beta-lactamases . Porin channel mutations did not decrease the efficacy of BZBTH2B against cells expressing AmpC . Also, this inhibitor did not induce expression of AmpC, a problem with many beta-lactams . The structure of the BZBTH2B/AmpC complex provides a starting point for the structure-based elaboration of this class of non-beta-lactam inhibitors.

Br J Clin Pharmacol, 1999 Dec, 48(6), 839 - 46
Cutaneous reactions to drugs . An analysis of spontaneous reports in four Italian regions; Naldi L et al.; AIMS: Cutaneous manifestations are frequently reported in association with drug use . The aim of this study was to analyse the skin reactions reported to the spontaneous surveillance systems of four Italian regions (Friuli Venezia Giulia, Lombardy, Sicily and the Veneto), and correlate the reports with estimated drug consumption during the same period, paying particular attention to the reactions to antimicrobial agents and nonsteroidal anti-inflammatory drugs (NSAIDs) . METHODS: All of the adverse drug reactions (ADRs) reported spontaneously between January 1996 and December 1997 to the surveillance systems of four Italian regions (a total population of about 20 million people) were analysed by a panel of experts including dermatologists . On the basis of the Critical Term List of the World Health Organization (WHO), the reactions were classified as either serious or nonserious events . Drug consumption was expressed as a daily defined dose (DDD)/1000 inhabitants/day . RESULTS: A total of 2224 adverse skin reaction reports (44.7% of all of the reported ADRs) were identified, making a reporting rate of about 5.5 per 100 000 inhabitants/year . The female/male ratio was 1.58, and the reporting rate progressively increased with age . The drug categories with the highest number of cutaneous reactions were antimicrobials, followed by NSAIDs, analgesics and radiology contrast media . There was a total of 372 (16.9%) serious reaction reports, the most frequent being angioedema (171 cases), erythema multiforme (68 cases) and photosensitivity (37 cases) . Co-trimoxazole, followed by the cephalosporins and fluoroquinolones, were associated with the highest consumption-related reporting rate among the antimicrobials, and aspirin and dipyrone among the NSAIDs and analgesics . CONCLUSIONS: Spontaneous reports from four Italian regions revealed that the skin was the organ most frequently affected by ADRs . The paper shows the validity of a regional decentralized system in Italy.

Aliment Pharmacol Ther, 1999 Dec, 13(12), 1639 - 45
Efficacy of two different dosage regimens of omeprazole, amoxycillin and metronidazole for the cure of Helicobacter pylori infection; Bayerdorffer E et al.; BACKGROUND: While addition of metronidazole to the omeprazole-amoxycillin combination has been shown to be advantageous, the optimal dosage and drug distribution of the antimicrobials has not been sufficiently evaluated . AIM: To investigate the efficacy of two different regimens of omeprazole, amoxycillin and metronidazole for the cure of Helicobacter pylori infection . METHODS: Two hundred and fifty-five patients with H . pylori associated duodenal ulcers were randomly treated with either a 1-week regimen of omeprazole 20 mg b.d., amoxycillin 1000 mg b.d . and metronidazole 800 mg b.d . (OAM b.d.) or a combination of omeprazole 40 mg o.d., amoxycillin 500 mg t.d.s . and metronidazole 400 mg t.d.s . (OAM t.d.s.) . All patients subsequently received omeprazole 20 mg o.d . for an additional 3 weeks . H . pylori status was assessed by histology and 13C-UBT prior to treatment and 8 weeks after randomization . Additional biopsies were obtained for H . pylori culture to determine primary and secondary resistance to metronidazole by agar dilution . RESULTS: Two hundred and thirty-seven patients were included in the intention-to-treat analysis and 198 patients in the per protocol analysis . With intention-to-treat analysis, the cure rate was 77% after treatment with OAM b.d . (95% CI, 69%-85%) and 76% after OAM t . d.s . therapy (95% CI, 67%-83%) . Ulcer healing (intention-to-treat analysis) was documented in 95% of patients in the OAM b.d . group (n=122) and in 97% of patients in the OAM t.d.s . group (n=115) . Adverse events were reported in 26 (20%) and in 18 (14%) patients in the OAM b.d . and OAM t.d.s . groups, respectively . None resulted in discontinuation of treatment . Overall primary resistance of H . pylori against metronidazole was found in 22 of 116 strains (19%) . CONCLUSIONS: The combination of omeprazole, amoxycillin and metronidazole achieves about an 80% cure rate of H . pylori infection even in active ulcers . The total daily dose, and the choice of twice or three times daily dosing does not seem critical with this regimen.

Curr Pharm Des, 1999 Nov, 5(11), 839 - 45
beta-Lactamases of increasing clinical importance; Bush K; Resistance to b-lactam-containing antimicrobial agents continues to increase, frequently due to the presence of b-lactamases in Gram-negative bacteria . Over the past twenty-five years broad-spectrum enzymes such as TEM- and SHV-variants and the metallo-b-lactamases have become more prolific . As a result of the ability of plasmids to continue to acquire additional resistance determinants, many of the b-lactamase-producing Gram-negative pathogens have become multi-drug resistant . In combination with decreased permeability, the organisms can become virtually untreatable with current therapies . The major groups of b-lactamases that pose the most serious therapeutic problems include the extended-spectrum b-lactamases, the plasmid-mediated cephalosporinases, the inhibitor-resistant TEM- or SHV-derived b-lactamases and the carbapenem-hydrolyzing b-lactamases . Those enzymes that can be transferred on mobile elements are the most serious of the newer b-lactamases, and include enzymes in each of the four groups outlined above.

Proteins, 1999 Nov 15, 37(3), 388 - 403
The three-dimensional solution structure of Aesculus hippocastanum antimicrobial protein 1 determined by 1H nuclear magnetic resonance; Fant F et al.; Aesculus hippocastanum antimicrobial protein 1 (Ah-AMP1) is a plant defensin isolated from horse chestnuts . The plant defensins have been divided in several subfamilies according to their amino acid sequence homology . Ah-AMP1, belonging to subfamily A2, inhibits growth of a broad range of fungi . So far, a three-dimensional structure has been determined only for members of subfamilies A3 and B2 . In order to understand activity and specificity of these plant defensins, the structure of a protein belonging to subfamily A2 is needed . We report the three-dimensional solution structure of Ah-AMP1 as determined from two-dimensional 1H nuclear magnetic resonance data . The structure features all the characteristics of the "cysteine-stabilized alpha beta-motif." A comparison of the structure, the electrostatic potential surface and regions important for interaction with the fungal receptor, is made with Rs-AFP1 (plant defensin of subfamily A3) . Thus, residues important for activity and specificity have been assigned.

Ned Tijdschr Geneeskd, 1999 Nov 20, 143(47), 2361 - 4
{Clinical results and costs due to improved antibiotics policies}; Gyssens IC et al.; Major reasons to conduct antibiotic policies are to improve the quality of patient care, to limit the emergence of resistance, and to contain costs . Many studies have addressed overconsumption and misuse of antibiotics . Studies have shown a correlation between antibiotic use in hospitals and the development of microbial resistance . Recommendations for the content and management of future antibiotic policy strategies in hospitals include educational programmes, consultation by infectious diseases physicians, restriction of the formulary, timely narrowing of empirical broad spectrum therapy ('streamlining'), and automatic stop orders . A recent study in a Dutch university hospital revealed overconsumption of antibiotics for prophylaxis in surgery and undertreatment with antibiotics in internal medicine departments . Intervention resulted in better compliance with guidelines, reduction of the consumption of antibiotics in surgical prophylaxis, and cost containment . However optimation of antimicrobial therapy also sometimes resulted in an increase of antimicrobial drug consumption.

Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi, 1996 Feb, 29(1), 18 - 30
Effect of vapor phase corrosion inhibitor on microbial corrosion of aluminum alloys; Yang SS et al.; Vapor phase corrosion inhibitors were used to investigate the antimicrobial activities and anticorrosion of aluminum alloy . Aspergillus flavus, A . niger, A . versicolor, Chaetomium globosum and Penicillium funiculosum had moderate to abundant growth on the aluminum alloy AA 1100 at Aw 0.901, while there was less growth at Aw 0.842 . High humidity stimulated microbial growth and induced microbial corrosion . Dicyclohexylammonium carbonate had a high inhibitory effect on the growth of test fungi and the microbial corrosion of aluminum alloy, dicyclohexylammonium caprate and dicyclohexylammonium stearate were the next . Aluminum alloy coating with vapor phase corrosion inhibitor could prevent microbial growth and retard microbial corrosion.

Biochim Biophys Acta, 1999 Dec 15, 1462(1-2), 223 - 34
The lantibiotic nisin, a special case or not?
Breukink E, de Kruijff B.
Nisin is a 34-residue-long peptide belonging to the group A lantibiotics with antimicrobial activity against Gram-positive bacteria . The presence of dehydrated residues and lanthionine rings (thioether bonds) in nisin, imposing structural restrains on the peptide, make it an interesting case for studying the mode of action . In addition, the relatively high activity (nM range) of nisin against Gram-positive bacteria indicates that nisin may be a special case in the large family of pore-forming peptides antibiotics . In this review, we attempted to dissect the mode of action of nisin concentrating on studies that used model membranes or biological membranes . The picture that emerges suggests that in model membrane systems, composed of only phospholipids, nisin behaves similar to the antimicrobial peptide magainin, albeit with an activity that is much lower as compared to its activity towards biological membranes . This difference can be contributed to a missing factor which nisin needs for its high activity . Novel results have identified the factor as Lipid II, a precursor in the bacterial cell wall synthesis . The special high affinity interaction of nisin with Lipid II resulting in high activity and the active role of Lipid II in the pore-formation process make nisin a special case.

Biochim Biophys Acta, 1999 Dec 15, 1462(1-2), 185 - 200
Simulation studies of the interaction of antimicrobial peptides and lipid bilayers; La Rocca P et al.; Experimental studies of a number of antimicrobial peptides are sufficiently detailed to allow computer simulations to make a significant contribution to understanding their mechanisms of action at an atomic level . In this review we focus on simulation studies of alamethicin, melittin, dermaseptin and related antimicrobial, membrane-active peptides . All of these peptides form amphipathic alpha-helices . Simulations allow us to explore the interactions of such peptides with lipid bilayers, and to understand the effects of such interactions on the conformational dynamics of the peptides . Mean field methods employ an empirical energy function, such as a simple hydrophobicity potential, to provide an approximation to the membrane . Mean field approaches allow us to predict the optimal orientation of a peptide helix relative to a bilayer . Molecular dynamics simulations that include an atomistic model of the bilayer and surrounding solvent provide a more detailed insight into peptide-bilayer interactions . In the case of alamethicin, all-atom simulations have allowed us to explore several steps along the route from binding to the membrane surface to formation of transbilayer ion channels . For those antimicrobial peptides such as dermaseptin which prefer to remain at the surface of a bilayer, molecular dynamics simulations allow us to explore the favourable interactions between the peptide helix sidechains and the phospholipid headgroups.

Biochim Biophys Acta, 1999 Dec 15, 1462(1-2), 157 - 83
The structure, dynamics and orientation of antimicrobial peptides in membranes by multidimensional solid-state NMR spectroscopy; Bechinger B; Linear peptide antibiotics have been isolated from amphibians, insects and humans and used as templates to design cheaper and more potent analogues for medical applications . Peptides such as cecropins or magainins are < or = 40 amino acids in length . Many of them have been prepared by solid-phase peptide synthesis with isotopic labels incorporated at selected sites . Structural analysis by solid-state NMR spectroscopy and other biophysical techniques indicates that these peptide antibiotics strongly interact with lipid membranes . In bilayer environments they exhibit amphipathic alpha-helical conformations and alignments of the helix axis parallel to the membrane surface . This contrasts the transmembrane orientations observed for alamethicin or gramicidin A . Models that have been proposed to explain the antibiotic and pore-forming activities of membrane-associated peptides, as well as other experimental results, include transmembrane helical bundles, wormholes, carpets, detergent-like effects or the in-plane diffusion of peptide-induced bilayer instabilities.

Biochim Biophys Acta, 1999 Dec 15, 1462(1-2), 141 - 56
Differential scanning calorimetry and X-ray diffraction studies of the specificity of the interaction of antimicrobial peptides with membrane-mimetic systems; Lohner K et al.; Interest in biophysical studies on the interaction of antimicrobial peptides and lipids has strongly increased because of the rapid emergence of antibiotic-resistant bacterial strains . An understanding of the molecular mechanism(s) of membrane perturbation by these peptides will allow a design of novel peptide antibiotics as an alternative to conventional antibiotics . Differential scanning calorimetry and X-ray diffraction studies have yielded a wealth of quantitative information on the effects of antimicrobial peptides on membrane structure as well as on peptide location . These studies clearly demonstrated that antimicrobial peptides show preferential interaction with specific phospholipid classes . Furthermore, they revealed that in addition to charge-charge interactions, membrane curvature strain and hydrophobic mismatch between peptides and lipids are important parameters in determining the mechanism of membrane perturbation . Hence, depending on the molecular properties of both lipid and peptide, creation of bilayer defects such as phase separation or membrane thinning, pore formation, promotion of nonlamellar lipid structures or bilayer disruption by the carpet model or detergent-like action, may occur . Moreover, these studies suggest that these different processes may represent gradual steps of membrane perturbation . A better understanding of the mutual dependence of these parameters will help to elucidate the molecular mechanism of membrane damage by antimicrobial peptides and their target membrane specificity, keys for the rationale design of novel types of peptide antibiotics.

Biochim Biophys Acta, 1999 Dec 15, 1462(1-2), 109 - 40
The monolayer technique: a potent tool for studying the interfacial properties of antimicrobial and membrane-lytic peptides and their interactions with lipid membranes; Maget-Dana R; Erudites of the antiquity already knew the calming effect of oil films on the sea waves . But one had to wait until 1774 to read the first scientific report on oil films from B . Franklin and again 1878 to learn the thermodynamic analysis on adsorption developed by J . Gibbs . Then, in 1891, Agnes Pockels described a technique to manipulate oil films by using barriers . Finally, in 1917, I . Langmuir introduced the experimental and theoretical modern concepts on insoluble monolayers . Since that time, and because it has been found to provide invaluable information at the molecular scale, the monolayer technique has been more and more extensively used, and, during the past decade, an explosive increase in the number of publications has occurred . Over the same period, considerable and ever-increasing interest in the antimicrobial peptides of various plants, bacteria, insects, amphibians and mammals has grown . Because many of these antimicrobial peptides act at the cell membrane level, the monolayer technique is entirely suitable for studying their physicochemical and biological properties . This review describes monolayer experiments performed with some of these antimicrobial peptides, especially gramicidin A, melittin, cardiotoxins and defensin A . After giving a few basic notions of surface chemistry, the surface-active properties of these peptides and their behavior when they are arranged in monomolecular films are reported and discussed in relation to their tridimensional structure and their amphipathic character . The penetration of these antimicrobial peptides into phospholipid monolayer model membranes, as well as their interactions with lipids in mixed films, are also emphasized.

Biochim Biophys Acta, 1999 Dec 15, 1462(1-2), 89 - 108
Lipid-induced conformation and lipid-binding properties of cytolytic and antimicrobial peptides: determination and biological specificity; Blondelle SE et al.; While antimicrobial and cytolytic peptides exert their effects on cells largely by interacting with the lipid bilayers of their membranes, the influence of the cell membrane lipid composition on the specificity of these peptides towards a given organism is not yet understood . The lack of experimental model systems that mimic the complexity of natural cell membranes has hampered efforts to establish a direct correlation between the induced conformation of these peptides upon binding to cell membranes and their biological specificities . Nevertheless, studies using model membranes reconstituted from lipids and a few membrane-associated proteins, combined with spectroscopic techniques (i.e . circular dichroism, fluorescence spectroscopy, Fourier transform infra red spectroscopy, etc.), have provided information on specific structure-function relationships of peptide-membrane interactions at the molecular level . Reversed phase-high performance chromatography (RP-HPLC) and surface plasmon resonance (SPR) are emerging techniques for the study of the dynamics of the interactions between cytolytic and antimicrobial peptides and lipid surfaces . Thus, the immobilization of lipid moieties onto RP-HPLC sorbent now allows the investigation of peptide conformational transition upon interaction with membrane surfaces, while SPR allows the observation of the time course of peptide binding to membrane surfaces . Such studies have clearly demonstrated the complexity of peptide-membrane interactions in terms of the mutual changes in peptide binding, conformation, orientation, and lipid organization, and have, to a certain extent, allowed correlations to be drawn between peptide conformational properties and lytic activity.

Biochim Biophys Acta, 1999 Dec 15, 1462(1-2), 55 - 70
Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides; Shai Y; Permeation of the cell membrane leading to cell death is a mechanism used by a large number of membrane-lytic peptides . Some are linear, mostly helical, and others contain one or more disulfide bonds forming beta-sheet or both beta-sheet and alpha-helix structures . They are all soluble in solution but when they reach the target membrane, conformational changes occur which let them associate with and lyse the membrane . Some lytic peptides are not cell-selective and lyse different microorganisms and normal mammalian cells, while others are specific to either type of cells . Despite extensive studies, the mode of action of membrane-lytic peptides is not fully understood and the basis for their selectivity towards specific target cells is not known . Many studies have shown that peptide-lipid interactions leading to membrane permeation play a major role in their activity . Membrane permeation by amphipathic alpha-helical peptides has been proposed to occur via one of two general mechanisms: (i) transmembrane pore formation via a 'barrel-stave' mechanism; and (ii) membrane destruction/solubilization via a 'carpet' mechanism . This review, which is focused on the different stages of membrane permeation induced by representatives of amphipathic alpha-helical antimicrobial and cell non-selective lytic peptides distinguishes between the 'carpet' mechanism, which holds for antimicrobial peptides versus the 'barrel-stave' mechanism, which holds for cell non-selective lytic peptides.

Biochim Biophys Acta, 1999 Dec 15, 1462(1-2), 29 - 54
Interaction of antimicrobial peptides with biological and model membranes: structural and charge requirements for activity; Sitaram N et al.; Species right across the evolutionary scale from insects to mammals use peptides as part of their host-defense system to counter microbial infection . The primary structures of a large number of these host-defense peptides have been determined . While there is no primary structure homology, the peptides are characterized by a preponderance of cationic and hydrophobic amino acids . The secondary structures of many of the host-defense peptides have been determined by a variety of techniques . The acyclic peptides tend to adopt helical conformation, especially in media of low dielectric constant, whereas peptides with more than one disulfide bridge adopt beta-structures . Detailed investigations have indicated that a majority of these host-defense peptides exert their action by permeabilizing microbial membranes . In this review, we discuss structural and charge requirements for the interaction of endogenous antimicrobial peptides and short peptides that have been derived from them, with membranes.

Biochim Biophys Acta, 1999 Dec 15, 1462(1-2), 11 - 28
Diversity of antimicrobial peptides and their mechanisms of action; Epand RM et al.; Antimicrobial peptides encompass a wide variety of structural motifs . Many peptides have alpha-helical structures . The majority of these peptides are cationic and amphipathic but there are also hydrophobic alpha-helical peptides which possess antimicrobial activity . In addition, some beta-sheet peptides have antimicrobial activity and even antimicrobial alpha-helical peptides which have been modified to possess a beta-structure retain part of their antimicrobial activity . There are also antimicrobial peptides which are rich in a certain specific amino acid such as Trp or His . In addition, antimicrobial peptides exist with thio-ether rings, which are lipopeptides or which have macrocyclic Cys knots . In spite of the structural diversity, a common feature of the cationic antimicrobial peptides is that they all have an amphipathic structure which allows them to bind to the membrane interface . Indeed, most antimicrobial peptides interact with membranes and may be cytotoxic as a result of disturbance of the bacterial inner or outer membranes . Alternatively, a necessary but not sufficient property of these peptides may be to be able to pass through the membrane to reach a target inside the cell . The interaction of these peptides with biological membranes is not just a function of the peptide but is also modulated by the lipid components of the membrane . It is not likely that this diverse group of peptides has a single mechanism of action, but interaction of the peptides with membranes is an important requirement for most, if not all, antimicrobial peptides.

Biochim Biophys Acta, 1999 Dec 15, 1462(1-2), 1 - 10
Why and how are peptide-lipid interactions utilized for self-defense? Magainins and tachyplesins as archetypes; Matsuzaki K; Animals as well as plants defend themselves against invading pathogenic microorganisms utilizing cationic antimicrobial peptides, which rapidly kill various microbes without exerting toxicity against the host . Physicochemical peptide-lipid interactions provide attractive mechanisms for innate immunity . Many of these peptides form cationic amphipathic secondary structures, typically alpha-helices and beta-sheets, which can selectively interact with anionic bacterial membranes by the aid of electrostatic interactions . Rapid, peptide-induced membrane permeabilization is an effective mechanism of antimicrobial action . This review article summarizes interactions with lipid bilayers of magainins (alpha-helix) and tachyplesins (beta-sheet) discovered in frog skin and horseshoe crab hemolymph, respectively, as archetypes, emphasizing that the mode of interaction is strongly dependent on the physicochemical properties not only of the peptide, but also of the target membrane.

Plant Cell, 1999 Dec, 11(12), 2419 - 28
Arabidopsis PAD3, a gene required for camalexin biosynthesis, encodes a putative cytochrome P450 monooxygenase; Zhou N et al.; Phytoalexins are low molecular weight antimicrobial compounds that are synthesized in response to pathogen attack . The phytoalexin camalexin, an indole derivative, is produced by Arabidopsis in response to infection with the bacterial pathogen Pseudomonas syringae . The phytoalexin deficient 3 (pad3) mutation, which causes a defect in camalexin production, has no effect on resistance to P . syringae but compromises resistance to the fungal pathogen Alternaria brassicicola . We have now isolated PAD3 by map-based cloning . The predicted PAD3 protein appears to be a cytochrome P450 monooxygenase, similar to those from maize that catalyze synthesis of the indole-derived secondary metabolite 2,4-dihydroxy-1, 4-benzoxazin-3-one . The expression of PAD3 is tightly correlated with camalexin synthesis and is regulated by PAD4 and PAD1 . On the basis of these findings, we conclude that PAD3 almost certainly encodes an enzyme required for camalexin biosynthesis . Moreover, these results strongly support the idea that camalexin does not play a major role in plant resistance to P . syringae infection, although it is involved in resistance to a fungal pathogen.

Clin Infect Dis, 1999 Dec, 29(6), 1440 - 9
Brucellar spondylitis: review of 35 cases and literature survey; Solera J et al.; Thirty-five patients aged 14-74 years (average, 54 years) who had brucellar spondylitis were treated between January 1991 and December 1997 . The time from onset of symptoms to diagnosis of spondylitis ranged from 1 week to 8 months (median, 9 weeks) . Back or neck pain (100% of patients), fever (66%), and constitutional symptoms (57%) were the most common symptoms . Cultures of blood specimens from 26 patients (74%) were positive for Brucella melitensis . The duration of antimicrobial therapy (median, 120 days; range, 45-535 days) varied according to clinical response and the presence of epidural and paravertebral masses . One of the 35 patients underwent surgical treatment of a spinal epidural abscess . Therapy failed for 9 patients (26%; 95% confidence interval {CI}, 12%-43%), and 5 (14%; 95% CI, 5%-30%) had a relapse . There were no deaths or severe sequelae in this study . Brucellar spondylitis causes considerable suffering and absenteeism from work, but long-term clinical responses are favorable.

Clin Infect Dis, 1999 Dec, 29(6), 1394 - 9
Outpatient parenteral antimicrobial therapy for central nervous system infections; Tice AD et al.; Patients with central nervous system (CNS) infections are increasingly treated with intravenous antimicrobials outside the hospital, but the safety and problems associated with this therapy have not been well defined . To examine this issue, we reviewed 68 cases in which outpatient intravenous antimicrobial therapy (OPAT) was received through our physician office-based infusion clinic . All infections were cured, and no deaths occurred during therapy . Seizures occurred in 2 patients but without significant injury and apparently were unrelated to antimicrobial therapy . Eleven patients (16%) were hospitalized after starting OPAT, 5 for procedures and 6 for medical reasons . The antimicrobial used was changed in 13 cases (19%) because of an adverse effect or clinical failure . OPAT can be safe and effective for patients with CNS infections, but patients must be carefully selected and monitored closely.

J Trop Pediatr, 1999 Oct, 45(5), 296 - 9
Stability of saliva for measuring HIV in the tropics; Thwe M et al.; If HIV is to be detected among pregnant women in remote regions of the tropics, HIV antibodies need to remain stable until specimens arrive at the laboratory . Our objective was to assess the stability of HIV antibodies in saliva held for up to 1 month at ambient temperature in Yangon, Myanmar . We gathered 10 saliva specimens from each of 102 HIV-infected persons with the Omni-Sal collection device (Saliva Diagnostic Systems, Inc.), and for each subject, divided the saliva into 15 portions . During 33 days, the 102 saliva specimens, kept at ambient temperature, were tested every 2-3 days for HIV antibodies (total 1530 assays) with the GACELISA (Murex Diagnostics Ltd), a highly sensitive test designed for use with saliva . We observed no reduction in test performance over 33 days, indicating that the antimicrobial and antiproteolytic transport medium in the Omni-Sal device can preserve HIV antibodies without refrigeration for up to a month before saliva specimens reach the laboratory.

Clin Infect Dis, 1999 Oct, 29(4), 922 - 4
Treatment of tularemia with fluoroquinolones: two cases and review; Limaye AP et al.; Streptomycin, gentamicin, and tetracycline are currently considered the antimicrobials of choice for the treatment of tularemia . Preliminary data suggest that quinolones may be effective alternative agents; however, clinical experience is limited, and their role in treating severe disease is uncertain . We recently treated two acutely ill immunocompromised patients who had presumed "atypical" pneumonia with levofloxacin . Both patients had an excellent clinical response and were diagnosed with tularemia only when blood cultures subsequently yielded Francisella tularensis . Neither patient relapsed during 12 months of follow-up . Including our two cases, a total of 10 cases of tularemia treated with quinolones have been reported . In all 10 cases, a favorable clinical response was documented, and no relapses occurred . We conclude that the quinolones appear promising for the treatment of even severe tularemia, and they should be considered efficacious alternative agents for patients who do not require parenteral therapy or are intolerant of more standard treatment regimens.

Microbiology, 1999 Nov, 145 ( Pt 11), 3177 - 84
Alteration of a single amino acid residue reverses fosfomycin resistance of recombinant MurA from Mycobacterium tuberculosis; De Smet KA et al.; Mycobacterium tuberculosis has innate resistance to a range of broad-spectrum antimicrobial agents . This may in part reflect the relative impermeability of the mycobacterial cell wall, but additional specific mechanisms may also be important . In the case of fosfomycin, it has been suggested that a key difference in the active site of the M . tuberculosis MurA enzyme might confer resistance . In Escherichia coli, fosfomycin covalently binds to a cysteine normally involved in the enzymic activity, while protein alignments predict an aspartate at this position in the M . tuberculosis MurA . In the present study, it is demonstrated that the wild-type M . tuberculosis MurA is indeed resistant to fosfomycin, and that it becomes sensitive following replacement of the aspartate residue in position 117 by a cysteine . In addition, the study illustrates the use of an inducible expression system in mycobacteria to allow functional characterization of an M . tuberculosis enzyme that is unstable during constitutive expression.

Vet Clin North Am Equine Pract, 1999 Dec, 15(3), 665 - 86, ix-x
Equine respiratory pharmacology; Foreman JH; Differentiation of diseases of the equine respiratory tract is based on history, clinical signs, auscultation, endoscopy, imaging, and sampling of airway exudate . Upper respiratory therapies include surgical correction of airway obstructions; flushing of localized abscesses (strangles), guttural pouch disease, or sinusitis; and oral or parenteral antibiotic and anti-inflammatory therapy if deemed necessary . Pneumonia usually is treated with antimicrobials, anti-inflammatories, and bronchodilators . Pleural drainage is indicated if significant pleural effusion is present . The most commonly used therapies for early inflammatory and chronic allergic obstructive conditions include bronchodilators and anti-inflammatories . Acute respiratory distress, particularly acute pulmonary edema, is treated with diuretics (usually furosemide), intranasal oxygen, bronchodilators, corticosteroids, and alleviation of the underlying cause . Furosemide also had been used in North America as a race-day preventative for exercise-induced pulmonary hemorrhage (EIPH), but recent data have shown that furosemide may be a performance-enhancing agent itself.

Vet Clin North Am Equine Pract, 1999 Dec, 15(3), 603 - 22
Modes of local drug delivery to the musculoskeletal system; Anderson BH et al.; A number of methods for the local delivery of drugs to musculoskeletal tissues in the horse are now available . Further research is required to document the disposition of drugs delivered by such methods and to correlate this information with efficacy . Perhaps the greatest potential area for the methods discussed is the treatment of synovial and bone infections . To be able to provide high and sustained therapeutic concentrations of antimicrobials to the site of infection should increase the chances of success in such cases . These methods of drug delivery need to be used in conjunction with other management procedures, however, including bacterial culture and sensitivity procedures, systemic antimicrobials, surgical drainage, removal of dead bone or surgical implants, establishment of fracture stability, use of autogenous bone grafts, systemic NSAIDs, and rest.

Clin Pharmacokinet, 1999 Nov, 37(5), 351 - 60
Treatment of ocular infections with topical antibacterials; Leeming JP; Topically applied ophthalmic antibacterial preparations are widely used in the treatment of patients with superficial ocular infections . In addition, they are frequently used to augment treatment for intraocular infection administered systemically or via local instillation . Direct application delivers high concentrations of antimicrobial agents to the surface of the eye conveniently, quickly and with minimal systemic exposure to the agent . However, antibacterials are rapidly dissipated from the tear film and intraocular penetration of topical antibacterial agents is generally poor, necessitating intensive application for successful treatment of corneal infections . Therapeutic concentrations are rarely achieved at other sites in the eye . This article reviews what is known of the pharmacokinetics of topical ocular agents and how this information can be used to optimise ocular persistence and penetration and minimise systemic absorption of antibacterials . A review of the features of the most commonly employed topical antibacterials suggests that for the treatment of uncomplicated bacterial conjunctivitis there is little difference between the various agents in terms of clinical efficacy, although chloram-phenicol should be used with care because of its potential haematological toxicity . Carefully considered therapy is imperative for bacterial keratitis; fortified beta-lactam/aminoglycoside combinations are often used for these infections . The fluoroquinolones appear promising, but caution is necessary in treating keratitis of unknown aetiology with these agents alone because of inherent and emerging acquired resistance among Gram-positive bacteria.

J Allergy Clin Immunol, 1999 Dec, 104(6), 1131 - 8
Defensins: key players or bystanders in infection, injury, and repair in the lung?
van Wetering S, Sterk PJ, Rabe KF, Hiemstra PS.
Antimicrobial peptides have been identified as key elements in the innate host defense against infection . Recent studies have indicated that the activity of antimicrobial peptides may be decreased in cystic fibrosis, suggesting a major role for these peptides in host defense against infection . One of the most intensively studied classes of antimicrobial peptides are defensins . Defensins comprise a family of cationic peptides that in human subjects can be divided into the alpha- and beta-defensin subfamilies . The alpha-defensins are produced by neutrophils and intestinal Paneth's cells, whereas beta-defensins are mainly produced by epithelial cells . Although studies on beta-defensins have so far focused on their antimicrobial activity, studies on alpha-defensins have suggested a role of these peptides in inflammation, wound repair, and specific immune responses . alpha-Defensins, which accumulate in airway secretions of patients with various chronic inflammatory lung disorders, were shown to be cytotoxic toward airway epithelial cells and to induce chemokine secretion in several cell types . Furthermore, the capacity of alpha-defensins to promote bacterial adherence to epithelial cells in vitro further supports a role for these peptides in the pathogenesis of chronic obstructive pulmonary disease and cystic fibrosis . Increased numbers of neutrophils are also present in the airways of patients with asthma, suggesting that neutrophils are involved in the pathogenesis of this disease . Because defensins are able to induce histamine release by mast cells and increase the airway hyperresponsiveness to histamine, it is tempting to speculate that defensins may also contribute to the inflammatory processes in asthma . Besides these proinflammatory effects, alpha-defensins may also display anti-inflammatory activities, including regulation of complement activation and proteinase inhibitor secretion . Finally, defensins may be involved in wound repair because defensins increase epithelial cell proliferation . Thus recent defensin research has revealed potential links between the innate and acquired immune system.

J Antimicrob Chemother, 1999 Oct, 44(4), 561 - 4
Modification of acquired immunity in mice by imipenem/cilastatin; Ortega E et al.; The immunomodulating properties of antimicrobial drugs may have important implications for clinical practice, particularly for those patients whose immune system has been compromised . In this study, we assessed the influence of different treatments with a beta-lactam antibiotic (imipenem/cilastatin) on several acquired immune responses of BALB/c mice; splenocyte responses to specific mitogens and to sheep red blood cells, IL-2 production and proportions of the different lympho-monocytic populations . Impenem/cilastatin was shown to modify some lymphocyte-associated immune functions and it would be useful to investigate whether immunomodulatory effects also occur in humans.

Masui, 1999 Nov, 48(11), 1186 - 93
{Antimicrobial peptides/proteins--application to the therapy of sepsis}; Sawa T et al.; Many antimicrobial peptides and proteins were discovered recently in various animals . Cecropins are insect-derived antimicrobial peptides which contain 35-39 amino acid residues . Magainins are amphibian-derived antimicrobial peptides with 21-27 amino acid residues . In mammals, defensins, 29-35 amino acid peptides, were identified in the granules of neutrophils and various epithelial cells . In addition, the granules of neutrophils in the mammal have been shown to have several antimicrobial proteins . Among them, bactericidal/permeability increasing protein (BPI) and cationic antimicrobial peptide-18 (CAP 18) have been found to have potent bactericidal activity against gram-negative bacteria and strong lipopolysaccharide-neutralizing function . The recombinant BPIs (recombinant BPI, 23-kDa N-terminal fragment of BPI, and lipopolysaccharide-binding protein-BPI fusion protein) and synthetic peptides derived from C-terminal of CAP 18 are now under investigation for the application to the therapy of sepsis or septic shock.

J Clin Pharmacol, 1999 Dec, 39(12), 1277 - 82
A pharmacokinetic evaluation of concomitant administration of linezolid and aztreonam; Sisson TL et al.; Linezolid, a new oxazolidinone antimicrobial agent, has a spectrum of activity encompassing a wide variety of Grampositive bacteria . The purpose of this study was to evaluate the pharmacokinetics of linezolid and aztreonam, an antimicrobial agent with selective activity against Gram-negative bacteria, when given alone and in combination . Healthy subjects were randomized to receive single, 30-minute intravenous infusions of (1) linezolid 375 mg, (2) aztreonam 1000 mg, and (3) linezolid 375 mg plus aztreonam 1000 mg in an open-label, crossover manner . The only statistically significant differences observed with combination treatment relative to each drug alone were an increase in the maximum plasma concentration of linezolid (approximately 18%) and an approximate 7% decrease in the apparent elimination rate of aztreonam, neither of which are expected to be clinically significant . In healthy subjects, the combination of linezolid and aztreonam was safe and well tolerated compared with each agent used alone . Pharmacokinetic data demonstrate that coadministration of linezolid and aztreonam does not alter the disposition of either agent under single-dose conditions . Therefore, it is not expected that a dose alteration of either agent will be necessary in a clinical setting.

Hinyokika Kiyo, 1999 Oct, 45(10), 687 - 90
{Clinical study of carcinoma of the penis}; Kondo T et al.; We reviewed six cases of carcinoma of the penis seen at our department during the last 12 years . The mean age and mean followup period were 56 +/- 11 years and 53 +/- 42 months, respectively . Inguinal lymphadenopathy was evident in all patients, one of whom was diagnosed as having nodal metastasis because of the persistence of adenopathy after antimicrobial therapy . Four patients, had Jackson Stage 1, 1 Stage 2 and 1 Stage 3 cancer . The patient with Stage 3 cancer underwent total penectomy and bilateral inguinal lymphadenectomy . He died of cancer 2 years after the operation . The 5 patients with stage 1 or 2 underwent partial penectomy without lymphadenectomy . Pathological examination showed moderately differentiated squamous cell carcinoma (SCC) in 2 patients with stage 2 and 3 cancer, well differentiated SCC in 3 and verrucous carcinoma in the other patient with stage 1 cancer . Prophylactic external radiation therapy to the groin was performed in 3 of the 4 patients with invasion to corpus spongiosum (pT2) . Two of the 3 patients developed mild radiation dermatitis, and no major complications were observed . The 5 patients with clinically negative nodes showed no evidence of recurrence after surgery . As reported by others, inguinal node metastasis appears to worsen the prognosis of patients with carcinoma of the penis.

J Immunol, 1999 Dec 15, 163(12), 6606 - 13
Negative regulation of macrophage activation in response to IFN-gamma and lipopolysaccharide by the STK/RON receptor tyrosine kinase; Liu QP et al.; IFN-gamma primes macrophages for antimicrobial activity, increased killing of intracellular pathogens, and Ag processing and presentation to lymphocytes by cooperating with a second signal (provided by LPS or endogenous TNF-alpha) to promote increased proinflammatory cytokine production, NO production, and MHC class II expression . Macrophage-stimulating protein (MSP) suppresses NO production by activated peritoneal macrophages in vitro . Furthermore, targeted deletion of the receptor for MSP, stem cell-derived tyrosine kinase receptor (STK/RON), resulted in increased production of NO by activated macrophages both in vitro and in vivo . Here we demonstrate that expression of STK in RAW264.7 cells resulted in suppression of NO production following IFN-gamma+/- LPS stimulation in the presence of MSP, reflecting a decrease in the levels of inducible NO synthase (iNOS) mRNA and protein, which was confirmed by decreased trans-activation of an iNOS reporter . The iNOS expression is regulated by the coordinate activity of the inducible transcription factors STAT-1, IFN response factor-1, and NF-kappaB . The presence of the STK receptor did not significantly alter the expression of the IFN-gamma receptor, STAT1 phosphorylation, or the up-regulation of IFN response factor-1 expression following IFN-gamma stimulation . However, nuclear translocation of NF-kappaB following stimulation of RAW cells with IFN-gamma and LPS was reduced in the presence of the MSP/STK signaling pathway . These results suggest that the negative regulation of macrophage responses by MSP/STK occurs at least in part via inhibition of costimulatory signals, resulting in NF-kappaB activation, that cooperate with IFN-gamma to promote activation.

Pediatrics, 1999 Dec, 104(6), 1251 - 7
Antimicrobial use for pediatric upper respiratory infections: reported practice, actual practice, and parent beliefs; Watson RL et al.; BACKGROUND: In response to the dramatic emergence of resistant pneumococci, more judicious use of antibiotics has been advocated . Physician beliefs, their prescribing practices, and the attitudes of patients have been evaluated previously in separate studies . METHODS: This 3-part study included a statewide mailed survey, office chart reviews, and parent telephone interviews . We compared survey responses of 366 licensed pediatricians and family physicians in Georgia to recently published recommendations on diagnosis and treatment of upper respiratory infections (URIs) . We further evaluated 25 randomly selected pediatricians from 119 surveyed in the Atlanta metropolitan area . For each, charts from the first 30 patients between the ages of 12 and 72 months seen on a randomly selected date were reviewed for encounters during the preceding year . A sample of parents from each practice were interviewed by telephone . RESULTS: In the survey, physicians agreed that overuse of antibiotics is a major factor contributing to the development of antibiotic resistance (97%), and that they should consider selective pressure for resistance in their decisions on providing antibiotic treatment for URIs in children in their practices (83%) . However, many reported practices do not conform to the recently published principles for judicious antibiotic use . For example, 69% of physicians considered purulent rhinitis a diagnostic finding for sinusitis; 86% prescribed antibiotics for bronchitis regardless of the duration of cough; and 42% prescribed antibiotics for the common cold . Reported practices by family physicians were more often at odds with the published principles: they were significantly more likely than pediatricians to omit pneumatic otoscopy (46% vs 25%); to omit the requirement for prolonged symptoms to diagnose sinusitis (median 4 vs 10 days); and to omit laboratory testing for pharyngitis (27% vs 14%) . Of the 7531 encounters analyzed in the chart review, 43% resulted in an antibiotic prescription, including 11% of checkups, 18% of telephone calls, and 72% of visits for URIs . There was wide variability in the overall antibiotic use rates among the 25 physicians (1-10 courses per child per year) . There was an even wider variability in some diagnosis-specific rates; bronchitis and sinusitis in particular . Those with the highest antibiotic prescribing rates had up to 30% more return office visits . Physicians who prescribed antibiotics for purulent rhinitis were more likely to see parents who believed that their children should be evaluated for cold symptoms . CONCLUSIONS: Physicians recognize the problem of antibiotic resistance but their reported practices are not in line with recently published recommendations for most pediatric URIs . The actual prescribing practices of pediatricians are often considerably different from their close colleagues . Patient beliefs are correlated with their own physician's practices.

J Obstet Gynecol Neonatal Nurs, 1999 Nov-Dec, 28(6), 639 - 48
Antimicrobial agents: pharmacology and clinical application in obstetric, gynecologic, and perinatal infections; Roe VA; The pharmacology of selective antimicrobial agents and their role in the treatment of obstetric, gynecologic, and neonatal infections is the focus of this clinical review . Defining and refining the use of antimicrobial therapy is significant on both an individual and a global level because the emergence of resistant organisms is a public health concern . Heath care providers must be knowledgeable about the risks and benefits of initiating pharmacologic treatment based on clinical evidence with regard to an agent's spectrum of activity, efficacy, and side effects.

Br J Surg, 1999 Nov, 86(11), 1371 - 7
Surgical management of severe secondary peritonitis; Bosscha K et al.; BACKGROUND: Despite advances in diagnosis, surgery, antimicrobial therapy and intensive care support, the mortality rate associated with severe secondary peritonitis remains unacceptably high . This article presents various surgical treatment strategies for severe secondary peritonitis, emphasizing the role of open management of the abdomen and planned relaparotomies . METHODS: Material was identified from previous review articles, references cited in original papers and a Medline search of the literature . RESULTS AND CONCLUSION: Surgical treatment of severe secondary peritonitis is highly demanding and very complex . The combination of improved surgical techniques, antimicrobial therapy and intensive care support has improved the outcome of such peritonitis following perforation or anastomotic disruption of the digestive tract, or infected necrotizing pancreatitis . However, aggressive surgical treatment strategies, such as open management of the abdomen and planned relaparotomies, may have reached their limits.

Appl Environ Microbiol, 1999 Dec, 65(12), 5394 - 7
Fate of pGFP-bearing Escherichia coli O157:H7 in ground beef at 2 and 10 degrees C and effects of lactate, diacetate, and citrate; Ajjarapu S et al.; Although beef has been implicated in the largest outbreaks of Escherichia coli O157:H7 infection in the United States, studies on the fate of this pathogen have been limited . Problems in such studies are associated with detection of the pathogen at levels considerably lower than the levels of the competing microorganisms . In the present study, a green fluorescent protein-expressing E . coli O157:H7 strain was used, and the stable marker allowed us to monitor the behavior of the pathogen in ground beef stored aerobically from freshness to spoilage at 2 and 10 degrees C . In addition, the effects of sodium salts of lactate (SL) (0.9 and 1.8%), diacetate (SDA) (0.1 and 0.2%), and buffered citrate (SC) (1 and 2%) and combinations of SL and SDA were evaluated . SC had negligible antimicrobial activity, and SL delayed microbial growth, while SDA and SL plus SDA were most inhibitory to the total-aerobe population in the meat . At 2 degrees C, the initial numbers of E . coli O157:H7 (3 and 5 log(10) CFU/g) decreased by approximately 1 log(10) CFU/g when spoilage was manifest (>7 log(10) CFU of total aerobes/g), irrespective of the treatment . There was no decline in the numbers of the pathogen during storage at 10 degrees C . Our results showed that the pathogen was resistant to the salts tested and confirmed that refrigerated meat contaminated with the pathogen remains hazardous.

Eur J Biochem, 1999 Dec, 266(3), 1021 - 8
The antimicrobial peptide trichogin and its interaction with phospholipid membranes; Epand RF et al.; The interaction of the antimicrobial peptide trichogin GA IV with phospholipid bilayers has been studied . A series of analogs of trichogin was synthesized in which the nitroxide spin label, 4-amino-4-carboxy-2,2,6,6-tetramethylpiperidino-1-oxyl (TOAC), replaced one of the three alpha-aminoisobutyric acid (Aib) residues in the sequence . These modified peptides were used to assess the location of different residues of the peptide in a phospholipid bilayer composed of egg phosphatidylcholine containing 0.4 mol% of a fluorescently labelled phospholipid . We demonstrate that the substitution of Aib residues with TOAC does not alter the manner in which the peptide affects membrane curvature or induces vesicle leakage . The proximity of the nitroxide group on the peptide to the 4,4-difluoro-4-bora-3a,4a-diaza-S-indacene (BODIPY) fluorophore attached to the phospholipid was estimated from the extent of quenching of the fluorescence . By this criterion it was concluded that the peptide penetrates into the bilayer and that Aib4 is the most deeply inserted of the Aib residues . The results suggest that the helix axis of the peptide is oriented along the plane of the membrane . All of the peptides were shown to raise the bilayer to the hexagonal phase transition temperature of dipalmitoleoylphosphatidylethanolamine, indicating that they promote positive membrane curvature . This is a property observed with peptides that do not penetrate deeply into the bilayer or are oriented along the bilayer normal . We also demonstrate trichogin-promoted leakage of the aqueous contents of liposomes . These results indicate that the peptides cause bilayer destabilization . The extent of leakage induced by trichogin is very sensitive to the peptide to lipid ratio over a narrow range.

Antimicrob Agents Chemother, 1999 Dec, 43(12), 3022 - 4
Antimicrobial resistance of diarrheagenic Escherichia coli isolated from children under the age of 5 years from Ifakara, Tanzania; Vila J et al.; Diarrhea caused by multidrug-resistant bacteria is an important public health problem among children in developing countries . The prevalence and antimicrobial susceptibility of diarrheagenic Escherichia coli in 346 children under 5 years of age in Ifakara, Tanzania, were studied . Thirty-eight percent of the cases of diarrhea were due to multiresistant enterotoxigenic E . coli, enteroaggregative E . coli, or enteropathogenic E . coli . Strains of all three E . coli categories showed high-level resistance to ampicillin, tetracycline, co-trimoxazole, and chloramphenicol but were highly susceptible to quinolones . Guidelines for appropriate use of antibiotics in developing countries need updating.

Antimicrob Agents Chemother, 1999 Dec, 43(12), 3001 - 4
Comparative in vitro antimicrobial activities of the newly synthesized quinolone HSR-903, sitafloxacin (DU-6859a), gatifloxacin (AM-1155), and levofloxacin against Mycobacterium tuberculosis and Mycobacterium avium complex; Tomioka H et al.; We compared the in vitro antimycobacterial activity of a new fluoroquinolone, HSR-903, with strong activity against gram-positive cocci with those of levofloxacin (LVFX), sitafloxacin (STFX), and gatifloxacin (GFLX) . The MICs of the quinolones for Mycobacterium tuberculosis and Mycobacterium avium complex were in the order STFX approximately GFLX < LVFX <== HSR-903 and STFX <== GFLX <== HSR-903 <== LVFX, respectively . HSR-903 effectively eliminated intramacrophagial M . tuberculosis, as did LVFX, and exhibited bacteriostatic effects against M . tuberculosis replicating in type II alveolar cells.

Am J Health Syst Pharm, 1999 Nov 15, 56(22 Suppl 3), S25 - 8
Pharmacoeconomics of antimicrobial therapy; Paladino JA; Switch therapy, sequential therapy, and step-down therapy are discussed in terms of their contribution to reducing antimicrobial expenditures . Pharmacoeconomics is the science used to identify and compare the costs and consequences of drug therapy in terms of efficacy, safety, and overall health care . Pharmacoeconomic studies of antimicrobials for respiratory-tract infections have identified significant cost savings associated with regimens that are optimized for a particular patient on the basis of a drug's pharmacokinetic profile . For fluoroquinolones, optimal therapy has been associated with targeting the specific pharmacodynamic variable known as the ratio of the area under the serum concentration-time curve from 0 to 24 hours (AUC) to the minimum inhibitory concentration, also referred to as the area under the inhibitory curve (AUIC) . Several studies have shown that regimens that achieve targeted AUIC values of 125 to 250 against gram-negative aerobic bacteria are cost-effective; cost savings are linked to decreased time to bacterial eradication and higher AUICs . Additional cost-effective measures for hospitals and health care institutions include the implementation of formalized i.v.-to-oral conversions and streamlining programs . Pharmacoeconomic analysis of therapies for respiratory-tract and other infections demonstrates that reducing health care costs may best be achieved by curing the infection in the shortest possible time through dosage optimization individualized to the patient.

Am J Health Syst Pharm, 1999 Nov 15, 56(22 Suppl 3), S21 - 4
Pharmacokinetic and pharmacodynamic surrogate markers: studies with fluoroquinolones in patients; Schentag JJ; Several relevant studies of fluoroquinolones are reviewed, and the pneumonia model is used to predict clinical efficacy . In vitro pharmacokinetic and pharmacodynamic relationships help the clinician understand the pharmacologic effects of an antimicrobial agent . The clinical translation of in vitro determinants has proved challenging, however . Surrogate markers that define specific relationships between pharmacokinetic and pharmacodynamic characteristics of antimicrobials have been used to predict positive patient outcomes . Studies have shown that the ratio of the area under the serum concentration-time curve from 0 to 24 hours to the minimum inhibitory concentration, also known as the area under the inhibitory curve, is uniquely suited as a surrogate for identifying fluoroquinolone concentrations that correlate with clinical efficacy . In patients, appropriate dosage levels can be readily examined with the nosocomial pneumonia model . Modeling patient responses to infection has become a useful way of interpreting the clinical effects of fluoroquinolone therapy.

Am J Health Syst Pharm, 1999 Nov 15, 56(22 Suppl 3), S16 - 20
Using pharmacodynamic and pharmacokinetic surrogate markers in clinical practice: optimizing antimicrobial therapy in respiratory-tract infections; Nicolau DP; Pharmacodynamic and pharmacokinetic surrogate markers and their relationship to outcomes in respiratory-tract infections are reviewed . While several limitations affect the universal application of antimicrobial pharmacodynamic principles in clinical practice, recent studies have suggested that these principles may allow optimization of selected therapies . For the fluoroquinolones, the pharmacodynamic variable that has been correlated with antimicrobial efficacy is the ratio of the area under the serum concentration-time curve to the minimum inhibitory concentration . On the basis of their pharmacodynamic profiles, the newer fluoroquinolones, including such investigational agents as gatifloxacin, should produce satisfactory clinical and microbiological outcomes against pathogens commonly associated with community-acquired respiratory-tract infections . An assessment of the individual agent's pharmacodynamic profile will assist in choosing the best fluoroquinolone regimen; however, consideration should also be given to the agent's adverse-event potential.

Infect Control Hosp Epidemiol, 1999 Nov, 20(11), 778 - 80
Satellite videoconferencing for healthcare workers: audience characteristics and the importance of continuing education credits; Chen IL et al.; To assess the opinions of healthcare workers (HCWs) about a satellite videoconference as a means of earning continuing education credit, a telephone survey was conducted in September 1998, 1 month after a live interactive satellite videoconference on antimicrobial use and resistance . There were 180 registered sites in 45 states surveyed, representing 1,589 viewers: 764 nurses (48.1%), 201 physicians (12.6%), and 624 other HCWs (39.3%) . Continuing education credit was requested by 51% of nurses, 31% of physicians, and 27% of all other HCWs . Although preferred learning formats varied, 70% of respondents said it was important to offer continuing education credit . Furthermore, 31% of the respondents stated that the videoconference influenced institutional strategies . We concluded that satellite videoconferences are a method to reach audiences around the world efficiently and effectively, provide the latest information, facilitate interaction, and meet some of the demand for continuing education credit for HCWs.

Gastroenterology, 1999 Dec, 117(6), 1316 - 25
Treatment of Helicobacter pylori infection in rhesus monkeys using a novel antiadhesion compound; Mysore JV et al.; BACKGROUND & AIMS: Helicobacter pylori can be eradicated by administration of antimicrobials, but resistant strains have emerged, and there is a need for novel therapeutic approaches against this infection . This study aimed to determine the safety and efficacy of 3'-sialyllactose sodium salt (3'SL), an oligosaccharide that occurs naturally in human and bovine milk and that can inhibit the adhesion of H . pylori to human epithelial cells in vitro . METHODS: Twelve H . pylori-positive rhesus monkeys were given 3'SL, either alone (regimens 1 and 2; n = 6) or in combination with omeprazole (regimen 3; n = 4), or bismuth subsalicylate (regimen 4; n = 6) . Videogastroscopies were performed before, during, and after treatment, and gastric biopsy specimens were obtained for quantitative cultures and histology . The H . pylori strains colonizing the animals were genotyped . RESULTS: After regimen 1 or 2, 2 of 6 animals were cured permanently, and a third animal was transiently cleared . The 3 other animals remained persistently colonized and did not respond to regimen 3 . Regimen 4 resulted in transient decreases in colony counts in 3 of 6 other animals . Gastritis was suppressed only in the 2 animals who became persistently H . pylori negative . There was no apparent relation between 3'SL efficacy and any of the H . pylori tested genotypes . No side effects were observed in any of the animals receiving 3'SL . CONCLUSIONS: Antiadhesive therapy is safe; it can cure or decrease H . pylori colonization in some rhesus monkeys, but the addition of a proton pump inhibitor or bismuth subsalicylate does not increase cure rate.

J Med Chem, 1999 Nov 4, 42(22), 4604 - 13
Solution structure of polymyxins B and E and effect of binding to lipopolysaccharide: an NMR and molecular modeling study; Pristovsek P et al.; The cyclic decapeptides polymyxin B (PmB) and E (PmE) (mo-K'TK'-cyclo-{K'K'XLK'K'T}; mo, methyl octanoate; K', diaminobutyric acid; X, D-Phe (PmB) or D-Leu (PmE)) display antimicrobial and lipopolysaccharide (LPS) antagonistic activities . We have investigated the conformational behavior of PmB and PmE in water solution, free and bound to LPS, by homonuclear NMR and molecular modeling methods . The free peptides exist in equilibria of fast exchanging conformations with local preferences for a distorted type II' beta-turn from residues 5-8, and/or a gamma-turn in residue 10 . These two motifs are not present in the bound conformation of the peptides . The latter is amphiphilic separating the two hydrophobic residues in the cycle from the positively charged diaminobutyric acid side chains by an envelope-like fold of the cycle . The bound conformation is used for the derivation of a model of the PmB-lipid A complex based on electrostatic interactions and reduction of hydrophobic area . The proposed mode of binding breaks up the supramolecular structure of LPS connected with its toxicity . The model should contribute to the understanding of entropy-driven PmB-lipid A binding at the molecular level and assist the design of inhibitors of endotoxic activity.

Dev Comp Immunol, 1999 Oct-Dec, 23(7-8), 585 - 96
Inhibition of macrophage activity by mitogen-induced goldfish leukocyte deactivating factor; Stafford J et al.; Macrophage activating and deactivating cytokines have been characterized in mammalian systems but little is known about these immunoregulatory molecules in fish . Using gel permeation and chromatofocusing fast performance liquid chromatography (GP-FPLC and C-FPLC) we partially purified a macrophage deactivating factor (MDF) from mitogen-induced goldfish kidney leukocytes . Inhibition of the macrophage-derived nitric oxide (NO) response induced by this MDF was time-, dose- and temperature-dependent . Macrophages pre-treated for 6 or 24 h with MDF before activation with macrophage activating factors (MAF) and/or bacterial lipopolysaccharide (LPS) exhibited a down-regulation in their NO response, while those treated with MDF 24 h after activation with MAF and LPS did not . MDF treatment also impaired the NO response of goldfish macrophages infected with the mammalian protozoan parasite Leishmania major . These results suggest that MDF exhibits its inhibitory effect downstream of the converging intracellular pathways induced by LPS and/or L . major . The novel teleost MDF has an approximate Mr of 15 kD and a pI < 4, and is the first endogenous molecule of teleosts known to down regulate macrophage antimicrobial responses.

J Clin Pharmacol, 1999 Nov, 39(11), 1143 - 50
Pharmacokinetics of clinafloxacin enantiomers in humans; Humphrey GH et al.; The pharmacokinetics of R-clinafloxacin and S-clinafloxacin enantiomers of the broad-spectrum fluoroquinolone antibiotic, clinafloxacin, were characterized in selected volunteer subjects and patients after the administration of oral and intravenous doses of racemic drug . The absorption of each enantiomer was rapid and nearly complete after a single, oral 400 mg racemic dose . The mean (+/- SD) bioavailability of R-clinafloxacin was 87.5% +/- 4.8% compared to 86.2% +/- 5.8% for S-clinafloxacin . The mean Cmax of each enantiomer was 1.19 micrograms/mL, with plasma concentrations of each enantiomer remaining above 0.1 microgram/mL for at least 12 hours . No notable differences in the disposition of R-clinafloxacin and S-clinafloxacin were observed . After a single 400 mg intravenous dose of racemic drug, mean (+/- SD) t1/2 was 5.6 +/- 0.3 hours and 5.7 +/- 0.4 hours, plasma Cl was 329 +/- 49 mL/min and 314 +/- 45 mL/min, and Vdss was 138 +/- 18 L and 134 +/- 16 L for R- and S-clinafloxacin, respectively . Two healthy volunteers each received a single 400 mg oral dose of racemic clinafloxacin (alone) and with oral administration of 1 gm probenecid separated by a 1-week washout period between treatments . With probenecid coadministration, the increase in AUC0-infinity was 75% and 83% for R-clinafloxacin and was 71% and 75% for S-clinafloxacin in each subject, respectively . Probenecid increased the total exposure (AUC) of both R-clinafloxacin and S-clinafloxacin, although it had no stereo-selective effects on the disposition of either enantiomer . The antimicrobial potency of the isomers was also evaluated . In vitro susceptibility testing showed that the two compounds were comparable in their inhibitory activities, as all MICs were within twofold for each organism tested . These results demonstrate that in addition to their similar antimicrobial potency, R- and S-clinafloxacin have nearly identical disposition characteristics and are eliminated by similar mechanisms that display no apparent enantioselectivity in man.

Diagn Microbiol Infect Dis, 1999 Oct, 35(2), 109 - 12
In vitro activity of antituberculous agents against Mycobacterium tuberculosis isolates from Bogota, DC (Colombia) evaluated by the ETest; Sanchez L et al.; Tuberculosis tests for antimicrobial susceptibility takes weeks . However, delayed therapy, can compromise the patient, as well as lead to an increase in disease incidence . Among infectious diseases, tuberculosis continues to be a leading cause of death in the world . The E-test is a new concept for Minimal Inhibitory Concentrations (MIC) determinations for antimicrobial agents that is based on a predefined antibiotic gradient on a plastic strip calibrated with a continuous logarithmic MIC scale covering 15 two-fold dilutions . MICs of rifampin, isoniazid, and ethambutol were determined by using the E-test (AB BIODISK, Solna, Sweden) for 30 clinical strains of Mycobacterium tuberculosis isolated from four hospitals, and were compared with the Bactec method . To make the inoculum with a turbidity equivalent to a McFarland 3.0 standard, we obtained a sample from an agar surface and the Bactec 460, as described by the manufacturer . Excellent agreement (100% for rifampin, 96.8% for ethambutol, and 90% for isoniazid) was demonstrated between the E-test MIC distributions and the Bactec interpretive criteria for all clinical isolates of M . tuberculosis tested . The E-test appears to be a good alternative method for testing the susceptibility of M . tuberculosis isolates to the three, most-commonly-used therapeutic agents.

Ned Tijdschr Geneeskd, 1999 Oct 30, 143(44), 2177 - 81
{Fournier's gangrene}; Pol AG et al.; Fournier's gangrene is a rapidly progressive, necrotizing fasciitis of the perineal, genital or perianal regions . Despite increasing knowledge about aetiology, diagnostic procedures and treatment, the gangrene is still a destructive and potentially lethal disease . In two patients, men aged 54 and 63 years, Fournier's gangrene was diagnosed . The first one died of septic shock 12 hours after admission . Surgical debridement had been performed immediately . He had a latent promyelocytic leukaemia . The second patient recovered fully after extensive surgical and antimicrobial therapy . Fournier's gangrene appears to be caused by the synergistic pathogenic action of various individually non-pathogenic commensal bacteria . Virtually all patients have an underlying systemic disorder, mainly chronic alcoholism or diabetes mellitus . Immunosupression is a predisposing factor . The gangrene requires an aggressive approach, treatment being based on the combination of haemodynamic stabilisation, antibiotic triple therapy and radical surgical debridement.

Bone Marrow Transplant, 1999 Nov, 24(10), 1079 - 87
Infectious complications after autologous peripheral blood progenitor cell transplantation followed by G-CSF; Offidani M et al.; Infectious complications after autologous peripheral blood progenitor cell transplantation (PBPCT) have been reported in a few studies including small patient numbers . The present study was performed to assess the incidence, types, outcome and factors affecting early and late infections in 150 patients aged 18 to 68 years (median 46.5) who underwent high-dose therapy, with G-CSF . Patients were kept in reverse isolation rooms and received antimicrobial chemoprophylaxis with oral quinolone and fluconazole . One hundred and fifteen patients (76.7%) developed fever (median 3 days, range 1-29); 20 patients (55.5%) had Gram-positive and 13 (36 . 2%) Gram-negative bacterial infections . There were no fungal infections or infection-related deaths . Mucositis grade II-IV (P = 0 . 0001; odds ratio 3.4) and >5 days on ANC <100/microl (P = 0.0001; odds ratio 2.3) correlated with development of infection . Only days with ANC <100/microl affected infection outcome (P = 0.0024) whereas the antibiotic regimen did not . After day +30 there were four cases of bacterial pneumonitis (2.7%), one case of fatal CMV pneumonia (0 . 8%) and 20 of localized VZV infection (13.3%) . Reduction of neutropenia duration with PBPCT and G-CSF is not enough to prevent early infectious complications since only a few days of severe neutropenia and mucositis are related to development of early infections . However, no infection-related deaths were seen . Although Gram-positive organisms were the major cause of bacteremia, a glycopeptide in the empirical antibiotic regimen did not affect infection outcome . In PBPCT recipients, early and late opportunistic infections were notably absent, which was at variance with what was seen with bone marrow recipients . Efforts should be made to prevent mucositis and neutropenia and identify new strategies of antibacterial prophylaxis.

Dent Clin North Am, 1999 Oct, 43(4), 713 - 42, vii
Fluoride mechanisms; ten Cate JM et al.; This article discusses fluoride mechanisms in relation to dental caries . The authors specifically address firmly bound versus loosely bound fluoride; different fluoride active ingredients; fluoride and demineralization and remineralization; fluoride slow-release devices and F-releasing dental materials; antimicrobial effects of fluoride; the uptake of fluoride by oral bacteria; inhibition of enolase, protein-intruding ATPase and sugar transport; the various aspects of plaque as it relates to fluoride; and the rational use of fluoride.

Rev Alerg Mex, 1999 Sep-Oct, 46(5), 140 - 4
{Leukocyte adhesion deficiency syndrome: case report}; Mogica-Martinez MD et al.; INTRODUCTION: Leukocyte adhesion deficiency syndrome (LAD) is an altered phagocytic disorder characterised by the deficiency of one or several integrins which are included within the adhesion molecules group and cell surface receptors superfamily . OBJECTIVE: To describe the clinical features of a rare primary immunodeficiency case . CLINICAL CASE: A nineteen days-old male newborn was referred to the pediatrics infectology service because a 15 days clinical course characterised by delayed cord detachment; fever and skin lesions in several arcas that evolved to, cellulitis and dermal necrosis: Then he was admitted with the diagnosis of septicemia secondary to omphalitis . There were a partial response to antimicrobial treatment . Thereafter he had recurrent respiratory and gastrointestinal fungal and bacterial infections . Then he suffered psychomotor impairment and severe malnutrition . The patient died because septicemia at 5 months-old . WBC counts showed persistent leukocytosis between 42,000 and 133,000 cells/mm3, mostly neutrophils (64%-88%) . We also found defective neutrophil quimiotaxis . By flow cytometer it was detected CDII/18 adhesins deficiency . Otherwise immunological, bone marrow biopsy and viral tests were, normal . CONCLUSIONS: Although its prevalence is rare, leukocyte adhesion defects must be considered in those patients with delayed cord detachment, recurrent severe infections and both persistent and elevated neutrophilia and with other primary and secondary immunodeficiencies previously discarded.

Khirurgiia (Mosk), 1999, (10), 69 - 71
{Multicomponent dressing media in treatment of suppurated wounds}; Abaev IuK et al.; The multicomponent dressing medium (MDM) has been developed for treatment of festered wounds . The first layer consists of hydrofibrosed gauze with chlorhexidine being introduced into its structure in quantity of 0.2-0.5 mass % . The second layer of MDM is chlorhexidinum salt of monocarboxylcellulose with carboxyl group content of 12-22 mass % and chlorhexidine content being 1-2 mass % . The third layer is polyamide pellicle with the pores less than 1 micron in diameter . The created MDM possess significant capillar-transport, absorption, anti-adhesive and prolongated antimicrobial properties, prevents development of secondary infection and "hotbed" effect in the wound.

Postgrad Med, 1999 Nov, 106(6), 47 - 54; quiz 252
Of bugs and drugs . A guide through the labyrinth of antimicrobial therapy for respiratory tract infections; Singh J et al.; Choosing appropriate antimicrobial therapy is no longer a simple process . Even for the common problems of respiratory tract disease in children and adults, selection is complicated by both increasing microbial resistance and the daunting number of extended-spectrum antibiotics now on the market . In this article, Drs Singh and Arrieta look at the problem from all aspects and give their specific recommendations.

Farmaco, 1999 Oct 30, 54(10), 666 - 72
New pyridine derivatives as potential antimicrobial agents; Klimesova V et al.; A set of pyridine derivatives bearing a substituted alkylthio chain or a piperidyl ring in position 2 or 4 were synthesized, and their antimycobacterial and antifugal activities were evaluated . Chemical structures were confirmed by IR and NMR data, and by elemental analysis . Minimum inhibitory concentrations (MIC) were used for the evaluation of microbiological activity in vitro . The compounds were moderately active against both Mycobacterium tuberculosis and nontuberculous mycobacteria . The most active compound was 2-cyanomethylthiopyridine-4-carbonitrile (7) with MIC against Mycobacterium kansasii in the range of 8-4 mumol/l . The antifungal activities of the compounds were relatively low.

Int J Lepr Other Mycobact Dis, 1999 Sep, 67(3), 302 - 5
A study on the methods for early serological diagnosis of leprosy and their potential use; Wu Q et al.; This is a serial study . In this series we have established 12 methods for the early serological diagnosis of leprosy, including the FLA-ABS test, ELISAs with artificial products (ND-O-, ND-P-, NT-O-, NT-P-BSA; PGL-I, whole M . leprae and M . smegmatis), monoclonal antibody specific binding assay (McAb/SBA), latex agglutination test (LAT), and MLPA . These methods were compared with each other on a large scale in leprosy patients and in the field . The results indicate that 1) Excellent results were obtained when ELISAs were conducted with skim milk or egg albumin as the blocking agent and by using blood from earlobes instead of from venipuncture . 2) According to the four "S" standard (sensitivity, specificity, simplicity and speed), among the 12 methods the ND-O-BSA-ELISA (ND-ELISA) is the best and the MLPA is more suitable for use in the field because it is simple and rapid . 3) In the ND-ELISA, the increase or decrease of the OD value has a positive correlation with the BI, and the order of positive rates was a) in various types of leprosy: LL > BL > BB > BT > TT; b) in household contacts (HC), random population (RP), normal controls in endemic areas (ENC) and normal controls in nonendemic areas (NNC): HC > RP > ENC > NNC . 4) In a population with subclinical M . leprae infection, the highest risk group was between the ages of 15 and 25 and had an increase or a persistence of high OD values prior to onset of disease . 5) OD values gradually decreased over time following treatment and these declines paralleled declines in the BI . 6) In cases cured with dapsone therapy, there was an increase or a persistence of high OD values in ND-ELISA prior to the onset of a leprosy relapse . In conclusion, we have compared and evaluated 12 immuno-assays and have shown that the ND-ELISA is the most practical one for use in investigating sero-immunological epidemiology, subclinical infection with M . leprae, early detection of disease, monitoring of antimicrobial therapy, and even for the prediction of leprosy relapse.

J Biomed Mater Res, 2000 Feb, 49(2), 192 - 9
Striated muscle microvascular response to silver implants: A comparative in vivo study with titanium and stainless steel; Kraft CN et al.; Local microvascular perfusion is the primary line of defense of tissue against microorganisms and plays a considerable role in reparative processes . The impairment of the microcirculation by a biomaterial may therefore have profound consequences . Silver is known to have excellent antimicrobial activity and, although regional and systemic toxic effects have been described, silver is regularly discussed as an implant material in bone surgery . Because little is known about the influence of silver implants on the adjacent host tissue microvasculature, we studied in vivo nutritive perfusion and leukocytic response, and compared these results with those of the conventionally used materials titanium and stainless steel . Using the hamster dorsal skinfold chamber preparation and intravital microscopy, the implantation of a commercially pure silver sample led to a distinct and persistent activation of leukocytes combined with a marked disruption of the microvascular endothelial integrity, massive leukocyte extravasation, and considerable venular dilation . Whereas animals with stainless-steel implants showed a moderate increase in these parameters with a tendency to recuperate, titanium implants caused only a transient increase of leukocyte-endothelial cell interaction within the first 120 min and no significant change in macromolecular leakage, leukocyte extravasation and venular diameter . After 3 days, five of six preparations with silver samples showed severe inflammation and massive edema . Thus, the use of silver as an implant material should be critically judged despite its bactericidal properties . The implant material titanium seems to be well tolerated by the local vascular system and currently represents the golden standard .

Plant J, 1999 Sep, 19(6), 699 - 710
A family of antimicrobial peptides is produced by processing of a 7S globulin protein in Macadamia integrifolia kernels; Marcus JP et al.; A new family of antimicrobial peptides has been discovered in Macadamia integrifolia . The first member of this new family to be purified from nut kernels was a peptide of 45 aa residues, termed MiAMP2c . This peptide inhibited various plant pathogenic fungi in vitro . cDNA clones corresponding to MiAMP2c encoded a 666 aa precursor protein homologous to vicilin 7S globulin proteins . The deduced precursor protein sequence contained a putative hydrophobic N-terminal signal sequence (28 aa), an extremely hydrophilic N-proximal region (212 aa), and a C-terminal region of 426 aa which is represented in all vicilins . The hydrophilic portion of the deduced protein contained the sequence for MiAMP2c as well as three additional segments having the same cysteine spacing pattern as MiAMP2c . Each member of the MiAMP2 family (i.e . MiAMP2a, b, c and d) consisted of approximately 50 amino acids and contained a C-X-X-X-C-(10-12)X-C-X-X-X-C motif . Subsequent isolations from seed exudates led to the purification of the predicted family members MiAMP2b and 2d, both of which also exhibited antimicrobial activity in vitro . These results suggest that some vicilins play a role in defence during seed germination.

Arch Intern Med, 1999 Nov 22, 159(21), 2576 - 80
Effect of macrolides as part of initial empiric therapy on length of stay in patients hospitalized with community-acquired pneumonia; Stahl JE et al.; BACKGROUND: The choice of antibiotics to treat community-acquired pneumonia (CAP) is primarily empiric, and the effect of this choice on length of stay (LOS) and mortality is largely unknown . OBJECTIVE: To examine the impact of antibiotic choice on these outcomes in general medical patients hospitalized with CAP . METHODS: One hundred patients hospitalized with CAP were prospectively identified . Seventy-six met inclusion criteria and were entered into the study . After hospital discharge, each medical chart was examined by 2 independent physicians who verified the admitting diagnosis and entered the data for antimicrobial regimens, a CAP mortality prediction tool, a social and disposition index, and other health outcomes . Patients were stratified according to the antibiotic received . Simple regression techniques were used to examine the correlation between initial therapy, specifically, ceftriaxone sodium or a macrolide, and LOS and mortality . RESULTS: Patients who received macrolides within the first 24 hours of admission had a markedly shorter LOS (2.8 days) than those not so treated (5.3 days; P = .01) . This effect diminished as the interval before administering macrolides increased . Including ceftriaxone as part of the initial therapy did not appear to affect LOS . Patients given a macrolide for initial treatment did not differ significantly from those not treated in terms of mean age, mortality prediction tool score, or Social and Disposition Index score . Eleven of the 12 patients who received macrolides also received a beta-lactam antibiotic . CONCLUSION: Use of macrolides as part of an initial therapeutic regimen appears to be associated with shorter LOS.

Arch Intern Med, 1999 Nov 22, 159(21), 2562 - 72
Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia; Gleason PP et al.; BACKGROUND: Although medical practice guidelines exist, there have been no large-scale studies assessing the relationship between initial antimicrobial therapy and medical outcomes for patients hospitalized with pneumonia . OBJECTIVE: To determine the associations between initial antimicrobial therapy and 30-day mortality for these patients . METHODS: Hospital records for 12945 Medicare inpatients (> or = 65 years of age) with pneumonia were reviewed . Associations between initial antimicrobial regimens and 30-day mortality were assessed with Cox proportional hazards models, adjusting for baseline differences in patient characteristics, illness severity, and processes of care . Comparisons were made with patients treated with a non-pseudomonal third-generation cephalosporin alone (the reference group) . RESULTS: Initial treatment with a second-generation cephalosporin plus macrolide (hazard ratio {HR}, 0.71; 95% confidence interval {CI}, 0.52-0.96), a non-pseudomonal third-generation cephalosporin plus macrolide (HR, 0.74; 95% CI, 0.60-0.92), or a fluoroquinolone alone (HR, 0.64; 95% CI, 0.43-0.94) was independently associated with lower 30-day mortality . Adjusted mortality among patients initially treated with these 3 regimens became significantly lower than that in the reference group beginning 2, 3, and 7 days, respectively, after hospital admission . Use of a beta-lactam/beta-lactamase inhibitor plus macrolide (HR, 1.77; 95% CI, 1.28-2.46) and an aminoglycoside plus another agent (HR, 1.21; 95% CI, 1.02-1.43) were associated with an increased 30-day mortality . CONCLUSIONS: In this study of primarily community-dwelling elderly patients hospitalized with pneumonia, 3 initial empiric antimicrobial regimens were independently associated with a lower 30-day mortality . The more widespread use of these antimicrobial regimens is likely to improve the medical outcomes for elderly patients with pneumonia.

Blood, 1999 Dec 1, 94(11), 3897 - 905
Granulocyte-macrophage colony-stimulating factor upregulates reduced 5-lipoxygenase metabolism in peripheral blood monocytes and neutrophils in acquired immunodeficiency syndrome; Coffey MJ et al.; Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway, which play a role in host defense, and are synthesized by both monocytes (peripheral blood monocyte {PBM}) and neutrophils (PMN) . Because 5-LO metabolism is reduced in alveolar macrophages and PMN from acquired immunodeficiency syndrome (AIDS) subjects, we investigated the synthesis of LT by PBM and PMN from these subjects . There was a reduction (74.2% +/- 8.8% of control) in LT synthesis in PBM from human immunodeficiency virus (HIV)-infected compared with normal subjects . Expression of 5-LO (51.2% +/- 8.8% of control), and 5-LO activating protein (FLAP) (48.5% +/- 8.0% of control) was reduced in parallel . We hypothesized that this reduction in LT synthetic capacity in PBM and PMN was due to reduced cytokine production by CD4 T cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) . We treated 10 AIDS subjects with GM-CSF for 5 days . PBM 5-LO metabolism ex vivo was selectively increased after GM-CSF therapy and was associated with increased 5-LO and FLAP expression . PMN leukotriene B(4) (LTB(4)) synthesis was also augmented and associated with increased 5-LO, FLAP, and cytosolic phospholipase A(2) expression . In conclusion, as previously demonstrated for PMN, PBM from AIDS subjects also demonstrate reduced 5-LO metabolism . GM-CSF therapy reversed this defect in both PBM and PMN . In view of the role of LT in antimicrobial function, cytokine administration in AIDS may play a role as adjunct therapy for infections.

Pediatr Infect Dis J, 1999 Nov, 18(11), 979 - 82
Determining duration of antibiotic use in children with complicated appendicitis; Hoelzer DJ et al.; BACKGROUND: The introduction of broad spectrum antibiotics has substantially decreased rates of mortality and morbidity associated with complicated appendicitis in children . The generally recommended therapy for children with complicated (gangrenous or perforated) appendicitis is administration of postoperative antibiotics for 3 to 14 days, but the decision as to the specific duration of treatment lies with the treating physician . AIM: This study evaluates whether the recommendation that the combination of the patient's being afebrile and eating and having a normal white blood cell (WBC) count and < or = 3% band forms can be used to decide when sufficient antibiotics have been given and can be safely discontinued . METHODS: Thirty-three consecutive patients seen in the pediatric surgical service with perforated or gangrenous appendicitis were studied prospectively . All patients received a standard protocol of resuscitation, appendectomy and broad spectrum antimicrobial therapy to be continued until they were eating, afebrile and had normal white blood cell counts with < or = 3% immature neutrophils (band forms) . RESULTS: Thirty-two children were treated until they met all criteria when antibiotics were stopped and the patients were discharged . Of these patients 31 had unremarkable courses of recovery with no development of intraabdominal abscess or wound infection {predictive value of criteria, 97% (31 of 32)} . The remaining patient who met the criteria required rehospitalization for treatment of intraabdominal abscess . Another patient was discharged prematurely when he failed to meet the criterion of afebrility . Although he was eating and his WBC count was normal, he had a temperature of 38.5 degrees C during the 24 h before discharge . He was readmitted for surgical drainage of an intraabdominal abscess, yielding a 100% predictive value for the criterion mismatch (1 of 1) . CONCLUSION: Based on our observations, when a patient with complicated appendicitis is afebrile for 24 h (temperature < 38 degrees C), is eating and has a WBC count with < or = 3% band forms, antibiotics can be safely discontinued with small risk of recurrent intraabdominal abscess.

J Food Prot, 1999 Nov, 62(11), 1248 - 54
Inactivation of Escherichia coli in milk by high-hydrostatic-pressure treatment in combination with antimicrobial peptides; Garcia-Graells C et al.; We studied the inactivation in milk of four Escherichia coli strains (MG1655 and three pressure-resistant mutants isolated from MG1655) by high hydrostatic pressure, alone or in combination with the natural antimicrobial peptides lysozyme and nisin and at different temperatures (10 to 50 degrees C) . Compared with that of phosphate buffer, the complex physicochemical environment of milk exerted a strong protective effect on E . coli MG1655 against high-hydrostatic-pressure inactivation, reducing inactivation from 7 logs at 400 MPa to only 3 logs at 700 MPa in 15 min at 20 degrees C . An increase in lethality was achieved by addition of high concentrations of lysozyme (400 microg/ml) and nisin (400 IU/ml) to the milk before pressure treatment . The additional reduction amounted maximally to 3 logs in skim milk at 550 MPa but was strain dependent and significantly reduced in 1.55% fat and whole milk . An increase of the process temperature to 50 degrees C also enhanced inactivation, particularly for the parental strain, but even in the presence of lysozyme and nisin, a 15-min treatment at 550 MPa and 50 degrees C in skim milk allowed decimal reductions of only 4.5 to 6.9 for the pressure-resistant mutants . A substantial improvement of inactivation efficiency at ambient temperature was achieved by application of consecutive, short pressure treatments interrupted by brief decompressions . Interestingly, this pulsed-pressure treatment enhanced the sensitivity of the cells not only to high pressure but also to the action of lysozyme and nisin.

Biochem Pharmacol, 1999 Dec 1, 58(11), 1791 - 9
Nitrofuran drugs as common subversive substrates of Trypanosoma cruzi lipoamide dehydrogenase and trypanothione reductase; Blumenstiel K et al.; Lipoamide dehydrogenase (LipDH), trypanothione reductase (TR), and glutathione reductase (GR) catalyze the NAD(P)H-dependent reduction of disulfide substrates . TR occurs exclusively in trypanosomatids which lack a GR . Besides their physiological reactions, the flavoenzymes catalyze the single-electron reduction of nitrofurans with the concomitant generation of superoxide anions . Here, we report on the interaction of clinically used antimicrobial nitrofurans with LipDH and TR from Trypanosoma cruzi, the causative agent of Chagas' disease (South American trypanosomiasis), in comparison to mammalian LipDH and GR . The compounds were studied as inhibitors and as subversive substrates of the enzymes . None of the nitrofurans inhibited LipDH, although they did interfere with the disulfide reduction of TR and GR . When the compounds were studied as substrates, T . cruzi LipDH showed a high rate of nitrofuran reduction and was even more efficient than its mammalian counterpart . Several derivatives were also effective subversive substrates of TR, but the respective reaction with human GR was negligible . Nifuroxazide, nifuroxime, and nifurprazine proved to be the most promising derivatives since they were redox-cycled by both T . cruzi LipDH and TR and had pronounced antiparasitic effects in cultures of T . cruzi and Trypanosoma brucei . The results suggest that those nitrofuran derivatives which interact with both parasite flavoenzymes should be revisited as trypanocidal drugs.

Biochem Pharmacol, 1999 Dec 1, 58(11), 1775 - 80
Effect of D-amino acid substitution on the stability, the secondary structure, and the activity of membrane-active peptide; Hong SY et al.; Several diastereomers and an enantiomer of KKVVFKVKFKK, an antimicrobial peptide that acts on the lipid membrane of pathogens were synthesized to investigate the effect of D-amino acid substitution on stability, secondary structure, and activity . The stability of the peptide in serum was improved greatly by the D-amino acid substitutions . D-Amino acid substitutions at the N- and/or C-terminal of the peptide, which had little effect on the alpha-helical structure, and all D-amino acid substitutions that formed a left-handed alpha-helix maintained antimicrobial activity, whereas D-amino acid substitutions in the middle of the amino acid sequence disrupted the alpha-helical structure, resulting in the complete loss of activity . This result confirmed that the peptide did not interact with chiral receptors, enzymes, or any chiral component of the membrane . D-Amino acid substitutions at the termini reduced the inhibition of the activity by heat-inactivated serum, which indicated that local change of chirality or change of secondary structure induced by D-amino acid substitutions might affect the interactions between the peptide and certain components in the serum . The present study suggests that partial D-amino acid substitution is a useful technique to improve the in vivo activity of antimicrobial peptides.

Bioorg Med Chem Lett, 1999 Oct 18, 9(20), 2983 - 8
New pyrrole derivatives as antimycobacterial agents analogs of BM212; Biava M et al.; During the course of our investigations in the field of azole antimicrobial agents, we have identified BM212 a pyrrole derivative with good in vitro activity against mycobacteria and candidae . These findings prompted us to prepare new pyrrole derivatives 2-6 in the hope of increasing the activity . The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria.

Curr Opin Pulm Med, 1999 Nov, 5(6), 371 - 7
New approaches to optimizing antimicrobial therapy in patients with cystic fibrosis; Beringer PM; Chronic pulmonary infections are a significant cause of morbidity and mortality in patients with cystic fibrosis . The traditional approach to managing patients with cystic fibrosis is to treat acute exacerbations with antimicrobial, airway clearance, and nutritional therapies . Advances in the understanding of the pharmacodynamics of antibiotics have led to the development of new dosing strategies to maximize the antibiotics' activity . Recent data on the use of aerosolized tobramycin as chronic maintenance therapy have demonstrated that it improves pulmonary function significantly and reduces hospitalization days . New insights into the pathogenesis of pulmonary disease have led to the development of novel therapies, including salt-insensitive antimicrobial peptides and rBPI21, as adjunctive therapy to increase the sensitivity of current antibiotics . In addition, macrolide antibiotics are being investigated for their anti-inflammatory effects as chronic maintenance therapy . Until effective therapies are available to correct the basic genetic defect that causes cystic fibrosis, antibacterial and anti-inflammatory agents will continue to be the mainstay of treatment.

Proc Natl Acad Sci U S A, 1999 Nov 23, 96(24), 14165 - 70
Transgenic tobacco plants with reduced capability to detoxify reactive oxygen intermediates are hyperresponsive to pathogen infection; Mittler R et al.; Reactive oxygen intermediates (ROI) play a critical role in the defense of plants against invading pathogens . Produced during the "oxidative burst," they are thought to activate programmed cell death (PCD) and induce antimicrobial defenses such as pathogenesis-related proteins . It was shown recently that during the interaction of plants with pathogens, the expression of ROI-detoxifying enzymes such as ascorbate peroxidase (APX) and catalase (CAT) is suppressed . It was suggested that this suppression, occurring upon pathogen recognition and coinciding with an enhanced rate of ROI production, plays a key role in elevating cellular ROI levels, thereby potentiating the induction of PCD and other defenses . To examine the relationship between the suppression of antioxidative mechanisms and the induction of PCD and other defenses during pathogen attack, we studied the interaction between transgenic antisense tobacco plants with reduced APX or CAT and a bacterial pathogen that triggers the hypersensitive response . Transgenic plants with reduced capability to detoxify ROI (i.e., antisense APX or CAT) were found to be hyperresponsive to pathogen attack . They activated PCD in response to low amounts of pathogens that did not trigger the activation of PCD in control plants . Our findings support the hypothesis that suppression of ROI-scavenging enzymes during the hypersensitive response plays an important role in enhancing pathogen-induced PCD.

Chemotherapy, 1999 Nov-Dec, 45(6), 512 - 20
Evaluation of phototoxic potential of gemifloxacin in healthy volunteers compared with ciprofloxacin; Vousden M et al.; This double-blind, randomized, parallel-group comparative study investigated the phototoxic potential of gemifloxacin mesylate, a potent, novel fluoroquinolone antimicrobial . Forty healthy male and female volunteers received repeat dosing for 7 days with 160 mg or 320 mg of gemifloxacin (o.d., p.m.), 500 mg of ciprofloxacin (b.d.) or placebo (b.d.) . On day 5 (large step) and day 6 (small step), graded series of wavebands were irradiated onto the back of each volunteer (phototesting) . Skin reactions were assessed 0-30 min (immediate erythema) and 24 and 48 h (delayed erythema) after irradiation . Both gemifloxacin, 320 mg o.d., and ciprofloxacin, 500 mg b.d., were associated with mild phototoxicity following 7 days of administration . The range of mean phototoxic indices (the ratio of minimal erythemal dose at baseline compared with that on day 7 at the end of dosing) was 1.00-2.19 for gemifloxacin and 0.97-2.23 for ciprofloxacin . The abnormal responses occurred within the ultraviolet A region (335-365 +/-30 nm) and were maximal at 24 h . Susceptibility to phototoxicity had cleared 48 h after stopping the drug . The phototoxicity observed with gemifloxacin, 160 mg o.d., was lower than that at the higher dose and similar to that of placebo, suggesting that gemifloxacin phototoxicity is dose dependent . There were no clinically important changes in the safety profiles of gemifloxacin and ciprofloxacin compared with placebo in healthy volunteers after 7 days of repeat dosing . This study demonstrated that gemifloxacin, 320 mg o.d . given for 7 days, has a low potential to cause mild photosensitivity which is similar to that of ciprofloxacin, 500 mg b.d., given for the same period . Copyright

Chemotherapy, 1999 Nov-Dec, 45(6), 504 - 11
Effect of Maalox on the bioavailability of oral gemifloxacin in healthy volunteers; Allen A et al.; This open, randomized, 4-way crossover study investigated the effect of the antacid Maalox on the bioavailability of gemifloxacin, a novel fluoroquinolone antimicrobial . Sixteen healthy male volunteers received gemifloxacin, 320 mg p.o., alone, 3 h after Maalox administration, or 10 min or 2 h before Maalox administration . Blood was sampled for 48 h after dosing to determine pharmacokinetic parameters . Estimates for the differences between regimens and 95% confidence intervals were calculated using the t-test for paired data . The administration of gemifloxacin 10 min before Maalox resulted in an average 85% reduction in the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)), whereas administration 3 h after Maalox produced a decrease in AUC(0-infinity), 15% of which was not considered to be clinically significant . The administration of gemifloxacin 2 h before Maalox had no notable effect on the gemifloxacin AUC(0-infinity) (average increase of 3%) . Similar results were seen for the maximum gemifloxacin plasma concentration (C(max)) . Neither the time to C(max) nor the half-life of gemifloxacin were notably altered by the administration of Maalox at any time relative to gemifloxacin dosing . There were no clinically important adverse experiences or changes in clinical laboratory parameters during this study . The findings of this study support the dosing recommendation that gemifloxacin can be administered either 2 h or more prior to, or 3 h or more after, the administration of Maalox . Copyright

Microb Drug Resist, 1999 Fall, 5(3), 227 - 33
Activities of eighteen antimicrobial regimens against Mycobacterium avium infection in beige mice; Fattorini L et al.; The therapeutic effect of 18 anti-Mycobacterium avium regimens was examined in beige mice after 91 days of infection . Treatments included monotherapy with clarithromycin (CLA), ethambutol (EMB), amikacin (AMI), rifabutin (RFB), ciprofloxacin (CIP), clofazimine (CLO), and combinations of CLA, CLA-EMB, or CLA-AMI with one of the other drugs . After monotherapy, only AMI and CLA displayed bacteriostatic and/or moderate bactericidal effects in spleens and lungs, while CIP and RFB were totally inactive and CLO and EMB showed intermediate effects against the isolate tested . Resistant mutants were isolated in spleens of mice treated with EMB, CIP, RFB, and CLO-Among two-drug combinations, CLA-RFB, CLA-CIP, and CLA-CLO were significantly more active than RFB, CIP, CLO, respectively, but not more active than CLA alone, in both organs; CLA-AMI and CLA-EMB were bactericidal in spleens and lungs, respectively . Although activity of CLA-EMB was significantly potentiated by RFB and CLO in spleens and lungs, that of CLA-AMI was significantly increased by RFB and CLO only in lungs . The most active regimen in spleens and lungs on day 91 was the combination of all three, namely CLA-AMI-EMB, which reduced the CFU numbers of 2.7 and 7.5 log10, in comparison with day 1 and day 91 counts in untreated control mice, respectively.

Rev Inst Med Trop Sao Paulo, 1999 Jul-Aug, 41(4), 249 - 53
In vitro evaluation of erythromycin in chloroquine resistant brazilian P . falciparum freshly isolates: modulating effect and antimalarial activity evidence; Menezes CM et al.; Erythromycin, a reversal agent in multidrug-resistant cancer, was assayed in chloroquine resistance modulation . The in vitro microtechnique for drug susceptibility was employed using two freshly isolates of Plasmodium falciparum from North of Brazil . The antimalarial effect of the drug was confirmed, with an IC50 estimates near the usual antimicrobial therapy concentration, and a significant statistical modulating action was observed for one isolate.

J Agric Food Chem, 1999 Apr, 47(4), 1356 - 61
Effect of lactoferrin on oxidative stability of corn oil emulsions and liposomes; Huang SW et al.; Interest in using lactoferrin in foods for its antimicrobial activity inspired the present study of its antioxidant activity . Natural bovine lactoferrin inhibited oxidation in buffered corn oil emulsions and lecithin liposome systems at pH 6.6 and 50 degrees C . The antioxidant activity increased with lactoferrin concentration in both phosphate- and Tris-buffered emulsions, but not in both buffered liposome systems . A mixture of 1 microM lactoferrin and 0.5 microM ferrous ions was a significantly better antioxidant than 1 microM lactoferrin alone in Tris-buffered emulsions and in phosphate-buffered liposomes . Lactoferrin was a prooxidant at 1 microM in phosphate-buffered liposomes and at 15 and 20 microM in Tris-buffered liposomes . Copper was a stronger prooxidant than iron in both buffered emulsions . Lactoferrin decreased the prooxidant effect of iron, but not of copper, in emulsions . The antioxidant or prooxidant activities of lactoferrin depended on the lipid system, buffer, its concentration, the presence of metal ions, and oxidation time.

J Agric Food Chem, 1999 Feb, 47(2), 584 - 7
Detection of antifungal activity in Anemarrhena asphodeloides by sensitive BCT method and isolation of its active compound; Iida Y et al.; Antifungal activity was detected from Anemarrhena asphodeloides by the Bio-Cell Tracer (BCT) method . An active fraction was separated by silica gel column chromatography and reverse-phase HPLC . The molecular weight was determined by GC-MS, and the molecular structure was analyzed by IR, (1)H NMR, and (13)C NMR . The isolated compound was found to be identical to nyasol, (Z)-1, 3-bis(4-hydroxyphenyl)-1,4-pentadiene, which formerly appeared in the literature without any remark on the antifungal activity . This compound showed antimicrobial activity against 38 strains of fungi and five strains of bacteria . The minimum inhibitory concentration (MIC) ranged from 12.5 to 200 microg mL(-)(1), except for two strains based on the broth dilution method.

J Agric Food Chem, 1999 Feb, 47(2), 485 - 9
Tentative identification of polyphenols in Sempervivum tectorum and assessment of the antimicrobial activity of Sempervivum L; Abram V et al.; Polyphenols were isolated from sliced fresh leaves of Sempervivum tectorum . After 21 h of extraction by methanol and removal of chlorophyll, ethyl acetate was used to separate oligomeric and polymeric polyphenols: 0.07% of oligomeric and 0.13% of polymeric polyphenols were found . After acidic hydrolysis of the oligomeric polyphenols, it was established by TLC, HPLC, and FAB mass spectra that kaempferol was the unique aglycon of the three main oligomeric constituents of S . tectorum . Paper chromatography suggested delphinidol to be the only anthocyanidin detectable in the material obtained by acidic hydrolysis of the polymeric polyphenol fraction . After Haslam degradation of the same polymeric polyphenol fraction, only 4-thiobenzyl-(-)-epigallocatechin and 4-thiobenzyl-(-)-epigallocatechin-3-gallate were found and tentatively identified . We concluded that procyanidins of B2 type could be the major components of the polymeric polyphenol fraction of this plant . Antimicrobial activity of Sempervivum L . leaves against six of seven selected microorganisms was observed.

J Agric Food Chem, 1999 Feb, 47(2), 444 - 7
Biologically active carbazole alkaloids from Murraya koenigii; Ramsewak RS et al.; The bioassay guided fractionation of the acetone extract of the fresh leaves of Murraya koenigii resulted in the isolation of three bioactive carbazole alkaloids, mahanimbine (1), murrayanol (2), and mahanine (3), as confirmed from their (1)H and (13)C NMR spectral data . Compound 2 showed an IC(50) of 109 microg/mL against hPGHS-1 and an IC(50) of 218 microg/mL against hPGHS-2 in antiinflammatory assays, while compound 1 displayed antioxidant activity at 33.1 microg/mL . All three compounds were mosquitocidal and antimicrobial and exhibited topoisomerase I and II inhibition activities.

J Agric Food Chem, 1999 Jan, 47(1), 1 - 6
Extending storage life of fresh-cut apples using natural products and their derivatives; Buta JG et al.; Prevention of browning of apples slices has been difficult to achieve because of the rapidity of the enzymatic oxidation of phenolic substrates even under reduced atmospheric pressure storage . Combinations of enzymatic inhibitors, reducing agents, and antimicrobial compounds containing calcium to extend storage life were tested to decrease the browning of Red Delicious apple slices stored at 5 and 10 degrees C under normal atmospheric conditions . Treatments were devised to prevent browning for up to 5 weeks at 5 degrees C with no apparent microbial growth using dipping solutions of compounds derived from natural products consisting of 4-hexylresorcinol, isoascorbic acid, a sulfur-containing amino acid (N-acetylcysteine), and calcium propionate . Analyses of organic acids and the major sugars revealed that the slices treated with the combinations of antibrowning compounds retained higher levels of malic acid and had no deterioration in sugar levels at 5 and 10 degrees C, indicating that higher quality was maintained during storage.

Eur J Biochem, 1999 Dec, 266(2), 665 - 74
Structural and functional implications of a proline residue in the antimicrobial peptide gaegurin; Suh JY et al.; Although it is commonly known as a helix breaker, proline residues have been found in the alpha-helical regions of many peptides and proteins . The antimicrobial peptide gaegurin displays alpha-helical structure and has a central proline residue (P14) . The structure and activity of gaegurin and its alanine derivative (P14A) were determined by various spectroscopic methods, restrained molecular dynamics, and biological assays . Both P14 and P14A exhibited cooperative helix formation in solution, but the helical stability of P14 was reduced substantially when compared to that of P14A . Chemical-shift analysis indicated that both of the peptides formed curved helices and that P14 showed diminished stability in the region around the central proline . However, hydrogen-exchange data revealed remarkable differences in the location of stable amide protons . P14 showed a stable region in the concave side of the curved helix, while P14A exhibited a stable region in the central turn of the helix . The model structure of P14 exhibited a pronounced kink, in contrast to the uniform helix of P14A . Both peptides showed comparable binding affinities for negatively charged lipids, while P14 had a considerably reduced affinity for a neutral lipid . With its destabilized alpha-helix, P14 exhibited greater antibacterial activity than did P14A . Hence, electrostatic interaction between helical peptides and lipid membranes is believed to be the dominant factor for antibacterial activity . Moreover, helical stability can modulate peptide binding to membranes that is driven by electrostatic interactions . The observation that P14 is a more potent antibacterial agent than P14A implies that the helical kink of P14 plays an important role in the disruption of bacterial membranes.

Eur J Biochem, 1999 Dec, 266(2), 335 - 46
Recombinant expression and range of activity of penaeidins, antimicrobial peptides from penaeid shrimp; Destoumieux D et al.; Penaeidins are 5.5- to 6.6-kDa antimicrobial peptides recently isolated from the plasma and haemocytes of the tropical shrimp Penaeus vannamei . These molecules differ from the other classes of antimicrobial peptides in that they are composed of a proline-rich N-terminus and of a C-terminus containing six cysteine residues engaged in three disulfide bridges . In order to gain information on their antimicrobial activity, two penaeidins (Pen-2 and Pen-3a) were expressed in Saccharomyces cerevisiae . The recombinant Pen-2 and -3a were characterized in terms of primary structure by Edman degradation, mass spectrometry and gas chromatography . A protocol was then established to purify the amount of penaeidins required for the determination of their activity spectrum . We demonstrate in this study that expression in yeast is appropriate for the large-scale production of functional penaeidins, whose activities are almost indistinguishable from those of the native molecules . Data on Pen-2 and -3a activity demonstrate that penaeidins have a broad spectrum of antifungal properties associated with a fungicidal activity, and that their antibacterial activities are essentially directed against Gram-positive bacteria, with a strain-specific inhibition mechanism . Despite a better efficiency of Pen-3a on most of the tested strains, similar activity spectra and inhibition mechanisms were observed for both Pen-2 and -3a . Finally, no synergistic effect could be observed between the two molecules.

Infect Immun, 1999 Dec, 67(12), 6643 - 51
Peptide localization and gene structure of cryptdin 4, a differentially expressed mouse paneth cell alpha-defensin; Ouellette AJ et al.; Paneth cells in crypts of the small intestine express antimicrobial peptides, including alpha-defensins, termed cryptdins in mice . Of the known Paneth cell alpha-defensins, the cryptdin 4 gene is unique, because it is inactive in the duodenum and expressed at maximal levels in the distal small bowel (D . Darmoul and A . J . Ouellette, Am . J . Physiol . 271:G68-G74, 1996) . With a cryptdin 4-specific antibody, immunohistochemical staining of ileal Paneth cells was strong and specific for cytoplasmic granules, demonstrating that this microbicidal peptide is a secretory product of Paneth cells in the distal small intestine . Consistent with the pattern of cryptdin 4 mRNA distribution along the length of the gut, the cryptdin 4 peptide was not detected in duodenum . Structurally, the cryptdin 4 gene resembles other Paneth cell alpha-defensin genes . Its two exons, transcriptional start site, intron, splice sites, and 3' flanking sequences are characteristic of the highly conserved mouse alpha-defensin genes . However, in the region upstream of the transcriptional initiation site, the cryptdin 4 gene contains a repeated 130-bp element that is unique to this alpha-defensin gene . Every independent cryptdin 4 genomic clone examined carries the repeated element, which contains putative recognition sequences for TF-IID-EIIA, cMyc-RS-1, and IgHC.2/CuE1.1; the repeat proximal to the start of transcription replaces DNA at the corresponding position in other mouse alpha-defensin genes . We speculate that this unique duplicated element may have a cis-acting regulatory role in the positional specificity of cryptdin 4 gene expression.

Infect Immun, 1999 Dec, 67(12), 6631 - 6
Calgranulin C has filariacidal and filariastatic activity; Gottsch JD et al.; The calgranulins are a family of calcium- and zinc-binding proteins produced by neutrophils, monocytes, and other cells . Calgranulins are released during inflammatory responses and have antimicrobial activity . Recently, one of the calgranulins, human calgranulin C (CaGC), has been implicated as an important component of the host responses that limit the parasite burden during filarial nematode infections . The goal of this work was to test the hypothesis that human CaGC has biologic activity against filarial parasites . Brugia malayi microfilariae and adults were exposed in vitro to 0.75 to 100 nM recombinant human CaGC . Recombinant CaGC affected adult and larval parasites in a dose-dependent fashion . Microfilariae were more sensitive to the action of CaGC than were adult parasites . At high levels, CaGC was both macrofilariacidal and microfilariacidal . At lower levels, the percentage of parasites killed was dependent on the level of CaGC in the culture system . The larvae not killed had limited motility . The filariastatic effect of low-level CaGC was reversed when the CaGC was removed from the culture system . Immunohistochemical analysis demonstrated that human CaGC accumulated in the cells of the hypodermis-lateral chord of adult and larval parasites . The antifilarial activity of CaGC was not due to the sequestration of zinc . Thus, the cellular and molecular mechanisms that result in the production and release of CaGC in humans may play a key role in the regulation of filarial parasite numbers.

Laryngoscope, 1999 Nov, 109(11), 1841 - 7
Penetration of cefuroxime into chronically inflamed sinus mucosa; Dinis PB et al.; OBJECTIVES: Despite its seeming relevance, limited information exists about antibiotic sinus tissue penetration and how it is affected by inflammation . Thus the reason for the present investigation . STUDY DESIGN: A randomized, open, multiple-dose, pharmacological study, employing cefuroxime axetil, an approved oral antimicrobial for the treatment of acute bacterial rhinosinusitis, was developed . METHODS: Twenty subjects, selected for surgery because of chronic rhinosinusitis, were randomly allocated to receive either a short (3-8 d) or a long (9-14 d) preoperative treatment regime with 500 mg cefuroxime axetil BID, the last dosage being taken 3 to 4 hours before surgery . At the operation, tissue samples were collected at specific sinonasal sites for both pharmacological determination of antibiotic levels and histopathological assessment of the degree of inflammation . The blood levels of the drug were simultaneously assayed . RESULTS: Cefuroxime kinetic behavior on chronically inflamed mucosa was shown to be, for the most part, dependent on the blood levels, regardless of the inflammatory state . Distribution was even throughout the different sinus cavities, and the tissue levels were still, 3 to 4 hours after dosing, above the reported minimum inhibitory concentration (MIC) values for some of the most prevalent sinus pathogens . The extended treatment course did not seem to add any extra histopathological or pharmacological benefit . CONCLUSIONS: Cefuroxime penetrates adequately and uniformly into chronically inflamed sinus mucosa, apparently unaffected by the degree of inflammation, in a way not dissimilar to its pharmacokinetic behavior in the normal state . Persistent MIC levels for common pathogens still warrant antimicrobial efficacy for a significant period of time after dosing.

Ceska Slov Farm, 1999 Sep, 48(5), 221 - 5
{Liberation of drugs from impregnated wound dressings}; Duckova K et al.; The present paper investigates drugs and polymers intended for the impregnation of textile carriers intended for use as wound covers . Their suitability was evaluated on the basis of the evaluation of the antimicrobial efficacy of a combination of trimetoprim and sulfadimidine with the local anaesthetics carbizocaine and lidocaine, and the immunomodulating substance fungal glucan . A greater inhibitory effect on the growth of microorganisms was shown by a combination of antimicrobial substances with carbizocaine . In the study of liberation of chlorohexidine from hydrophilic macromolecular dispersions its bond to glucan was confirmed . Dispersions of Natrosol proved to be more advantageous; chlorohexidine as well as local anaesthetics were released from them more rapidly than from methylcellulose gels . The dispersions under study are of a non-Newton character with pseudoplastic flow, glucan-containing gels are thixotropic.

Respir Care Clin N Am, 1999 Dec, 5(4), 617 - 31
Inhaled antimicrobial therapy; O'Riordan T et al.; Although antimicrobial therapy has been administered through the inhaled route for decades, it has always been controversial . There are relatively few accepted indications for this mode of administration . Well-controlled studies of aerosolized antibiotics in cystic fibrosis demonstrate that tobramycin on a cyclical basis may reduce sputum volume, bacterial counts, and improve pulmonary function . Preliminary data indicate that inhaled antibiotic therapy of ventilator-associated tracheobronchitis may reduce sputum volume, but the clinical significance of this finding remains to be determined . Inhaled pentamidine is used for prophylaxis of Pneumocystis carinii in patients with human immunodeficiency virus infection who are intolerant of oral prophylactic agents . Ribavirin has been used for 30 years to treat respiratory syncytial virus . The role, if any, of inhaled antifungal therapy with amphotericin B remains undetermined.

Curr Opin Clin Nutr Metab Care, 1998 Nov, 1(6), 539 - 47
Chemoprevention--a novel approach in dietetics; Andlauer W et al.; Chemoprotective potential of naturally occurring phytochemicals in food is a major area of scientific interest . Results acquired from epidemiologic studies suggest a reduced risk of degenerative diseases with high phytochemical consumption . Bioavailability of phytochemicals is a critical issue, though their significant absorption has been demonstrated . Phytochemicals possess an array of biochemical and pharmacological qualities like antioxidative, anticarcinogenic, antimicrobial, cholesterol-lowering and antithrombotic activities.

Biochemistry, 1999 Nov 16, 38(46), 15193 - 203
Fourier transform infrared spectroscopic studies of the interaction of the antimicrobial peptide gramicidin S with lipid micelles and with lipid monolayer and bilayer membranes; Lewis RN et al.; We have utilized Fourier transform infrared spectroscopy to study the interaction of the antimicrobial peptide gramicidin S (GS) with lipid micelles and with lipid monolayer and bilayer membranes as a function of temperature and of the phase state of the lipid . Since the conformation of GS does not change under the experimental conditions employed in this study, we could utilize the dependence of the frequency of the amide I band of the central beta-sheet region of this peptide on the polarity and hydrogen-bonding potential of its environment to probe GS interaction with and location in these lipid model membrane systems . We find that the GS is completely or partially excluded from the gel states of all of the lipid bilayers examined in this study but strongly partitions into lipid micelles, monolayers, or bilayers in the liquid-crystalline state . Moreover, in general, the penetration of GS into zwitterionic and uncharged lipid bilayer coincides closely with the gel to liquid-crystalline phase transition of the lipid . However, GS begins to penetrate into the gel-state bilayers of anionic phospholipids prior to the actual chain-melting phase transition, while in cationic lipid bilayers, GS does not partition strongly into the liquid-crystalline bilayer until temperatures well above the chain-melting phase transition are reached . In the liquid-crystalline state, the polarity of the environment of GS indicates that this peptide is located primarily at the polar/apolar interfacial region of the bilayer near the glycerol backbone region of the lipid molecule . However, the depth of GS penetration into this interfacial region can vary somewhat depending on the structure and charge of the lipid molecule . In general, GS associates most strongly with and penetrates most deeply into more disordered bilayers with a negative surface charge, although the detailed chemical structure of the lipid molecule and physical organization of the lipid aggregate (micelle versus monolayer versus bilayer) also have minor effects on these processes.

Intern Med, 1999 Nov, 38(11), 910 - 6
Nosocomial pneumonia likely caused by Stenotrophomonas maltophilia in two patients with polymyositis; Amano K et al.; We report two cases of polymyositis (PM) complicated with nosocomial pneumonia probably caused by Stenotrophomonas maltophilia, which was resistant to multiple antimicrobials . In the first case, the chest CT findings and high serum endotoxin level as well as sputum culture results were helpful for the proper diagnosis and the therapy was successful . However the second patient died of a lung abscess in spite of the intensive antibiotic therapy . When PM patients develop pneumonia unresponsive to various antibiotics, a multi-drug-resistant bacteria such as Stenotrophomonas maltophilia should be considered as the pathogen.

Burns, 1999 Nov, 25(7), 636 - 9
The treatment of paediatric burns using topical papaya; Starley IF et al.; Due to the limited resources for the management of burns in most regions of Africa there is a significant role for many aspects of traditional African medicine . The active component of many traditional preparations is often of plant origin and more than 25 plants have been described as useful in relations to burns and wound healing . Carica papaya is currently used in The Gambia at the Royal Victoria Hospital, Banjul in the Paediatric Unit as the major component of burns dressings, where it is well tolerated by the children . Cheap and widely available, the pulp of the papaya fruit is mashed and applied daily to full thickness and infected burns . It appears to be effective in desloughing necrotic tissue, preventing burn wound infection, and providing a granulating wound suitable for the application of a split thickness skin graft . Possible mechanisms of action include the activity of proteolytic enzymes chymopapain and papain, as well as an antimicrobial activity, although further studies are required.

J Biomol Struct Dyn, 1999 Oct, 17(2), 367 - 80
Androctonin, a novel antimicrobial peptide from scorpion Androctonus australis: solution structure and molecular dynamics simulations in the presence of a lipid monolayer; Mandard N et al.; Androctonin is a highly cationic antimicrobial peptide from scorpion exhibiting a broad spectrum of activities against bacteria and fungi . It contains 25 amino acids including four cysteine residues forming two disulfide bridges . We report here on the determination of its solution structure by conventional two-dimensional (2D) 1H-NMR spectroscopy and molecular modelling using distance geometry and molecular dynamics methods . The structure of androctonin involves a well-defined highly twisted anti-parallel beta-sheet with strands connected by a more variable positively charged turn . A comparison with the structure of tachyplesin I (horseshoe crab) reveals that the amphiphilic character of the protein surface of this homologous peptide is not observed in androctonin . We have undertaken a 200-ps molecular dynamics simulation study on a system including one androctonin molecule and a monolayer of DMPG (1,2-dimyristoylphosphatidylglycerol) lipids . On the basis of this simulation, the first steps of the membrane permeabilization process are discussed.

Int J Antimicrob Agents, 1999 Sep, 13(1), 57 - 60
Antiviral effects of synthetic membrane-active peptides on herpes simplex virus, type 1; Egal M et al.; Magainins are cationic peptides with antimicrobial activity which were originally isolated from the skin of the African clawed frog (Xenopus laevis) . Several synthetic derivatives of this class of peptides were evaluated for antiviral activity against herpes simplex virus, type 1 (HSV) . Some of the peptides (MSI-102, -248, -420, -499/500 combination, -591, -594, and -1251) showed significant reduction of HSV plaque-forming units . The antiviral effect was enhanced when HSV was pretreated with the peptides prior to inoculation onto Vero monolayers, suggesting a direct effect on the virion . Most of the peptides with anti-HSV activity were lysine-rich, and the addition of octanoyl groups to the peptides appeared to enhance the antiviral effect.

Int J Antimicrob Agents, 1999 Sep, 13(1), 53 - 6
Duration of intravenous therapy and hospital stay according to choice of empirical antimicrobial treatment for community-acquired respiratory infection; Laing RB et al.; A review of patients admitted to medical wards with respiratory infection was undertaken to look for differences in duration of intravenous (IV) therapy and length of patient stay based on the class of IV antimicrobial used in treatment . Data was analysed from 231 patients with community-acquired respiratory infection who were treated empirically for at least 24 h with either an IV cephalosporin (146 patients) or an IV penicillin or macrolide (85 patients) . The severity of illness and indication for IV treatment was similar in each group . Those treated with a cephalosporin received IV therapy for a significantly longer period (mean = 4.44 days, SD = 2.6) than those given a penicillin or macrolide (mean = 3.3 days, SD = 1.8): P < 0.001 . Patient stay was significantly longer in the cephalosporin group (mean = 11.6 days, SD = 10.4) than the penicillin/macrolide group (mean = 9.4 days, SD = 6.3): P = 0.04 . These differences are most readily accounted for by the absence from the hospital formulary of a third generation oral cephalosporin, a drug that might be regarded as an obvious form of follow-on therapy in patients treated empirically with an injectable cephalosporin.

Drug Ther Bull, 1999 Feb, 37(2), 9 - 16
Tackling antimicrobial resistance; Ethical issues in the history of prophylactic antibiotic use in neurosurgery; Division of Neurosurgery and Microbiology Laboratory, Nyack Hospital, Nyack, New York, USAThere has always been controversy about the indications for prescribing antibiotics to prevent postoperative sepsis in patients undergoing cranial and spinal surgery . The earlier specialists in infectious diseases warned that the effectiveness of antimicrobial drugs was leading to indiscriminate administration for the prevention of wound infection . Three clinical researchers present a review of the history of prophylactic antibiotic use in neurosurgery, including their own work, and raise a number of ethical issues not previously discussed in the literature about: (1) scientific methodology; (2) random selection; (3) prospective study; (4) blinded control; (5) placebo medication; (6) professional equipoise; (7) statistical analysis; (8) informed consent; (9) utilitarian philosophy; and (10) managed care . Also discussed are the dual role of physician and investigator and the ethical dilemma of depending upon meticulous technique versus adopting regimens of prophylactic antibiotics.

Poult Sci, 1999 Nov, 78(11), 1506 - 9
Effects of daily oral doses of L-arginine on coccidiosis infections in chickens; Allen PC; L-arginine is an essential amino acid for chickens, as well as the substrate for biosynthesis of nitric oxide (NO), a bioregulatory free radical molecule known to have antimicrobial activity . Biosynthesis of NO by induced nitric oxide synthase (iNOS) can be stimulated during immunological response to infection . Therefore, in chickens, production of NO as a response to an infection should be influenced by dietary levels of L-arginine . Two experiments were carried out to determine whether oral dosing with L-arginine during coccidia infections could influence the associated pathology or the development of the parasites . Neither single nor dual daily doses (500 mg/kg) of L-arginine reversed weight gain reduction, augmented plasma NO2- + NO3- levels, or lessened lesion scores in chicks infected with Eimeria acervulina, Eimeria maxima, or Eimeria tenella . Although the oocyst shedding from E . maxima (1x dose) or E . acervulina (2x dose) infections were not affected, the oocyst shedding from E . tenella infections was significantly reduced by both dose regimens.

J Neuropathol Exp Neurol, 1999 Nov, 58(11), 1163 - 9
Inducible nitric oxide synthase immunoreactivity in the Alzheimer disease hippocampus: association with Hirano bodies, neurofibrillary tangles, and senile plaques; Lee SC et al.; Inducible nitric oxide synthase (iNOS) is involved in the generation of nitric oxide, a molecule with multiple biological activities . Although iNOS expression may be part of antimicrobial armamentarium, inappropriate expression of iNOS can potentially lead to damage to the host . In this report, we determined the expression of iNOS by immunocytochemistry in the hippocampus of the Alzheimer brains (AD) as well as in young and old normal brains . The results showed localization of iNOS immunoreactivity to Hirano bodies of the AD hippocampus . In addition, small granular iNOS immunoreactive profiles were detected associated with senile plaques and extracellular neurofibrillary tangles . In the hippocampus of control brains, morphologically similar profiles were immunoreactive for iNOS, but in far fewer numbers than in AD hippocampus . The results suggest that iNOS is expressed in a subset of pyramidal neurons in the AD hippocampus, and that iNOS may be involved in the pathogenesis of neuronal degeneration in AD.

West J Med, 1999 Sep, 171(3), 159 - 62
Prevention of adverse events in hospitalized patients using an antimicrobial review program; Guglielmo BJ et al.; OBJECTIVE: To evaluate whether an antimicrobial review system is associated with a reduction in antimicrobial-associated adverse events . DESIGN: All antimicrobial medication orders for patients hospitalized over a two-year period were evaluated . High-level interventions intended to prevent adverse antimicrobial events were collated . Based on literature estimates of adverse antimicrobial events, potential reduction of high-level adverse antimicrobial events was estimated . SETTING: Department of Clinical Pharmacy and Division of Infectious Diseases at a tertiary care teaching hospital . RESULTS: A total of 452 interventions were classified as "high-level." The incidence of preventable adverse antimicrobial events requiring intervention was 16 per 1000 antimicrobial orders . The incidence of high-level errors necessitating intervention was 4.4 per 1000 antimicrobial orders . An estimated 125 to 198 high-level adverse events were avoided . CONCLUSION: An antimicrobial review program has the potential to reduce significant adverse events in hospitalized patients.

Pharmacoeconomics, 1999 Sep, 16(3), 297 - 306
Cost effectiveness of Helicobacter pylori eradication therapies in patients with duodenal ulcer . An analysis of triple therapy versus two dual therapy alternatives; Tennvall GR et al.; OBJECTIVE: Recent research has focused on eradication therapy as the principal treatment of patients with duodenal ulcers and Helicobacter pylori infection . The aim of this study was to analyse the cost effectiveness of triple therapy versus 2 dual therapies . DESIGN: A health economic evaluation of triple therapy with lansoprazole, amoxicillin and clarithromycin versus 2 dual therapies (lansoprazole or omeprazole, each with amoxicillin) in the eradication of Helicobacter pylori in patients with duodenal ulcers was performed in parallel with a randomised clinical trial . Direct and indirect costs were estimated for 1 year using data elicited from patient questionnaires and from the clinical trial . MAIN OUTCOME MEASURES AND RESULTS: Despite the initial drug cost for triple therapy being 650 Swedish kronor (SEK; 1996 values) higher, the average total direct cost in this group was only SEK150 to SEK200 higher than in the dual therapy groups . This was a result of fewer outpatient visits and lower drug use after treatment failure in the triple therapy group . Triple therapy had a more favourable cost-effectiveness ratio than the dual therapies . CONCLUSION: In spite of higher initial antimicrobial costs, triple therapy with lansoprazole, amoxicillin and clarithromycin is more cost effective than dual therapy because of a higher eradication rate and greater symptom relief.

Proc Natl Acad Sci U S A, 1999 Nov 9, 96(23), 13496 - 500
A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window; Yrjanheikki J et al.; The only treatment of patients with acute ischemic stroke is thrombolytic therapy, which benefits only a fraction of stroke patients . Both human and experimental studies indicate that ischemic stroke involves secondary inflammation that significantly contributes to the outcome after ischemic insult . Minocycline is a semisynthetic second-generation tetracycline that exerts antiinflammatory effects that are completely separate from its antimicrobial action . Because tetracycline treatment is clinically well tolerated, we investigated whether minocycline protects against focal brain ischemia with a wide therapeutic window . Using a rat model of transient middle cerebral artery occlusion, we show that daily treatment with minocycline reduces cortical infarction volume by 76 +/- 22% when the treatment is started 12 h before ischemia and by 63 +/- 35% when started even 4 h after the onset of ischemia . The treatment inhibits morphological activation of microglia in the area adjacent to the infarction, inhibits induction of IL-1beta-converting enzyme, and reduces cyclooxygenase-2 expression and prostaglandin E(2) production . Minocycline had no effect on astrogliosis or spreading depression, a wave of ionic transients thought to contribute to enlargement of cortical infarction . Treatment with minocycline may act directly on brain cells, because cultured primary neurons were also salvaged from glutamate toxicity . Minocycline may represent a prototype of an antiinflammatory compound that provides protection against ischemic stroke and has a clinically relevant therapeutic window.

Blood, 1999 Nov 1, 94(9), 3141 - 50
Myeloid transcription factor C/EBPepsilon is involved in the positive regulation of lactoferrin gene expression in neutrophils; Verbeek W et al.; Targeted mutation of the myeloid transcription factor C/EBPepsilon in mice results in gram-negative septic death at 3 to 5 months of age . This study defines the underlying molecular defects in their terminal granulocytic differentiation . The mRNA for the precursor protein of the cathelin-related antimicrobial peptides was almost completely absent in the bone marrow cells of C/EBPepsilon-/- mice . This finding may help explain their susceptibility to gram-negative sepsis, because both are bacteriocidal peptides with potent activity against gram-negative bacteria . Superoxide production was found to be reduced in both granulocytes and monocytes of C/EBPepsilon-/- mice . While gp91 phox protein levels were normal, p47phox protein levels were considerably reduced in C/EBPepsilon -/- granulocytes/monocytes, possibly limiting the assembly of the NADPH oxidase . In addition, expression of mRNA of the secondary and tertiary granule proteins, lactoferrin and gelatinase, were not detected, and levels of neutrophil collagenase mRNA were reduced in bone marrow cells of the knock-out mice . The murine lactoferrin promoter has a putative C/EBP site close to the transcription start site . C/EBPepsilon bound to this site in electromobility shift assay studies and mutation of this site abrogated binding to it . A mutation in the C/EBP site reduced the activity of the promoter by 35% . Furthermore, overexpression of C/EBPepsilon in U937 cells increased the activity of the wild-type lactoferrin promoter by 3-fold . In summary, our data implicate C/EBPepsilon as a critical factor of host antimicrobial defense and suggests that it has a direct role as a positive regulator of expression of lactoferrin in vivo.

Farmaco, 1999 Sep 30, 54(9), 624 - 8
Synthesis and antimicrobial activity of Schiff and Mannich bases of isatin and its derivatives with pyrimidine; Pandeya SN et al.; Isatin and its derivatives have been reacted with 4-(4'-chlorophenyl)-6-(4"-methyl phenyl)-2-aminopyrimidine to form Schiff bases and the N-Mannich bases of these compounds were synthesized by reacting them with formaldehyde and several secondary amines . Investigation of antimicrobial activity of the compounds was made by the agar dilution method against 28 pathogenic bacteria, eight pathogenic fungi and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells . The compounds are significantly active against bacteria and fungi.

Arzneimittelforschung, 1999 Oct, 49(10), 853 - 7
Synthesis and antimicrobial activity of some new flavonyl oxime ether derivatives; Tuncbilek M et al.; The synthesis of a series of 6 compounds related to 2-(4'-formyl-phenyl)-4}H-1-benzopyran-4-one O-substituted oxime and the results of a study of their biological activity are reported . The structural assignments of the compounds is based upon various spectral data . The prepared compounds were screened for their in vitro antibacterial and antifungal activities . Compound F3 exhibited the best antifungal activity compared with ketoconazole and fluconazole.

An R Acad Nac Med (Madr), 1999, 116(1), 41 - 68; discussion 69-72
{Infectious disease trends}; del Rey Calero J; Infectious disease mortality has increased during the last decades: from a rate of 38.10(5) inhabitants in 1980-95 to 41, 5.10(5) in 1998 . Demographic changes have modified susceptibility to infections, due to the increment of elderly people--who have less immunity--, and the increase in drug-abusers and HIV-infected subjects . Social and technological environmental factors have had some influence on emergent and re-emergent diseases . Key issues to be considered are problems with antimicrobial resistance, infectious related- to chronic diseases, infections in immunodeficient subjects, and new vaccines to use . Among the challenges to public health is the need for incorporating new and rapidly technologies as microarrays, strategies of planning, multisectorial approaches to detecting preventing and controlling emerging and re-emerging infectious diseases.

Am Surg, 1999 Nov, 65(11), 1035 - 7
Ventral hernia synthetic mesh repair infected by Mycobacterium fortuitum; Matthews MR et al.; We report the occurrence of a refractory infection caused by the "rapidly growing" nontuberculous mycobacterium, Mycobacterium fortuitum, after incisional hernia repair using synthetic mesh . The patient had previously undergone three herniorrhaphies incorporating polypropylene mesh . Multiple surgical debridements were required, along with complete removal of all the mesh, to eradicate the infection . Prolonged antimicrobial therapy with sulfamethoxazole, an agent active against the patient's isolate, was also used . Although this atypical mycobacterium has been reported to cause a variety of infections, including many types of periprosthetic infections, this case represents successful treatment of M . fortuitum infecting abdominal wall mesh.

Lancet, 1999 Oct 30, 354(9189), 1504 - 7
Rapid diagnosis of central-venous-catheter-related bloodstream infection without catheter removal; Kite P et al.; BACKGROUND: Current methods for the diagnosis of bloodstream infection related to central venous catheters (CVC) are slow and in many cases require catheter removal . Since most CVC that are removed on suspicion of causing infection prove not to be infected, removal of catheters unnecessarily exposes patients to the risks associated with reinsertion . METHODS: The gram stain and acridine-orange leucocyte cytospin test (AOLC) is rapid (30 min), inexpensive, and requires only 100 microL catheter blood (treated with edetic acid) and the use of light and ultraviolet microscopy . We assessed the gram stain and AOLC test in suspected cases of catheter-related bloodstream infection, in comparison with two methods requiring catheter removal (tip roll and tip flush), and a third technique, done in situ (endoluminal brush) in conjunction with quantitative peripheral-blood cultures . FINDINGS: 128 cases of suspected catheter-related bloodstream infection were assessed in 124 adult surgical patients (median duration of CVC placement was 16 days) . In 112 (88%) cases CVC blood was obtainable . Catheter-related bloodstream infection was diagnosed in 50 cases (culture of the same organism from the catheter, in significant numbers, and from peripheral-blood culture) . The sensitivity of the gram stain and AOLC test was 96% and the specificity was 92%, with a positive predictive value of 91% and a negative predictive value of 97% . By comparison, the tip-roll, tip-flush, and endoluminal-brush methods had sensitivities of 90%, 95%, and 92%, and specificities of 55%, 76%, and 98%, respectively . INTERPRETATION: The gram stain and AOLC test is a simple, and rapid method for the diagnosis of catheter-related bloodstream infection . This diagnostic method compares favourably with other diagnostic methods, particularly those that require the removal of the catheter, and can permit early targeted antimicrobial therapy.

Oral Microbiol Immunol, 1999 Oct, 14(5), 281 - 7
Protective effect of serum antibodies against a 110-kilodalton protein of Actinobacillus actinomycetemcomitans following periodontal therapy; Beikler T et al.; Thirty-four adult patients with untreated periodontitis were randomly assigned to receive full mouth scaling alone or scaling with an adjunctive antimicrobial therapy, both followed by supportive periodontal therapy . At 24 months, specific serum immunoglobulin A (IgA), IgG and IgG subclass antibody reactivities against a 110-kDa protein of Actinobacillus actinomycetemcomitans were assessed by Western blot . In patients harboring A . actinomycetemcomitans intraorally, the IgG4 antibody reactivity against the 110-kDa protein of A . actinomycetemcomitans was associated with significantly increased survival rates of teeth and of sites not exhibiting 2 mm or more of probing attachment loss . The same trend was found for IgG3 and IgG2 antibody reactivities, but it was statistically insignificant . No association with clinical treatment outcome was observed for IgA, IgG and IgG1 antibody reactivities . The results indicated that systemic IgG4 antibody reactivity against the 110-kDa protein of A . actinomycetemcomitans may have a protective effect against periodontal disease progression in patients harboring A . actinomycetemcomitans and receiving periodontal therapy.

Int Endod J, 1999 Aug, 32(4), 257 - 82
Calcium hydroxide pastes: classification and clinical indications; Fava LR et al.; REVIEW ARTICLE: Calcium hydroxide has been used in endodontology for many years . The aim of this paper is to review the various formulations of calcium hydroxide that have been described, with specific reference to the vehicle used to carry the compound . The requirements for a vehicle are described, and ex vivo and in vivo studies reviewed . Vehicles can be classified into aqueous, viscous and oily, the clinical properties of calcium hydroxide changing depending on the vehicle . The review also describes the use of various active components that have been added to calcium hydroxide, including antimicrobial and anti-inflammatory agents . This review will help clinicians to make informed judgements about which formulations of calcium hydroxide should be used for specific endodontic procedures.

Int Endod J, 1999 Sep, 32(5), 361 - 9
Mechanisms of antimicrobial activity of calcium hydroxide: a critical review; Siqueira Junior JF et al.; Literature review The primary function of calcium hydroxide as a routine intracanal medicament is to provide antimicrobial activity . However, the mechanisms of antimicrobial activity of calcium hydroxide are not well known . Physicochemical properties of this substance may limit its effectiveness in disinfecting the entire root canal system . In addition, calcium hydroxide is not effective against all bacterial species found in root canal infections . Association with other medicaments may enhance the efficacy of the intracanal medication in eliminating residual bacteria in the root canal system.

Chirurg, 1999 Oct, 70(10), 1156 - 62
{Prevention of infection in war wounds}; Czymek R et al.; Medical treatment of injured patients by international missions of non-governmental organisations in crisis areas and out-of-area operations by troops, and also national disasters require special trauma management . Deviations from peacetime surgical guidelines are obligatory because of long-distance medical evacuation, the possibility of gaps in supply and the typical pattern of war injuries . Massive contamination combined with the high risk of infection is one typical attribute of wounds inflicted during a war or a disaster . In contrast to peacetime surgical guidelines, aggressive wound debridement is often needed . Timely and prophylactically prescription of a broad-spectrum antibiotic with a long half-life has great importance in the treatment of these wounds . Suitable antibiotics for these indications are: piperacillin/tazobactam and ceftriazon . Nevertheless the use of antimicrobial agents will only be effective with early surgical debridement.

QJM, 1999 Nov, 92(11), 659 - 67
Out-patient parenteral antimicrobial therapy--a viable option for the management of cutaneous leishmaniasis; Seaton RA et al.; Cutaneous infection with Leishmania braziliensis complex requires treatment with parenteral pentavalent antimonials to prevent development of mucocutaneous leishmaniasis . Patients with imported disease are usually managed in hospital because of concerns over drug toxicity . This study describes the clinical features and outcome of infection treated in the UK in an out-patient setting . Thirteen marines (aged 19-35 years) who acquired leishmaniasis in Belize were studied prospectively . Three had at least two lesions (0 . 6-3 cm diameter), eight had regional lymphadenopathy and one had localized painless lymphatic thickening . Histology for amastigotes and PCR for Leishmania braziliensis complex was positive in all . Culture was positive in six . Patients received 1.5-2 g (mean 1.7 g) (20 mg/kg) sodium stibogluconate intravenously daily for 20 days . All developed transient musculoskeletal symptoms and asymptomatic hepatitis . Eleven developed biochemical pancreatitis, and one thrombocytopenia . Three developed transient ECG changes and one herpes zoster . There were four device-related infections, two requiring hospitalization (one required surgical drainage of an abscess) . All lesions re-epithelialized . A total of 250 bed-days were saved over a 67-day period . These results indicate that in selected patients, out-patient therapy for cutaneous leishmaniasis with parenteral high-dose sodium stibogluconate may be appropriate, provided there is adequate monitoring of therapy.

Clin Lab Med, 1999 Sep, 19(3), 505 - 21
Escherichia coli . EAEC, EHEC, EIEC, ETEC; Gilligan PH; There are at least four different ways in which E . coli can cause diarrheal disease: invasion of the intestinal epithelium, enterotoxin production, STx production, and adherence with disruption of the normal functioning of the intestinal epithelium . Fecally contaminated food and water are the source of E . coli infections in humans . Travelers from industrialized countries with good sanitation systems are at risk for obtaining these organisms when they travel to the developing world, where these organisms are endemic . In the developing world, these organisms are a major cause of infant mortality . Infections in adults are usually self-limited and typically respond to oral rehydration therapy . Only in severe illness is antimicrobial therapy needed . Prevention of these infections requires good sanitation and food handling practices . In addition, travelers to the developing world should avoid certain types of food and contaminated water.

Biochem J, 1999 Nov 15, 344 Pt 1, 211 - 9
Functional analysis of the human NRAMP family expressed in fission yeast; Tabuchi M et al.; The Bcg/Ity/Lsh locus in the mouse genome regulates macrophage activation for antimicrobial activity against intracellular pathogens, and the positional cloning of this locus identified the Nramp1 (natural resistance-associated macrophage protein) gene . Nramp2 was initially isolated as a homologue of Nramp1 . Recently, the rat divalent metal transporter DMT1 was identified electrophysiologically, and was found to be an isoform of Nramp2, a mutation which was subsequently identified in rats suffering from hereditary iron-deficiency anaemia . Despite the 64% amino acid sequence identity of Nramp1 and Nramp2, no divalent metal transport activity has yet been detected from Nramp1, and the function of Nramp1 on the molecular level is still unclear . To investigate the divalent metal transport activity of NRAMP molecules, we constructed four chimeric NRAMP genes by swapping the domains of human NRAMP1 and NRAMP2 with each other . The functional characteristics of wild-type NRAMP1, NRAMP2 and their chimeras were determined by expression in the divalent metal transporter-disrupted strain of fission yeast, pdt1Delta, and we analysed the divalent metal transport activity by complementation of the EGTA- and pH-sensitive phenotype of pdt1Delta . Replacement of the N-terminal cytoplasmic domain of NRAMP2 with the NRAMP1 counterpart resulted in inactive chimeras, indicating that the functional difference between NRAMP1 and NRAMP2 is located in this region . However, results obtained with the reverse construct and other chimeras indicated that these regions are not solely responsible for the differences in EGTA- and pH-sensitivity of NRAMP1 and NRAMP2 . These findings indicate that NRAMP1 itself cannot represent the divalent metal transport activity in S . pombe and the additional protein segments of the molecules located elsewhere in NRAMP1 are also functionally distinct from their NRAMP2 counterparts.

Int Ophthalmol, 1998-99, 22(3), 133 - 43
Retinal toxicity of liposome-incorporated and free ofloxacin after intravitreal injection in rabbit eyes; Wiechens B et al.; BACKGROUND: Ofloxacin (OFLX) is a fluoroquinolone-antibiotic with a broad antimicrobial spectrum that may have a potential role in the treatment of bacterial endophthalmitis . However, its elimination half life after intravitreal injection is short . To prolong the intravitreal antibacterial level OFLX was incorporated into liposomes . This study was performed to investigate the retinal toxicity of liposome-incorporated and free OFLX . MATERIALS AND METHODS: OFLX was incorporated into multilamellar large vesicles . 0.1 ml of this suspension (= 180.2 microg OFLX) was injected into the midvitreous of rabbit eyes (n = 6) . Free OFLX in doses of 100 microg, 500 microg and 1,000 microg was injected into the midvitreous of a second group of rabbit eyes (n = 18) . The other eye served as a control and received empty liposomes or normal saline solution, respectively . Before injection and at the end of follow-up an ERG was obtained . After a follow-up of 1 day, 14 and 28 days the animals were perfused with glutaraldehyde and the eyes were examined by light- and transmission electron microscopy . RESULTS: The ERG as well as the histologic studies did not reveal any pathological changes after injection of liposome-incorporated OFLX compared to the control eyes . Significant reduction of the ERG was observed after 500 microg free OFLX in 2 out of 6 eyes after 1 and 14 days, respectively, and in 2 eyes 1 day after 1,000 microg free OFLX . Three days after injection of 1,000 microg OFLX the retina showed focal destruction in 1 out of 6 eyes . In another eye with the same dose 14 days after injection the photoreceptor outer segments showed disorganisation . CONCLUSION: This study shows that liposome-incorporated OFLX did not have any retinal toxicity in this animal model . Free OFLX appears to have no retinal toxicity in rabbit eyes at a dose of 100 microg after intravitreal injection . Injection of higher doses resulted in ERG changes and marked retinal damage.

Dtsch Tierarztl Wochenschr, 1999 Sep, 106(9), 376 - 80
{Individual animal risk factors for Prototheca mastitis in cattle}; Tenhagen BA et al.; Risk factors for mastitis caused by Prototheca zopfii were determined in a retrospective case control study . 248 cows culled for protothecal mastitis in a large dairy herd were included in the study . The diseased cows were compared to their non affected herdmates in respect to age, stage of lactation, production and milk composition . The effect of previous cases of mastitis during the same lactation or in previous lactations and the effect of antibiotic pretreatment were determined in a split udder analysis comparing left quarters to right quarters . Age and mastitis history especially antimicrobial pretreatment were important risks factors for developing protothecal mastitis . Risk of protothecal mastitis increased with parity . Quarters with a history of clinical mastitis during the same or during previous lactations were at higher risk than other quarters (OR 1.98, p < 0.01 and 1.44, p = 0.06, respectively) . Pretreatment with antibiotics increased the risk of protothecal mastitis (OR 3.19, p < 0.001) . Milk yield was lower in cows that developed protothecal mastitis . Somatic cell counts were higher than in control cows . Incidence of protothecal mastitis peaked in the second month of lactation.

Monaldi Arch Chest Dis, 1999 Aug, 54(4), 307 - 10
The oral glucose tolerance test in patients with respiratory infections; Basoglu OK et al.; The aim of this study, carried out in a specialized centre for chest diseases in Turkey, was to determine the prevalence of glucose intolerance in tuberculosis (TB) and pneumonia so as to assess the specificity of the association of TB with diabetes mellitus . The study group comprised 58 active pulmonary TB patients without any history of diabetes mellitus and the matched control group consisted of 23 community-acquired pneumonia patients . An oral glucose tolerance test (OGTT) was performed at the time of diagnosis and 3 months after the treatment was started in both groups . Glucose intolerance was found in six (10.4%) patients and diabetes mellitus in five (8.6%) patients in the TB group . In the control group, four (17.4%) patients were found to be diabetic and none of them were glucose intolerant . There was no significant difference between the two groups (p > 0.05) . There was a higher prevalence of abnormal OGTT results among elderly patients in both groups . OGTT results returned to normal in both the TB and pneumonia groups after treatment . The results suggest that glucose intolerance occurs in the setting of infection and is reversible following adequate antimicrobial treatment.

Nurse Pract, 1999 Oct, 24(10 Suppl), 10 - 4
Acute otitis media in an era of drug resistance: implications for NP practice; Fitzgerald MA; Nearly two-thirds of all children will have at least one episode of acute otitis media (AOM) by age 2 years . Acute otitis media is the most common indication for pediatric outpatient and antibiotic therapy . Minimizing AOM risk factors, prescribing the most appropriate and effective AOM therapy while limiting inappropriate antimicrobial use is an important part of the pediatric primary care.

J Mol Biol, 1999 Oct 29, 293(3), 629 - 38
MiAMP1, a novel protein from Macadamia integrifolia adopts a Greek key beta-barrel fold unique amongst plant antimicrobial proteins; McManus AM et al.; MiAMP1 is a recently discovered 76 amino acid residue, highly basic protein from the nut kernel of Macadamia integrifolia which possesses no sequence homology to any known protein and inhibits the growth of several microbial plant pathogens in vitro while having no effect on mammalian or plant cells . It is considered to be a potentially useful tool for the genetic engineering of disease resistance in transgenic crop plants and for the design of new fungicides.The three-dimensional structure of MiAMP1 was determined through homonuclear and heteronuclear ((15)N) 2D NMR spectroscopy and subsequent simulated annealing calculations with the ultimate aim of understanding the structure-activity relationships of the protein . MiAMP1 is made up of eight beta-strands which are arranged in two Greek key motifs . These Greek key motifs associate to form a Greek key beta-barrel.This structure is unique amongst plant antimicrobial proteins and forms a new class which we term the beta-barrelins . Interestingly, the structure of MiAMP1 bears remarkable similarity to a yeast killer toxin from Williopsis mrakii . This toxin acts by inhibiting beta-glucan synthesis and thereby cell wall construction in sensitive strains of yeast . The structural similarity of MiAMP1 and WmKT, which originate from plant and fungal phyla respectively, may reflect a similar mode of action .

Antimicrob Agents Chemother, 1999 Nov, 43(11), 2747 - 52
Antimicrobial susceptibility testing of Helicobacter pylori in a large multicenter trial: the MACH 2 study; Megraud F et al.; Culture and susceptibility testing of Helicobacter pylori strains was performed in a large multinational, multicenter randomized clinical trial . Culture was carried out on gastric biopsy samples obtained from 516 patients at entry and had a sensitivity of 99% when the {(13)C}urea breath test was used as a reference . Susceptibility testing was performed for clarithromycin and metronidazole on 485 strains by an agar dilution method and the epsilometer test (Etest) and for amoxicillin by an agar dilution method only . Resistance to clarithromycin (>1 microgram/ml) was found in 3% of the H . pylori strains, with a perfect correlation between Etest and agar dilution methods . Resistance to metronidazole (>8 microliter/ml) was found in 27% of the strains by agar dilution, but there were important discrepancies between it and the Etest method . No resistance to amoxicillin was found . The logarithms of the MICs of the three antibiotics against susceptible strains had a distribution close to normal . The impact of resistance was tested in the four arms of the trial . There were not enough clarithromycin-resistant strains to evaluate the impact of resistance on the cure rate of clarithromycin-based regimens . For metronidazole-resistant strains, the impact noted in the clarithromycin-metronidazole arm was partially overcome when omeprazole was added (76% eradication for resistant strains versus 95% for susceptible strains) . Secondary resistance to clarithromycin occurred in strains from 12 of 105 patients (11.4%) after the failure of a clarithromycin-based regimen to effect eradication . The detection of point mutations in clarithromycin-resistant strains was performed by a combination of PCR and restriction fragment length polymorphism . Mutations (A2142G and 2143G) were found in all strains tested except one . This study stresses the importance of performing susceptibility tests in clinical trials in order to explain the results of different treatments.

Vet Res Commun, 1999 Oct, 23(6), 343 - 60
Pharmacological, therapeutic and toxicological properties of furazolidone: some recent research; Ali BH; Some of the recent publications on the pharmacological, therapeutic and toxicological properties of the antimicrobial agent furazolidone (FZ) are briefly reviewed . In animals, most of the recently published papers focus on (1) the methodology of measuring the residues of the drug and its metabolites in edible tissues; (2) the carcinogenicity and genotoxicity of FZ; (3) the cellular and molecular basis of FZ-induced cardiomyopthy, and the action of different cardioprotectant drugs thereon; and (4) hormonal effects . In humans, the use of FZ as an anti-ulcer drug and in controlling infectious diseases, especially opportunistic infections in AIDS patients, is described.

Int Urogynecol J Pelvic Floor Dysfunct, 1999, 10(5), 308 - 15
The interaction of buccal mucosal epithelial cells with E . coli bacteria enhances the intraepithelial calcium flux and the release of prostaglandin E2 (PgE2); Mannhardt W et al.; Mucosal epithelial cells contribute significantly to host defense mechanisms . Uroepithelial cells (UEC) from healthy donors suppress bacterial growth in vitro . Bacterial adherence to UEC has been shown to be a prerequisite . Similar results have been shown for buccal epithelial cells (BEC) . The host response triggered by the host-parasite interaction seems to involve signal transduction and intracellular activation of second messengers . In this study the intraepithelial calcium flux was analyzed in individual BEC after bacterial contact . BEC were derived from scrapes of the buccal mucosa and labelled with fluo-3 (a calcium indicator) . Thereafter the cells were analyzed immediately with a FACscan flowcytometer . The intracellular events were evaluated before and after the addition of viable E . coli bacteria (strain 4389, K1O1H7, pili II pos.) . For control, the influence of prostaglandins, histamine, PMA, LPS and opsonized avital E . coli on the epithelial calcium flux was investigated . Additionally, supernatants of BEC-E . coli cocultures were analyzed with respect to their PgE2 content . PgE2 concentrations in supernatants of BEC, cultured alone or together with E . coli, were measured by a commercial PgE2 ELISA kit . The addition of vital E . coli to BEC was promptly answered by a significant intracellular calcium flux . PgE2, histamine and PMA, but not PgF2alpha, PgE1, LPS and opsonized E . coli, increased intracellular calcium . BEC alone did not release PgE2 . After coculture with E . coli increased levels of PgE2 were measured in the supernatants . PgE2 release was still enhanced by coactivation of the BEC with phorbolester (PMA) . Our results confirm that calcium flux in mucosal epithelial cells is stimulated by the cell-bacteria contact . We suggest that the increased PgE2 release amplifies the stimulation of intraepithelial second messengers . The resulting cell activation may lead to the secretion of antimicrobial peptides, thereby contributing to the regulation of mucosal host resistance to bacterial infections.

Eur Respir J, 1999 Sep, 14(3), 678 - 85
The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study; Robinson M et al.; It has been postulated that hypertonic saline (HS) might impair the antimicrobial effects of defensins within the airways . Alternative non-ionic osmotic agents such as mannitol may thus be preferable to HS in promoting bronchial mucus clearance (BMC) in patients with cystic fibrosis (CF) . This study reports the effect of inhalation of another osmotic agent, dry powder Mannitol (300 mg), compared with its control (empty capsules plus matched voluntary cough) and a 6% solution of HS on BMC in 12 patients with cystic fibrosis (CF) . Mucus clearance was measured using a radioaerosol/gamma camera technique . Post-intervention clearance was measured for 60 min, followed by cough clearance for 30 min . Neither mannitol nor HS improved BMC during the actual intervention period compared with their respective controls . However during the post-intervention measurement there was a significant improvement in BMC for both the mannitol (8.7+/-3.3% versus 2.8+/-0.7%) and HS (10.0+/-2.3% versus 3.5+/-0.8%) . There was also a significant improvement in cough clearance with the Mannitol (9.7+/-2.4%) compared with its control (2.5+/-0.8%) . Despite premedication with a bronchodilator, a small fall in forced expiratory volume in one second (FEV1) was seen immediately after administration of both the mannitol (7.3+/-2.5%) and HS (5.8+/-1.2%) . Values of FEV1 returned to baseline by the end of the study . Inhaled mannitol is a potential mucoactive agent in cystic fibrosis patients . Further studies are required to establish the optimal dose and the long-term effectiveness of mannitol.

Support Care Cancer, 1999 Nov, 7(6), 386 - 90
Intravascular catheters impregnated with antimicrobial agents: a milestone in the prevention of bloodstream infections; Raad I et al.; Vascular catheters impregnated with antimicrobial agents have been shown to decrease the risk of catheter-related colonization and bloodstream infections . Various antimicrobials and antiseptics have been used . In a recent meta-analysis of 12 studies, catheters coated with chlorhexidine and silver sulfadiazine (CH/SS) were shown to be significantly less likely to be associated with catheter-related bloodstream infections than uncoated catheters . However, these catheters were coated only on the external surface and they are associated with short antimicrobial durability (3-7 days) . In addition, anaphylactic reactions to them were reported in Japan . Vascular catheters impregnated with minocycline and rifampin (M/R) were found to be highly efficacious in preventing catheter-related infections . In a recent prospective, randomized trial, the likelihood of catheter-related bloodstream infections associated with the use of M/R catheters was one-twelfth of that observed with catheters coated with CH/SS . The M/R catheters are coated on the external and internal surfaces and have an antimicrobial durability of 4 weeks . Although no resistance to either minocycline or rifampin has been seen in two trials, further studies are required to determine whether the risk of resistance outweighs the benefits derived from their use . In conclusion, antimicrobial catheters have been shown to be highly cost effective in decreasing the risk of catheter-related bloodstream infection.

Curr Opin Ophthalmol, 1999 Jun, 10(3), 209 - 16
Ocular manifestations of cat-scratch disease; Ormerod LD et al.; Bartonella henselae has only recently been isolated, characterized, and found to be the principal cause of cat-scratch disease (CSD) . The availability of specific serologic investigations has allowed the recognition of a spectrum of ocular CSD syndromes that previously were ill defined and considered idiopathic . The primary inoculation complex causing regional lymphadenopathy is represented in the eye by Parinaud's oculoglandular syndrome; B . henselae is the most common cause . Leber's neuroretinitis has been identified for 80 years, and new data suggest that it is commonly a manifestation of CSD; the extent of the association remains to be determined . CSD optic neuritis is also described . The vitreoretinal manifestations include anterior uveitis, vitritis, pars planitis, focal retinal vasculitis, a characteristic retinal white spot syndrome, Bartonella retinitis, branch retinal arteriolar or venular occlusions, focal choroiditis, serous retinal detachments, and peripapillary angiomatous lesions . The pattern of ocular disease in AIDS-associated B . henselae infections is poorly delineated; unusual manifestations include conjunctival and retinal bacillary angiomatosis . The benefit of antimicrobial therapy for CSD in immunocompetent individuals has been difficult to establish, partly because most infections are self limited . Empirically, azithromycin, ciprofloxacin, rifampin, parenteral gentamicin, or trimethoprim-sulfamethoxazole provide the best therapeutic choices to minimize damage to the eye.

FEMS Immunol Med Microbiol, 1999 Nov, 26(2), 101 - 8
Chemotherapy for enterohemorrhagic Escherichia coli O157:H infection in a mouse model; Yoshimura K et al.; The aim of this study is to evaluate the therapeutic effect of the antimicrobial agents, fosfomycin (FOM), minocycline (MINO), kanamycin (KM) and norfloxacin (NFLX) in the enterohemorrhagic Escherichia coli (EHEC) infected mouse model which we established previously (Infect . Immun . 62 (1994) 3447-3453) . Each of the antimicrobial agents, 1/16 LD(50), was given to the mice per os (p.o . ) or intraperitoneally (i.p.) for 3 days after bacterial inoculation and then we observed their mortality rate for 2 weeks . The mortality rates of mice administered with MINO (p.o./i.p.), KM (p.o.), NFLX (p . o./i.p.) were significantly lower than those of the control group . Both the bacterial number and VT2c level in the feces of the FOM group were lower than those of the NFLX group on day 1, but reversed on day 3 . In an in vitro experiment, each of the four drugs in combination with mitomycin C (MMC) caused a more significant decrease in the bacterial number than sole MMC, and they consequently indicated the suppressive effect on the release of VT2c.

Proc Natl Acad Sci U S A, 1999 Oct 26, 96(22), 12923 - 8
Compromised disease resistance in saponin-deficient plants
Papadopoulou K, Melton RE, Leggett M, Daniels MJ, Osbourn AE.
Saponins are glycosylated plant secondary metabolites found in many major food crops {Price, K . R., Johnson, I . T . & Fenwick, G . R . (1987) CRC Crit . Rev . Food Sci . Nutr . 26, 27-133} . Because many saponins have potent antifungal properties and are present in healthy plants in high concentrations, these molecules may act as preformed chemical barriers to fungal attack . The isolation of plant mutants defective in saponin biosynthesis represents a powerful strategy for evaluating the importance of these compounds in plant defense . The oat root saponin avenacin A-1 fluoresces under ultraviolet illumination {Crombie, L., Crombie, W . M . L . & Whiting, D . A . (1986) J . Chem . Soc . Perkins 1, 1917-1922}, a property that is extremely rare among saponins . Here we have exploited this fluorescence to isolate saponin-deficient (sad) mutants of a diploid oat species, Avena strigosa . These sad mutants are compromised in their resistance to a variety of fungal pathogens, and a number of lines of evidence suggest that this compromised disease resistance is a direct consequence of saponin deficiency . Because saponins are widespread throughout the plant kingdom, this group of secondary metabolites may have general significance as antimicrobial phytoprotectants.

Can J Physiol Pharmacol, 1999 Feb, 77(2), 79 - 88
Pharmacological uses and perspectives of heavy water and denatured compounds; Kushner DJ et al.; Since the discovery of D20 (heavy water) and its use as a moderator in nuclear reactors, its biological effects have been extensively, although seldom deeply, studied . This article reviews these effects on whole animals, animal cells, and microorganisms . Both "solvent isotope effects," those due to the special properties of D20 as a solvent, and "deuterium isotope effects" (DIE), which result when D replaces H in many biological molecules, are considered . The low toxicity of D20 toward mammals is reflected in its widespread use for measuring water spaces in humans and other animals . Higher concentrations (usually >20% of body weight) can be toxic to animals and animal cells . Effects on the nervous system and the liver and on formation of different blood cells have been noted . At the cellular level, D20 may affect mitosis and membrane function . Protozoa are able to withstand up to 70% D20 . Algae and bacteria can adapt to grow in 100% D2O and can serve as sources of a large number of deuterated molecules . D2O increases heat stability of macromolecules but may decrease cellular heat stability, possibly as a result of inhibition of chaperonin formation . High D2O concentrations can reduce salt- and ethanol-induced hypertension in rats and protect mice from gamma irradation . Such concentrations are also used in boron neutron capture therapy to increase neutron penetration to boron compounds bound to malignant cells . D2O is more toxic to malignant than normal animal cells, but at concentrations too high for regular therapeutic use . D2O and deuterated drugs are widely used in studies of metabolism of drugs and toxic substances in humans and other animals . The deuterated forms of drugs often have different actions than the protonated forms . Some deuterated drugs show different transport processes . Most are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 systems . Deuteration may also change the pathway of drug metabolism (metabolic switching) . Changed metabolism may lead to increased duration of action and lower toxicity . It may also lead to lower activity, if the drug is normally changed to the active form in vivo . Deuteration can also lower the genotoxicity of the anticancer drug tamoxifen and other compounds . Deuteration increases effectiveness of long-chain fatty acids and fluoro-D-phenylalanine by preventing their breakdown by target microorganisms . A few deuterated antibiotics have been prepared, and their antimicrobial activity was found to be little changed . Their action on resistant bacteria has not been studied, but there is no reason to believe that they would be more effective against such bacteria . Insect resistance to insecticides is very often due to insecticide destruction through the cytochrome P450 system . Deuterated insecticides might well be more effective against resistant insects, but this potentially valuable possibility has not yet been studied.

Kekkaku, 1999 Sep, 74(9), 677 - 81
{Chemoprophylaxis against Mycobacterium avium complex infection induced in mice}; Saito H et al.; M . avium complex (MAC) is one of the important causative agents of opportunistic infections among AIDS patients . Recent evidence showed that the entry of infection is through the gastrointestinal tract . In the present study, we compared the prophylactic effect of some antimicrobials against MAC infection induced in mice . Different groups of beige mice were fed with pellets containing 0.0067% (10 mg/kg) of KRM-1648, rifabutin (RFB) and clarithromycin (CAM) . Seven days after the administration of drugs, the mice were infected with M . intracellular N-241 (5 x 10(8) CFU) orally, five times, every other day and killed one and 126 days after the last infection . The effect of drug was evaluated using the frequency and severity of gross lung lesions in the mice and by the total CFU recovered from the lungs and spleen . MAC infection was not likely to be established since there was no macroscopic evidence of lesion in organs and the recovery of cultures from lungs and spleen tested was negative, in 3 of 10 mice in the control group, 2 of 9 in the CAM group, 4 of 9 in the RFB group and 4 of 10 in the KRM group . These mice were excluded from the analysis of the study results . Thus, we examined 7 mice in the control group, 7 in the CAM group, 5 in the RFB group, and 6 in the KRM group . Tubercle-like lesions were observed in the lungs of all 7 mice in the control group (severity: 3+ in 5 mice; 4+ in 2 mice), in 5 of 7 mice (71%) in the CAM group (severity: 2+ in 1 mouse; 3+ in 4 mice), and in 4 of 5 mice (80%) in the RFB group (severity: 1+ in 1 mouse; 2+ in 1 mouse; 4+ in 2 mice), while only slight lesions (severity: 1+) were observed in 4 of 6 mice (67%) in the KRM group . There was no macroscopic evidence of lesion in spleen, liver and kidneys . The log CFU was determined at the next day of the completion of the last infection . The log CFU of the lungs was 2.49 and 2.28 in the control group and the CAM group, respectively . The bacteria were not recovered either from the lungs in the RFB and KRM groups, nor from the spleen in all the groups . The order of efficacy of the drugs on the basis of the CFUs recovered from the lungs and spleen in each group determined 126 days after the completion of the last infection was as follows; KRM > CAM > RFB in the lungs and KRM > CAM {symbol: see text} RFB in the spleen, although there was no significant difference among the three drugs (P < 0.05) . However, the significantly preferable effect was obtained in the three drug groups as compared with the control group.

Kekkaku, 1999 Sep, 74(9), 661 - 6
{Effects of the Chinese traditional medicines "mao-bushi-saishin-to" and "yokuinin" on the antimycobacterial activity of murine macrophages against Mycobacterium avium complex infection}; Shimizu T et al.; We previously examined the effects of two Chinese traditional medicines "Mao-Bushi-Saishin-To" (MBST) and "Yokuinin", on the therapeutic efficacies of a benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex (MAC) infection induced in mice . MBST but not Yokuinin potentiated the therapeutic activity of KRM-1648 against MAC infection . In the present study, we examined the effects of these traditional medicines on some M phi cell functions . First, MBST significantly potentiated M phi anti-MAC antimicrobial activity, while Yokuinin did so to a much lesser extent . Secondly, MBST and Yokuinin each strongly inhibited production of nitric oxide (NO) in MAC-infected M phi s . Thirdly, treatment of M phi s with MBST or Yokuinin caused reductions in the accumulation of IL-10 in culture fluids by MAC-infected M phi s during the first 2-days cultivation . On the other hand, in the separate experiment, treatment of M phi s with these drugs caused no significant change in the accumulation of TGF-beta by MAC-infected M phi s at day 7 . These findings suggest that these Chinese traditional medicines, particularly MBST, potentiate M phi anti-MAC antimicrobial activity, however, NO do not appear to be crucial effectors in the anti-MAC activity of MBST- or Yokuinin-treated M phi s . Moreover, MBST- and Yokuinin-mediated down-regulation of the production of IL-10 in MAC-infected M phi s may be related to their potentiating effects on M phi anti-MAC activity.

Ceska Slov Farm, 1998 Nov, 47(6), 255 - 60
{Postantibiotic effects of antimicrobial agents}; Majtanova L et al.; The present authors review data from the literature concerning the postantibiotic effect (PAE) and the postantibiotic effect of subinhibitory concentrations (PA SME) of some antibiotics on clinically significant G- and G+ bacterial species . Attention is paid to the influence on their physiological characteristics with regard to virulence factors.

Pediatr Infect Dis J, 1999 Oct, 18(10), 896 - 901
Chloramphenicol pharmacokinetics in infants less than three months of age in the Philippines and The Gambia; Weber MW et al.; BACKGROUND: The broad antimicrobial spectrum and affordable price of chloramphenicol make it an attractive first line treatment option for children with severe illnesses in developing countries . Little is known, however, about its pharmacokinetics in young infants in these settings . METHODS: We studied infants younger than 3 months of age hospitalized in Manila, Philippines and The Gambia with possible severe bacterial infections likely to benefit from treatment with chloramphenicol . Infants in the first week of life received intramuscular doses of 25 mg/kg chloramphenicol once daily, twice daily in the second through fourth week of life and three times daily from 5 to 12 weeks of age . Blood samples were taken at 0.5, 1, 2 and 3 h after the first dose, 1 h before the second dose and before the repetition doses on subsequent days . In the Philippines a second group of infants was treated with oral chloramphenicol according to the same dosage schedule . RESULTS: Thirty-eight infants received intramuscular chloramphenicol, and 20 received oral drug . Intramuscular administration resulted in therapeutic concentrations (10 to 25 microg/ml) in 73 to 86% of children in each of the three age groups in the first 6 h and in 50 to 80% on Days 2 and 3 . Between 33 and 38% of children had potentially toxic values on Days 2 and 3 . In contrast, after oral administration, only about one-half of the children reached therapeutic values in serum at any time up to Day 3 after start of treatment . CONCLUSIONS: Intramuscular chloramphenicol can be used as a second line drug for the treatment of severe infections in infants younger than 90 days of age, where third generation cephalosporins are not available . It quickly achieves therapeutic values in a high proportion of children . However, severe infections should not be treated with oral chloramphenicol in this age group, because therapeutic serum concentrations were inconsistently achieved.

Viral Immunol, 1999, 12(3), 197 - 203
Plasma lactoferrin levels are decreased in end-stage AIDS patients; van der Strate BW et al.; The antimicrobial protein lactoferrin (Lf) is present in plasma and in mucosal secretions . Using ELISA we analysed plasma and saliva of HIV-infected patients, patients with AIDS, and healthy controls for the presence of secreted Lf . The plasma Lf levels of AIDS patients (classification C3) were significantly lower (p < 0.001) as compared to asymptomatic and symptomatic HIV infected patients, or controls . In addition, plasma Lf levels closely correlated with neutrophilic granulocyte counts in the HIV-infected patients . Thus, basal plasma Lf levels are likely the result of Lf release by neutrophilic granulocytes . The Candida titres present in the oral cavity were determined in a part of the HIV-infected patient group . As it appeared, the presence of this opportunistic pathogen always coincided with low levels of salivary Lf levels . We conclude that Lf, as part of the nonspecific immune system, might play an important role in the first line of defense against opportunistic microbial infections in AIDS patients.

Infect Immun, 1999 Nov, 67(11), 5811 - 4
Consequence of Nramp1 deletion to Mycobacterium tuberculosis infection in mice; North RJ et al.; 129sv mice functionally deleted of the antimicrobial resistance gene, Nramp1, were found to be as resistant as wild-type mice to infection with the virulent H37Rv strain of Mycobacterium tuberculosis, as determined by monitoring bacterial growth in major organs and recording host survival times . Death of infected mice of both types was associated with extensive infection-induced pathology in the lungs but not in other major organs . These findings are in keeping with the view that Nramp1 is of limited importance in resistance to tuberculosis in mice.

Chest, 1999 Oct, 116(4), 1075 - 84
Blood cultures have limited value in predicting severity of illness and as a diagnostic tool in ventilator-associated pneumonia; Luna CM et al.; STUDY OBJECTIVES: To define the usefulness of blood cultures for confirming the pathogenic microorganism and severity of illness in patients with ventilator-associated pneumonia (VAP) . DESIGN: Prospective observational study using BAL and blood cultures collected within 24 h of establishing a clinical diagnosis of VAP . SETTING: A 15-bed medical and surgical ICU . PATIENTS: One hundred and sixty-two patients receiving mechanical ventilation hospitalized for > 72 h who had new or progressive lung infiltrate plus at least two of three clinical criteria for VAP . INTERVENTIONS: BAL and blood culture performed within 24 h of establishing a clinical diagnosis of VAP . MEASUREMENTS AND RESULTS: Ninety patients were BAL positive (BAL+), satisfying a microbiological definition of VAP (>/= 10(4) cfu/mL), 72 patients were BAL negative (BAL-) . Bacteremia was diagnosed when at least two sets of blood cultures yielded a microorganism or when only one set was positive, but the same bacteria was present at a concentration >/= 10(4) cfu/mL in the BAL fluid . Bacteremia was significantly more frequent in the BAL+ than in the BAL- group (22/90 patients vs 5/72 patients; p = 0.006) . In 6 of 22 BAL+ patients with bacteremia, an extrapulmonary site of infection was the source of bacteremia . Sensitivity of blood culture for disclosing the pathogenic microorganism in BAL+ patients was 26%, and the positive predictive value to detect the pathogen was 73% . Factors associated with mortality were age > 50 years, simplified acute physiology score > 14, prior inadequate antibiotic therapy, PaO(2)/fraction of inspired oxygen < 205, and use of H(2) blockers . By multivariate analysis, only the use of prior inadequate antimicrobial therapy (odds ratio {OR}, 6.47) and age > 50 years (OR, 5.12) were independently associated with higher mortality . The rate of complications was not different in patients with bacteremia . CONCLUSIONS: Blood cultures have a low sensitivity for detecting the same pathogenic microorganism as BAL culture in patients with VAP . The presence of bacteremia does not predict complications, it is not related to the length of stay, and it does not identify patients with more severe illness . Inadequacy of prior antimicrobial therapy and age > 50 years were the only factors associated with mortality in a multivariate analysis . Blood cultures in patients with VAP are clearly useful if there is suspicion of another probable infectious condition, but the isolation of a microorganism in the blood does not confirm that microorganism as the pathogen causing VAP.

Clin Infect Dis, 1999 Sep, 29(3), 632 - 58
Novelties in the field of anti-infectives in 1998; Bryskier A; In 1998, about 30 new medicinal chemical entities in the field of antibacterials and antifungals were presented during the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, held in San Diego . Among these compounds, only a few of them seem to be candidates for preclinical and clinical development: GAR 936, RWJ 54,418, ME 1209, L-084, FK 483, and DC 756 . Other compounds seem to be in the preselection stage or potential lead compounds.

Clin Infect Dis, 1999 Sep, 29(3), 568 - 72
Bacteremic pneumococcal pneumonia in children; Toikka P et al.; We carried out a nationwide retrospective study on bacteremic pneumococcal pneumonia diagnosed from 1985 to 1994 in Finland . The records of 85 children were reviewed for symptoms, signs, laboratory data, and response to antibiotic therapy . The chest radiographs were reevaluated . Bacteremic pneumococcal pneumonia was characterized by high fever (> or =39.0 degrees C in 93%), leukocytosis (WBC count on admission of > or =15x10(9)/L in 84%), and ill appearance (in 79%) . Lobar or segmental consolidation was found in 79% of the chest radiographs . Of the patients, 28% had no respiratory symptoms, 6% presented with only gastrointestinal symptoms in addition to fever, and 4% had fever only . Tachypnea was recorded in 19% and rales in 14% of the patients . After onset of antimicrobial treatment, children became afebrile within an average of 22 hours . One patient developed pleural empyema, and none of the patients died.

Clin Infect Dis, 1999 Sep, 29(3), 548 - 52
Escherichia coli: epidemiology and analysis of risk factors for infections caused by resistant strains; Lepelletier D et al.; This study analyzes the epidemiology of hospital and community-acquired infections caused by Escherichia coli . The antimicrobial resistance pattern was used to characterize the isolates, and a prospective observational study was performed to assess the relationship between antimicrobial use and bacterial resistance . The study was conducted during a 3-month period in a 1,200-bed tertiary care hospital in Nantes, France . An E . coli infection was diagnosed in 3.8% of the patients (507 of 13,384) admitted to the hospital between 1 January and 31 March 1996 . Of the 507 isolates, 205 (40.4%) were resistant to at least one antimicrobial; 40% were resistant to amoxicillin, 30% to amoxicillin/clavulanate, 38% to ticarcillin, and 16% to trimethoprim-sulfamethoxazole, while resistance to other antimicrobials was low . Prior receipt of antimicrobial and/or immunosuppressive therapy was significantly associated with infection caused by a resistant organism.

Clin Infect Dis, 1999 Sep, 29(3), 515 - 21
New trends in patient management: risk-based therapy for febrile patients with neutropenia; Rolston KV; Standard management of febrile neutropenia includes the prompt administration of empirical, broad-spectrum, parenteral antibiotic therapy . This is generally done in a hospital-based setting . Although effective (overall survival of >90%), such therapy leads to prolonged hospitalization, excessive resource utilization, and increased costs . Recently, risk-assessment models have been developed that reliably differentiate febrile patients with neutropenia that are at low risk for morbidity and/or mortality . This has enabled clinicians to administer risk-based treatment to such patients . High-risk patients still receive standard, hospital-based, parenteral treatment . Many patients, however, defervesce promptly and can be discharged home with parenteral or oral antibiotics . Low-risk patients need not be hospitalized at all and can be safely treated with parenteral or oral antibiotics in the outpatient or home setting . Careful risk assessment and patient selection, appropriate antimicrobial regimen(s), and meticulous monitoring for response or the development of complications or toxicity are essential for the success of risk-based therapy.

Clin Infect Dis, 1999 Sep, 29(3), 495 - 502
Contemporary antimicrobial susceptibility patterns of bacterial pathogens commonly associated with febrile patients with neutropenia; Jones RN; One of the most challenging problems in antimicrobial chemotherapy is the effective empirical treatment of infection in patients with neutropenia . The rates of occurrence for pathogens have significantly changed (from predominance of gram-negative to gram-positive organisms) under selective pressure of broad-spectrum antimicrobial therapy or prophylaxis, and novel resistance mechanisms have emerged . To address the need for appropriate monotherapy or combination regimens for patients with neutropenia, physicians must prescribe agents with a spectrum of antimicrobial activity to inhibit the major, prevalent pathogens encountered in bloodstream infection and pneumonia; in addition, these selected agents must be active against recently described resistant organisms . Data from the SENTRY Antimicrobial Surveillance Program indicate that several broad-spectrum agents remain highly active and can be used alone or in combinations . In most cases, the newer compounds with increased activity and spectrum against gram-positive cocci (i.e., carbapenems, cefepime, levofloxacin, and trovafloxacin) offer a greater inhibitory potential for empirical therapy among patients with neutropenia and severe infections.

Indian J Dent Res, 1998 Oct-Dec, 9(4), 124 - 30
Local antimicrobial delivery in periodontal therapy; Ranadive KS et al.; Treatment strategies towards periodontal diseases have evolved to eliminate specific pathogens or suppress destructive host response . The inherent activity of the antibiotic against the target microorganism and various Pharmacokinetic parameters such as potency, permeability, intrinsic efficacy, and substantivity of the drug dictate the success of the therapeutic outcome . However selection of an appropriate delivery system is an important factor . Rapid advances in molecular biology have helped to overcome the disadvantages of systemic and topical applications, by direct placement of antimicrobial agent (s) into subgingival sites, thus minimizing antimicrobial impact on non-oral body sites . As periodontitis is a 'localized' disease condition it is amenable to localized drug treatments . By means of controlled local delivery from within the periodontal pocket, a single administration of a few milligram of an antibacterial agent can maintain therapeutic concentrations within the crevicular fluid for a longer period of time than any other mode of delivery . This paper shall review the different local delivery systems along with the commonly employed drugs through these delivery systems.

J Calif Dent Assoc, 1999 Aug, 27(8), 611 - 8
Routine prophylactic antibiotic use in diabetic dental patients; Alexander RE; There is no scientific evidence in the literature to support the premise that well-controlled, or even moderately well-controlled, nonketotic diabetic patients are prone to infection when undergoing uncomplicated dentoalveolar surgery . Routine administration of prophylactic antibiotics should be considered only in situations where prophylactic antimicrobials would be used for a nondiabetic patient . Poorly controlled diabetics (whether Type I or II), with fasting glucose levels above 250 mg/dL, should be referred for improved control of their blood sugar before non-emergency surgery is performed . If emergency surgery is needed for a poorly controlled patient, then prophylactic antibiotics are prudent, using the accepted principles of such use . Infections in diabetic patients, regardless of their control levels, should be managed aggressively, including possible early referral to oral and maxillofacial surgeons.

Int J Antimicrob Agents, 1999 Aug, 12 Suppl 2, S3 - 9
Fusidic acid adverse drug reactions; Christiansen K; Unlike trials conducted today on new antimicrobials, the introduction of fusidic acid was not accompanied by extensive studies on toxicity and side effects . The early studies on small numbers of patients reported fusidic acid to be a nontoxic drug with the main side effects being gastrointestinal tract discomfort, diarrhoea and headache . Case reports of hepatotoxicity were reported from 1972 . A retrospective analysis showed this to be reversible and mainly associated with intravenous administration . Rarely reported side effects are granulocytopenia, thrombocytopenia and venous spasm . Skin reactions, including contact dermatitis, are uncommon . After many years of use the most common side effects reported for fusidic acid are minor and relate to the gastrointestinal tract.

J Calif Dent Assoc, 1999 May, 27(5), 386 - 92
Antibiotic resistance and maxillofacial pathogens: emerging treatment issues; Molinari JA; The practice of using antibiotics to treat and control microbial infections is a little more than 50 years old . Widespread administration of multiple classes of antibiotics over the years has had the unfortunate secondary effect of inducing the emergence of an increasing array of drug-resistant microbial strains . This article will discuss the evolution of certain forms of antibiotic resistance, as well as the mechanisms by which bacteria render numerous antimicrobials ineffective . Special emphasis is placed on emerging issues relating to organisms making up portions of the normal oral microflora.

Biochem Biophys Res Commun, 1999 Oct 14, 264(1), 281 - 6
Effects of tryptophan residues of porcine myeloid antibacterial peptide PMAP-23 on antibiotic activity; Kang JH et al.; PMAP-23 is a 23-residue antimicrobial peptide from porcine myeloid cells . In order to determine the effects of two Trp residues in positions 7 and 21 of PMAP-23 on antibacterial activity and phospholipid vesicle interacting property, two analogues in which Ala is substituted for Trp residue in position 7 or 21 were synthesized . A(21)-PMAP-23 exhibited reduced antibacterial activity and phospholipid vesicle disrupting activity when compared to those of PMAP-23 and A(7)-PMAP-23 . PMAP-23 readily interacted with model lipid membrane and induced membrane destabilization . Therefore antibacterial activity induced by PMAP-23 is due to the interaction of cell membrane with peptide followed by membrane perturbation . A significant structural change on the SDS micelle was not found by Ala substitution of the Trp residue of PMAP-23 . Also, there is a good correlation between hydrophobic interaction on RP-HPLC, expressed as retention time on RP-HPLC, and antibacterial activity . The vesicle titration experiment indicated that Trp residues located at near C-terminus are accessible to hydrophobic tail of phospholipid vesicle . This result suggests that the C-terminal end of PMAP-23 penetrates into the lipid bilayer in the course of the interaction with phospholipid membranes and is important for its antibacterial activity .

Pharmacol Res, 1999 Nov, 40(5), 429 - 34
Cellular toxicity of N-substituted 2,2'-dicarboxamidodiphenyldisulphides with high antimicrobial activity; Favari E et al.; In the present paper we evaluate the cellular toxicity of some N-substituted 2,2'-dicarboxamidodiphenyldisulphides with high antimicrobial activities, in view of their potential application in humans or animals . The toxicological studies have been conducted in the murine cell line of 3T3 fibroblasts as eucaryotic cellular model . Our results have allowed the identification of a series of derivatives exhibiting antimicrobial activity and low cellular toxicity . Structure-cytotoxic activity relationships are also discussed .

Tech Urol, 1999 Sep, 5(3), 146 - 51
Repetitive prostatic massage therapy for chronic refractory prostatitis: the Philippine experience; Nickel JC et al.; Patients frustrated with failure of traditional therapy for prostatitis have traveled to the Philippines and elsewhere for repetitive prostatic massage combined with antibiotic therapy . The aim of our study was to evaluate prospectively the response of patients who traveled to Manila to undergo this treatment . Twenty-six patients consented and were registered by the Prostatitis Foundation (B.H.) and subsequently evaluated (J.C.N., J.D.) prior to and following treatment (A.E.F.) . Evaluation at baseline and after treatment consisted of standardized history and previously validated prostatitis-specific Symptom Frequency Questionnaire (SFQ) and Symptom Severity Index (SSI), International Prostate Symptom Score (I-PSS) and Quality of Life (QoL) questionnaire, the O'Leary Sexual Function Inventory (SFI), and a Subjective Global Assessment (SGA) . Treatment in Manila consisted of triweekly prostatic massage combined with specific culture directed and/or empirical antimicrobial therapy for 6 to 12 weeks . Twenty-two patients completed at least one follow-up assessment and 12 patients completed 2-year assessment (average follow-up of 17 months in 22 patients) . There was a significant decrease in average symptom severity (SSI) by 4 months that continued for 2 years, but less improvement in symptom frequency (SFQ) and quality of life (QoL), and no significant improvement in voiding symptoms (I-PSS) or sexual function (SFI) at time of last assessment . Forty-six percent of the 22 evaluable patients had >60% decrease (significant improvement) in symptom severity (SSI), whereas 27% had similar significant improvement in frequency of symptoms (SFQ) when last assessed . Thirty-three percent reported marked subjective improvement (SGA) at last evaluation . Of the 12 patients who completed the 2-year follow-up, 5 of the original 26 had a significant and sustainable improvement in objective and subjective measurements of frequency and severity of symptoms . The combination of prostatic massage and antibiotics for treating difficult refractory cases of prostatitis may be promising, but its ultimate value needs to be confirmed . Studies in patients with less refractory and shorter duration disease may allow us to predict who will respond to this therapeutic approach.

Tech Urol, 1999 Sep, 5(3), 123 - 8
Review of antibiotic prophylaxis recommendations for office-based urologic procedures; Kraklau DM et al.; Prophylactic antibiotic recommendations for urologic procedures are not well established . Any assessment of the need for antibiotics entails thorough cost-benefit analysis . The subject of this article is an evaluation of the role of antimicrobial prophylaxis for outpatient office-based diagnostic procedures, including diagnostic flexible cystoscopy, transrectal ultrasound biopsy, and urodynamics . Relevant studies were identified using MEDLINE database searches and review of selected bibliographies . Studies of infections after transrectal ultrasound and biopsy suggest that periprocedure antibiotics are indicated, but that the exact course and timing have not been defined . Most evidence suggests that outpatient cystoscopy is associated with minimal infectious risk and that the routine administration of oral antibiotics is not indicated . Support in the literature for the use of prophylactic antibiotics at the time of urodynamic evaluation is equivocal . The current prophylactic regimens at the University of Michigan are presented as recommendations, but optimization of antimicrobial prophylaxis will require multicenter studies with large numbers of patients.

Int J Antimicrob Agents, 1999 Aug, 12 Suppl 1, S21 - 5; discussion S26-7
Antibiotic prophylaxis in head and neck oncologic surgery: the role of gram-negative coverage; Callender DL; Many studies have elucidated the risk factors associated with peri-operative infection following head and neck cancer surgery (HNS), the implications of infection for total treatment cost, and the clinical benefits of successful antimicrobial prophylaxis . The most appropriate antibiotic use is achieved by focusing on patients with clean, contaminated wounds . Thereafter, the usefulness of an antibiotic agent depends on its antimicrobial spectrum, tolerability profile, and cost . Successful antimicrobial prophylaxis requires antimicrobial activity against gram-positive, gram-negative, and anaerobic organisms . The beta-lactam/beta-lactamase inhibitor combination, sulbactam-ampicillin, has just such an antimicrobial spectrum . A double-blind, randomized clinical trial, involving patients undergoing HNS, recorded a lower post-operative infection rate among patients receiving peri-operative sulbactam-ampicillin 0.5 g/1.0 g i.v . q6h compared with those receiving clindamycin 600 mg i.v . q6h (13.3 vs . 27.1%; P = 0.02) . Culture of strains from infected individuals indicated a significantly lower proportion of gram-negative organisms for sulbactam-ampicillin than for clindamycin (32 vs . 81%; P < 0.05) . There was a significant difference in the median duration of surgery between infected and non-infected individuals (8.5 vs . 5.9 h; P < 0.0001) . These data support the use of sulbactam-ampicillin to reduce the incidence of post-operative infection following HNS.

Can J Microbiol, 1999 Sep, 45(9), 732 - 9
Effect of subinhibitory concentrations of antimicrobial agents (quinolones and macrolide) on the production of verotoxin by enterohemorrhagic Escherichia coli O157:H7; Yoh M et al.; In Japan, antimicrobial agent therapy for patients with diarrhea due to enterovirulent organisms including enterohemorrhagic Escherichia coli (EHEC) is common, and norfloxacin (NFLX), fosfomycin, and kanamycin are recommended for EHEC treatment by the Japanese Ministry of Health and Welfare . The aim of this study was to analyze the effects of antimicrobial agents which have been used or recommended for the treatment of EHEC on the production of verotoxin (VT) in vitro . Subinhibitory concentrations of quinolones, NFLX, sparofloxacin (SPFX), and grepafloxacin (GPFX) markedly stimulated the productions of VT1 and VT2 . The macrolide azithromycin (AZM), erythromycin (EM), and clarithromycin (CAM) did not stimulate the production of VT at a wide range of concentrations . These in vitro results indicate that when quinolones are prescribed for a patient infected with EHEC, the concentration of antimicrobial agents used in vivo and the susceptibility of the EHEC strains against quinolones should be taken into consideration.

Infect Dis Obstet Gynecol, 1999, 7(5), 248 - 52
Pelvic inflammatory disease in the postmenopausal woman; Jackson SL et al.; OBJECTIVE: Review available literature on pelvic inflammatory disease in postmenopausal women . DESIGN: MEDLINE literature review from 1966 to 1999 . RESULTS: Pelvic inflammatory disease is uncommon in postmenopausal women . It is polymicrobial, often is concurrent with tuboovarian abscess formation, and is often associated with other diagnoses . CONCLUSION: Postmenopausal women with pelvic inflammatory disease are best treated with inpatient parenteral antimicrobials and appropriate imaging studies . Failure to respond to antibiotics should yield a low threshold for surgery, and consideration of alternative diagnoses should be entertained.

Scand J Gastroenterol, 1999 Sep, 34(9), 849 - 55
Therapy and diagnostic tests used for Helicobacter pylori infection in the Scandinavian countries in 1998; Olafsson S et al.; BACKGROUND: We wanted to ascertain how Helicobacter pylori infection is managed in Scandinavia . METHODS: A one-page questionnaire with seven questions was mailed in April 1998 to 1718 gastroenterologists in Finland, Denmark, Norway, and Sweden (excluding Swedish surgeons) . RESULTS: The questionnaire was returned by 36% . Antimicrobials were used by 99% for peptic ulcer associated with H . pylori, by 67% for mucosa-associated lymphoid tissue lymphoma, by 27% before long-term therapy with a proton-pump inhibitor (PPI), by 16% for non-ulcer dyspepsia, by 11% for reflux disease, and by 11% for other indications . In Finland several conditions other than ulcer were treated more frequently than in the other countries . The commonest primary therapy is PPI triple therapy (94%), followed by bismuth-based (11%), 'other' (2%), and PPI dual therapy (0.2%) . Primary bismuth-based therapy was almost completely limited to Norway . The commonest secondary therapy for failures was also PPI triple therapy (71%), followed by bismuth-based (41%), 'other' (10%), and PPI dual therapy (1%) . Clarithromycin for primary therapy was used much less frequently in Finland than in the other countries . Follow-up to ascertain whether eradication is successful was done always or often by 90% in Finland, 63% in Norway, 62% in Sweden, and 21% in Denmark and by 61% of the internists and 42% of the surgeons . The commonest method to confirm eradication was gastroscopy (69%), followed by the breath test (52%) and serology (11%) . CONCLUSIONS: In Scandinavia H . pylori associated with peptic ulcer disease is treated with antimicrobials by virtually all gastroenterologists . PPI triple therapy is the commonest regimen for primary and secondary eradication . PPI dual therapy has essentially disappeared . Fifty-four per cent confirm eradication always or often, with gastroscopy being the commonest method.

Oral Dis, 1999 Apr, 5(2), 139 - 42
Defensin-1, an antimicrobial peptide present in the saliva of patients with oral diseases; Mizukawa N et al.; OBJECTIVES AND DESIGN: A preceding paper has noted a detection of defensin-1 (HNP-1), a peptide with antimicrobial and cytotoxic properties, in the saliva of patients with oral squamous cell carcinoma . The present study deals with the presence of HNP-1 in the saliva of patients with various oral diseases . METHODS: Whole saliva samples were obtained from the patients . HNP-1 in the saliva was isolated and purified by HPLC and the amino acid sequence of the peptide was determined . The molecular weight of HNP-1 was measured by mass spectrometry . The concentration of HNP-1 in saliva was determined by comparing the height of eluted HNP-1 with that of a synthetic HNP-1 standard . RESULTS: The concentrations of HNP-1 in the saliva of patients with oral lichen planus (n = 5), leukoplakia (n = 4), and glossitis associated with iron deficiency (n = 4) were 8.3 +/- 4.3 micrograms ml-1, 13.2 +/- 7.9 micrograms ml-1, and 11.4 +/- 4.9 micrograms ml-1, (mean +/- s.d.), respectively . These concentrations were significantly higher than those in healthy subjects (0.8 microgram ml-1) (P < 0.01) . In contrast, salivary HNP-1 concentrations in patients with glossodynia (n = 4) and oral discomfort (n = 4) were similar to those in healthy subjects . CONCLUSIONS: Since HNP-1 is a non-specific defensive peptide present in neutrophils, it may play an important role in the protection against diseases such as oral lichen planus, leukoplakia, and glossitis associated with iron deficiency.

Clin Oral Implants Res, 1999 Jun, 10(3), 195 - 203
Resolution of peri-implantitis following treatment . An experimental study in the dog; Persson LG et al.; The aim of the present experiment was i) to study the effect of anti-microbial therapy of experimentally induced peri-implantitis lesions and ii) to assess features of bone regrowth following treatment . Four beagle dogs were used . Three titanium fixtures (Branemark System) were installed in each quadrant of the mandible (premolars previously extracted) . Abutment connection was performed 5 months later and ligature induced breakdown was initiated . The ligatures were removed when approximately 50% of the initial bone support was lost . A 3-week antibiotic regimen (amoxicillin and metronidazole) was initiated 1 month later . Two days after the start of the antibiotic administration, the experimental implant sites were exposed to local therapy . The abutments were removed and the exposed fixture surfaces were treated with an abrasive (pumice) administered via a rotating brush (left side) or cleaned with cotton pellets soaked in saline (right side) . Cover screws were attached to the fixtures and the implants were submerged . Fluorochromes were injected intravenously 2 weeks, 4 weeks and 12 weeks after surgery . The animals were killed 7 months after surgery and block biopsies of each implant site were dissected and prepared for histological analysis . The findings of the examinations disclosed that the inflammatory lesion was resolved and new bone formation had occurred in the previous defect following antimicrobial and local therapy . The amount of "re-osseointegration" that had taken place, however, was small . Indeed, at all experimental implant sites, a thin connective tissue capsule was found to separate the implant surface from the newly formed bone.

Hepatogastroenterology, 1999 Jul-Aug, 46(28), 2713 - 7
The effect of intragastric acidity on Helicobacter pylori eradication with bismuth-metronidazole-amoxicillin; Chang CS et al.; BACKGROUND/AIMS: Adding an acid secretion inhibitor to anti-H . pylori regimens may be potentially valuable for enhancing the effectiveness of antimicrobials that exhibit markedly reduced activity at low pH . This study was conducted to evaluate intragastric acidity as a factor in H . pylori eradication with bismuth-based triple therapy . METHODOLOGY: Forty patients with duodenal ulcer and H . pylori infection were included . The patients were divided into 2 groups--normacid (n = 20) and hyperacid (n = 20)--based on the amount of time that 24-hour intragastric pH took to reach the level pH > or = 3 . All patients received bismuth subsalicylate (600 mg 3 times daily), metronidazole (500 mg 3 times daily) and amoxicillin (500 mg 3 times daily) for 2 weeks . Then, all patients continued treatment with ranitidine (150 mg twice daily) for 8 weeks prior to the follow-up examination . Blood samples were collected before treatment for measurement of fasting gastrin and pepsinogen-I . RESULTS: Nine patients (45%) in the normacid group and 8 patients (40%) in the hyperacid group reported side effects . However, there were only 2 patients (10%) in each group who withdrew from the study due to intolerance of side-effects . There was no difference in the H . pylori eradication rate between the normacid and hyperacid groups (16/18, 88.9% vs . 15/18, 83.3%) . CONCLUSIONS: Without co-administration of anti-secretary agents, intragastric acid is not a significant factor in the effectiveness of H . pylori eradication with bismuth-based triple therapy.

Am J Obstet Gynecol, 1999 Oct, 181(4), 816 - 21
Antibiotic use in pregnancy and drug-resistant infant sepsis; Mercer BM et al.; OBJECTIVE: We sought to evaluate the effect of antepartum and intrapartum antibiotic use on antimicrobial-resistant neonatal sepsis . STUDY DESIGN: We analyzed perinatal outcomes for 8474 pregnancies (8593 live births) delivered at 6 hospitals . Data were collected regarding maternal antibiotic use and perinatal course, neonatal cultures, and outcomes . The diagnosis of confirmed neonatal sepsis required at least one positive blood or cerebrospinal fluid culture . Neonatal cultures were evaluated on the basis of the occurrence and timing of maternal antibiotic exposure . RESULTS: There were 96 neonates with confirmed sepsis (11.2/1000 live births) . Sepsis was 19.3-fold more common after preterm birth (57 vs 3 . 1/1000; P <.001), with 76% of septic infants being delivered preterm . Forty-five percent of pathogens were ampicillin resistant . Ampicillin resistance increased with preterm birth (50% vs 26%; P = . 04), antepartum antibiotics (57% vs 34%; P =.03), intrapartum antibiotics (55% vs 28%; P <.01), and any prenatal antibiotic exposure (52% vs 22%; P =.01) . Infection with an organism resistant to at least one maternal antibiotic was more common with intrapartum antibiotic exposure than with antepartum exposure only (57% vs 17%; P =.01) . Regarding early-onset sepsis (n = 55), ampicillin resistance was more common with intrapartum antibiotics (50% vs 16%; P <.01), and resistance to at least one maternally administered antibiotic was more frequent with intrapartum exposure (56.7% vs 0%; P <.01) . CONCLUSIONS: Maternal antibiotic treatment is associated with neonatal sepsis by organisms resistant to ampicillin and to maternally administered antibiotics.

J Biol Chem, 1999 Oct 22, 274(43), 30811 - 7
Inhibitor binding studies on enoyl reductase reveal conformational changes related to substrate recognition; Roujeinikova A et al.; Enoyl acyl carrier protein reductase (ENR) is involved in fatty acid biosynthesis . In Escherichia coli this enzyme is the target for the experimental family of antibacterial agents, the diazaborines, and for triclosan, a broad spectrum antimicrobial agent . Biochemical studies have suggested that the mechanism of diazaborine inhibition is dependent on NAD(+) and not NADH, and resistance of Brassica napus ENR to diazaborines is thought to be due to the replacement of a glycine in the active site of the E . coli enzyme by an alanine at position 138 in the plant homologue . We present here an x-ray analysis of crystals of B . napus ENR A138G grown in the presence of either NAD(+) or NADH and the structures of the corresponding ternary complexes with thienodiazaborine obtained either by soaking the drug into the crystals or by co-crystallization of the mutant with NAD(+) and diazaborine . Analysis of the ENR A138G complex with diazaborine and NAD(+) shows that the site of diazaborine binding is remarkably close to that reported for E . coli ENR . However, the structure of the ternary ENR A138G-NAD(+)-diazaborine complex obtained using co-crystallization reveals a previously unobserved conformational change affecting 11 residues that flank the active site and move closer to the nicotinamide moiety making extensive van der Waals contacts with diazaborine . Considerations of the mode of substrate binding suggest that this conformational change may reflect a structure of ENR that is important in catalysis.

Science, 1999 Oct 15, 286(5439), 498 - 502
A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins; Tang YQ et al.; Analysis of rhesus macaque leukocytes disclosed the presence of an 18-residue macrocyclic, tridisulfide antibiotic peptide in granules of neutrophils and monocytes . The peptide, termed rhesus theta defensin-1 (RTD-1), is microbicidal for bacteria and fungi at low micromolar concentrations . Antibacterial activity of the cyclic peptide was threefold greater than that of an open-chain analog, and the cyclic conformation was required for antimicrobial activity in the presence of 150 millimolar sodium chloride . Biosynthesis of RTD-1 involves the head-to-tail ligation of two alpha-defensin-related nonapeptides, requiring the formation of two new peptide bonds . Thus, host defense cells possess mechanisms for synthesis and granular packaging of macrocyclic antibiotic peptides that are components of the phagocyte antimicrobial armamentarium.

Int J Biol Macromol, 1999 Oct, 26(1), 63 - 7
Antimicrobial films produced from chitosan; Begin A et al.; Antimicrobial films were prepared by dissolving chitosan into hydrochloric, formic, acetic, lactic and citric acid solutions . Below 40 degrees C, the counter ions could be classified into two groups based on their effect on zero-shear-rate viscosity in 2% solutions of organic acids . Chloride and citrate produced solutions with much lower viscosities than formate, acetate and lactate . At higher temperatures, these differences vanished, and the activation energies of viscous flow were all similar between 40 and 60 degrees C . Films prepared from these solutions were evaluated in tension for Young's modulus, stress and elongation at yield and break points . Films made from hydrochloric, formic and acetic acids were hard and brittle, whereas those from lactic and citric acids were soft and could be stretched . Good correlation was found between Young's modulus and volume of the counter ion . Film properties are essentially governed by the volume of the counter ion and not by the interactions between this counter ion and the macromolecule . Results suggest that acetate has the maximum molecular volume above which the film strength decreases very rapidly.

Compr Ther, 1999 Aug-Oct, 25(8-10), 411 - 7
Orthopedic management of pyogenic arthritis; Donatto KC; Septic arthritis results from bacterial invasion of the joint cavity . Joint infection is curable if timely, appropriate treatment is rendered . Antimicrobial drugs and removal of harmful substances produced by host defenses interacting with the organism are essential for restoring joint function.

Curr Med Chem, 1999 Dec, 6(12), 1125 - 49
Bioactivities of chalcones; Dimmock JR et al.; This review outlines the different bioactivities of a variety of chalcones . The cytotoxic, anticancer, chemopreventative and mutagenic properties of a number of chalcones are described followed by an account of various of these unsaturated ketones as antimicrobial agents . The antiviral, antiprotozoal and insecticidal activities of a variety of chalcones are reviewed as well as the enzyme-inhibitory properties and miscellaneous activities of some of these molecules.

Proc Assoc Am Physicians, 1999 Sep-Oct, 111(5), 390 - 5
Oxygen-independent microbicidal mechanisms of phagocytes; Ganz T; The principal biological function of phagocytic cells is the destruction of invading microorganisms . Following phagocytosis, microbes are exposed to multiple antimicrobial substances ranging in complexity from simple oxygen radicals to large proteins . These substances disrupt various microbial structures and eventually kill and digest most of the invaders . This review is focused on oxygen-independent microbicidal mechanisms in granulocytes and macrophages.

J Clin Dent, 1998, 9(4), 105 - 9
A clinical study of bacterial contamination of chlorhexidine-coated filaments of an interdental brush; Suido H et al.; The purpose of this study was to assess the effectiveness of a chlorhexidine coating on the nylon filaments of an interdental brush in reducing bacterial contamination from actual clinical usage . In addition, the residual antimicrobial capacity of the coating over time from clinical exposure was studied . The same type of interdental brush, one with chlorhexidine-coated nylon filaments (antibacterial) and one with uncoated (control) nylon filaments was used with 20 subjects who were participating in a periodontal maintenance program . All subjects had more than four interproximal spaces large enough to accommodate the interdental brush at the start of the study . The subjects served as their own controls in this cross-over design . They used their brushes daily for one and two weeks, respectively . After the last use, each brush was kept in a controlled environment (20-22 degrees C, 65% relative humidity) for 24 hours for air drying . It was found that antimicrobial activity was detected on the chlorhexidine-coated filaments, even after one or two weeks of storage . The mean residual antimicrobial activity of the test filaments at one week was significantly higher than that found on the filaments after two weeks . The mean number of bacteria attached to the antimicrobial filaments were significantly fewer than those on uncoated, control filaments at both one week and two weeks of usage . These results suggest that chlorhexidine-coated filaments on an interdental brush can significantly reduce bacterial contamination and retain this antimicrobial activity for up to two weeks of use.

J Clin Dent, 1998, 9(4), 83 - 8
Breath effects of three marketed dentifrices: a comparative study evaluating single and cumulative use; Gerlach RW et al.; This randomized and controlled, examiner blind, parallel group study was undertaken to evaluate the efficacy of three commercial dentifrices on breath malodor . A total of 384 healthy adult subjects with oral malodor were randomized to one of four brushing groups, using either an antimicrobial dentifrice containing 0.45% stannous fluoride, an antitartar dentifrice containing 0.243% sodium fluoride and 5% pyrophosphate, an antimicrobial dentifrice containing 0.24% sodium fluoride and 0.30% triclosan/copolymer, or bottled distilled water which served as the negative experimental control . Breath quality was evaluated over a five-day period by second-person organoleptic grading and measurement of volatile sulfur levels . Following treatment, adjusted mean organoleptic scores and volatile sulfur levels were lowest for the stannous fluoride dentifrice group, with this group exhibiting superior breath quality compared to the negative control at three hours after a single brushing, and again at all cumulative use time points . While all test dentifrices showed some activity, only stannous fluoride had a second-person breath benefit . Breath effects for the other two dentifrices were limited to reductions in volatile sulfur levels at hours 99 and 104 for the antitartar sodium fluoride pyrophosphate dentifrice, and at hour 99 only for the antimicrobial sodium fluoride triclosan/copolymer dentifrice . This research establishes the comparative breath efficacy of three commercial dentifrices in a study model that may prove relevant for other dentifrice clinical trials.

FEMS Microbiol Lett, 1999 Oct 15, 179(2), 217 - 22
Cationic amphipathic peptides, derived from bovine and human lactoferrins, with antimicrobial activity against oral pathogens; Groenink J et al.; Peptides derived from the N-terminal domain that comprises an amphipathic alpha-helix in human lactoferrin (LFh 18-31 and LFh 20-38) and bovine lactoferrin (LFb 17-30 and LFb 19-37) were chemically synthesised . Since many positively charged amphipathic alpha-helices contain antimicrobial activity, the peptides were tested for their antimicrobial activity against various oral pathogens . Both peptides from bovine lactoferrin had more potent antimicrobial activities than the human equivalents . Peptide LFb 17-30, containing the largest number of positively charged amino acids, showed the highest antimicrobial activity to both Gram-positive and Gram-negative bacteria . Since native lactoferrin molecules had no killing activity, release of these peptides from the native protein should be investigated to explore the use in oral care products.

Int J Pharm, 1999 Oct 28, 189(1), 43 - 55
Lysosubtilin modification, Fermosorb, designed for polymeric carrier-mediated intestinal delivery of lytic enzymes: pilot-scale preparation and evaluation of this veterinary medicinal product; Biziulevicius GA et al.; Antimicrobial enzymotherapy/enzymoprophylaxis has potential for use as a measure to overcome problems associated with resistance to commonly applied antibiotics . Lysosubtilin, an authorized veterinary medicinal product, when used per os for the treatment and prophylaxis of intestinal infections in newborn calves, is not always efficient due to partial inactivation of lytic enzymes in the gastric region . In this contribution a simple technology for preparation of pH-dependent reversibly dissociating acid stable enzyme-polymer complex (two-component oral delayed-release lysosubtilin formulation, Fermosorb) designed for intestinal delivery of lytic enzymes is described . The technology is based on immobilization of lytic enzymes, using 1% lysosubtilin solution in 10 mM acetate buffer of pH 5.0, onto commercial highly porous carboxylic cation exchanger Biocarb L (v/w ratio 10:1, process duration 1 h) with after-following procedures of vacuum-filtration, oven-drying and standardization of the enzyme-polymer complex formed . The technology process of pilot-scale Fermosorb fabrication on the whole revealed itself as simply employed and highly repeatable, totalling in the final lytic enzyme activity yield of 40.2% (the average value obtained from the analysis of the 11 batches running) and approximately 4000 (3938) kg of Fermosorb (200 batches) produced . The proposed technological approach can be successfully applied for fabrication of other enzyme preparations as well and this was shown in the example of Polyferm, a preparation with both lytic and proteolytic enzyme activities . In vitro evaluation of Fermosorb revealed it was more stable when exposed to the acidic environment as well as in storage when compared with the native lysosubtilin . No negative change in the antimicrobial spectrum of action of Fermosorb versus lysosubtilin, influenced by immobilization of lytic enzymes onto Biocarb L, was observed . Moreover, all six lysosubtilin-resistant microbial strains tested have been found to be Fermosorb-susceptible . In vivo evaluation studies performed on 1200 newborn calves revealed 95.2% therapeutic as well as 95.0% prophylactic efficacy of Fermosorb in respect to colibacillosis versus 74.0 and 80.0% for lysosubtilin, respectively, the differences being statistically significant (P<0.01) . As a consequence of these studies Fermosorb was authorized for use throughout the former Soviet Union . Data collected during postmarketing surveillance of Fermosorb, which was applied for more than 163 inverted question mark omitted inverted question mark000 newborn calves, confirmed high efficacy (92.3 and 95.5% for treatment and prophylaxis, respectively) and safety of this veterinary medicinal product.

Clin Chest Med, 1999 Sep, 20(3), 499 - 506
Drug-resistant pathogens in community- and hospital-acquired pneumonia; Cross JT Jr et al.; Antimicrobial resistance has been a problem since the early days of the antibiotic era, but in recent years, this resistance has increased in the hospital and is being recognized more in the community setting . Respiratory pathogens such as S . pneumoniae and H . influenzae, for example, have developed resistance to traditional antimicrobial therapy, often over a very short period of time . This increase in resistance patterns requires physicians to closely monitor antimicrobial resistance in their community and to appreciate that some antimicrobial resistance mechanisms may result in resistance for a complete class of antibiotics or different classes of antibiotics with similar mechanisms of action.

J Pept Res, 1999 Sep, 54(3), 237 - 41
Antibacterial activity of multiple antigen peptides homologous to a loop region in human lactoferrin; Azuma M et al.; An 11-residue peptide (FQWQRNMRKVR) homologous to just over half the loop region of human lactoferricin is thought to be responsible for antimicrobial properties of human lactoferricin . Multiple antigen peptides (MAP) of the 11-residue peptide exerted significant antibacterial effects against a broad spectrum of bacteria including MRSA . More than eight branching was favourable for increasing its antibacterial activity . Our report shows a novel possibility for MAP to increase the activity of antibiotic peptides other than simply to stimulate antibody production, as reported so far.

Jpn J Antibiot, 1999 Jul, 52(7), 511 - 6
{Effects of levofloxacin once-a-day therapy on uterine cervicitis}; Mikamo H et al.; An investigation was carried out to determine the therapeutic effect of levofloxacin (LVFX) once-a-day oral therapy at the dose of 200 mg/day for 7 days on uterine cervicitis, in comparison with LVFX twice-a-day oral therapy at the dose of 200 mg/day for 7 days . Of the 102 patients enrolled in the study, 90 were subjected to the analysis . The efficacy rate on uterine cervicitis of the once-a-day therapy and twice-a-day therapy groups according to the evaluation of the Drug Efficacy Evaluation Committee were 72.0% (36/50) and 82.5% (33/40), respectively . The efficacy rate on uterine chlamydial cervicitis of the once-a-day therapy and twice-a-day therapy groups according to the evaluation of the Drug Efficacy Evaluation Committee were 88.0% (22/25) and 85.7% (18/21), respectively . Safety was evaluated as "safe" in 88 of the 90 assessable patients (97.8%) . Side effects were seen in two cases, which belong to the once-a-day therapy group; mild candidiasis and mild breast distension sense . As the antimicrobial treatment started, the levels of the inflammatory cytokines, interleukin-6 (IL-6) and interleukin-8 (IL-8) in the cervical mucus, decreased . It is suggested that IL-6 and IL-8 can be useful indicators of the antimicrobial treatment in the uterine cervicitis . These results suggested that the LVFX once-a-day therapy can be useful on uterine cervicitis.

Clin Chest Med, 1999 Sep, 20(3), 589 - 98, ix
Antibiotic therapy for community-acquired pneumonia; Mandell LA; This article takes a broad perspective of community-acquired pneumonia (CAP) . The arguments and data that support or refute the current approaches to initial antimicrobial treatment of CAP as outlined in the American Thoracic Society and Infectious Disease Society of America documents are provided . The complex issues involved in the decision of how to properly treat CAP are addressed.

Clin Chest Med, 1999 Sep, 20(3), 575 - 87
Severe community-acquired pneumonia; Ewig S et al.; Severe CAP is a life-threatening condition defined by the presence of respiratory failure or symptoms of severe sepsis or septic shock . It accounts for approximately 10% of hospitalized patients with CAP . The majority of patients with severe pneumonia have underlying comorbid illnesses, with COPD, alcoholism, chronic heart disease, and diabetes mellitus being the most frequent . S . pneumoniae, Legionella spp, GNEB (especially K . pneumoniae), H . influenzae, S . aureus/spp, Mycoplasma pneumoniae, respiratory viruses (especially influenza viruses), and P . aeruginosa represent the most important causative organisms of severe CAP . Rapid initiation of appropriate antimicrobial treatment is crucial for a favorable outcome . Initial antimicrobial treatment should be based on an epidemiological (empiric) approach . Microbial investigation may be helpful in the individual case but is probably more useful to define local antimicrobial policies based on local epidemiologic and susceptibility patterns . Mortality rates range from 21% to 54% . The most important prognostic factors include general health state of the patient, appropriateness of initial antimicrobial treatment, and the existence of bacteremia, as well as factors reflecting severe respiratory failure, severe sepsis, septic hypotension or shock, and the extent of infiltrates in chest radiograph . Initial antimicrobial treatment should consist of a second (or third) generation cephalosporin and erythromycin . Modifications of this basic regimen should be considered in the presence of distinct comorbid conditions and risk factors for distinct pathogens . Promising new approaches of nonantimicrobial treatment, including noninvasive ventilation, treatment of hypoxemia, and immunomodulation, are under investigation.

Clin Chest Med, 1999 Sep, 20(3), 489 - 97
Atypical pathogens in community-acquired pneumonia; Lieberman D; The atypical pathogens are an important and significant cause of CAP . The clinical and radiologic manifestations of CAP caused by these pathogens are modulated by the immunologic and physiologic status of the host, and therefore are not pathogen-specific . The range of frequencies found in various studies for the atypical pathogens among the causes of CAP is broad . These frequencies are affected by very important factors that should be recognized . In a significant percentage of patients, an atypical pathogen can be identified together with an additional cause . The significance of multiple causes has not been clarified sufficiently . The principal diagnostic techniques in use today for the causative diagnosis of CAP are serologic tests . Different serologic methods have been used in various studies and diagnostic criteria are not standardized . In the future it is likely that diagnostic testing will be based on the PCR technique on serum samples . The effectiveness and importance of antimicrobial therapy in some patients with atypical pathogen CAP are unclear . The accepted therapy today for atypical pathogen CAP, which is based on erythromycin, will probably be changed in the near future in favor of the new generations of fluoroquinolone or the new macrolide preparations.

Clin Microbiol Rev, 1999 Oct, 12(4), 583 - 611
Antifungal activities of antineoplastic agents: Saccharomyces cerevisiae as a model system to study drug action; Cardenas ME et al.; Recent evolutionary studies reveal that microorganisms including yeasts and fungi are more closely related to mammals than was previously appreciated . Possibly as a consequence, many natural-product toxins that have antimicrobial activity are also toxic to mammalian cells . While this makes it difficult to discover antifungal agents without toxic side effects, it also has enabled detailed studies of drug action in simple genetic model systems . We review here studies on the antifungal actions of antineoplasmic agents . Topics covered include the mechanisms of action of inhibitors of topoisomerases I and II; the immunosuppressants rapamycin, cyclosporin A, and FK506; the phosphatidylinositol 3-kinase inhibitor wortmannin; the angiogenesis inhibitors fumagillin and ovalicin; the HSP90 inhibitor geldanamycin; and agents that inhibit sphingolipid metabolism . In general, these natural products inhibit target proteins conserved from microorganisms to humans . These studies highlight the potential of microorganisms as screening tools to elucidate the mechanisms of action of novel pharmacological agents with unique effects against specific mammalian cell types, including neoplastic cells . In addition, this analysis suggests that antineoplastic agents and derivatives might find novel indications in the treatment of fungal infections, for which few agents are presently available, toxicity remains a serious concern, and drug resistance is emerging.

Clin Microbiol Rev, 1999 Oct, 12(4), 564 - 82
Plant products as antimicrobial agents; Cowan MM; The use of and search for drugs and dietary supplements derived from plants have accelerated in recent years . Ethnopharmacologists, botanists, microbiologists, and natural-products chemists are combing the Earth for phytochemicals and "leads" which could be developed for treatment of infectious diseases . While 25 to 50% of current pharmaceuticals are derived from plants, none are used as antimicrobials . Traditional healers have long used plants to prevent or cure infectious conditions; Western medicine is trying to duplicate their successes . Plants are rich in a wide variety of secondary metabolites, such as tannins, terpenoids, alkaloids, and flavonoids, which have been found in vitro to have antimicrobial properties . This review attempts to summarize the current status of botanical screening efforts, as well as in vivo studies of their effectiveness and toxicity . The structure and antimicrobial properties of phytochemicals are also addressed . Since many of these compounds are currently available as unregulated botanical preparations and their use by the public is increasing rapidly, clinicians need to consider the consequences of patients self-medicating with these preparations.

J Nat Prod, 1999 Sep, 62(9), 1319 - 21
Antibacterial diterpenoid acids from Azorella compacta; Wachter GA et al.; The two novel diterpenoid acids mulin-12,14-dien-11-on-20-oic acid (1) and mulin-12-ene-11,14-dion-20-oic acid (2) have been isolated from Azorella compacta . Their structures have been elucidated by 1D and 2D NMR methods . In contrast to the closely related known mulinolic acid (3) and its dehydration product (4) these new natural products have been shown to exhibit antimicrobial activity.

J Nat Prod, 1999 Sep, 62(9), 1316 - 8
A new cacospongionolide derivative from the sponge Fasciospongia cavernosa; De Rosa S et al.; Cacospongionolide F (4a), a new bioactive cacospongionolide-related sesterterpene, has been isolated from the Northern Adriatic sponge Fasciospongia cavernosa . The structure was proposed on the basis of spectroscopic data and chemical transformations . The absolute configuration was established using the modified Mosher's method . A molecular mechanics study of the dehydrodecalin ring explained the observed differences in dynamic behavior between cacospongionolide F and mamanuthaquinone, a related compound . Antimicrobial activity, brine shrimp and fish lethalities of this new compound are reported.

J Nat Prod, 1999 Sep, 62(9), 1304 - 5
Methanol adduct of puupehenone, a biologically active derivative from the marine sponge Hyrtios species; Bourguet-Kondracki ML et al.; A methanol adduct of puupehenone (1), 15alpha-methoxypuupehenol (2), an artifact resulting from the action of MeOH on puupehenone, was isolated during purification of the CH(2)Cl(2) extract of the New Caledonian marine sponge Hyrtios sp., as the major constituent . Its chemical structure was elucidated by 2D NMR experiments . Compound 2 displayed similar antimicrobial and antifungal activity as puupehenone and a lower cytotoxic activity toward KB cells with ED(50) values of 6 and 0.5 microg/mL, respectively . Compound 2 was slightly more active against three strains of Plasmodium falciparum than puupehenone.

J Med Chem, 1999 Oct 7, 42(20), 4202 - 13
Synthesis and antimicrobial activity of 4H-4-oxoquinolizine derivatives: consequences of structural modification at the C-8 position; Ma Z et al.; The antibacterial 4H-4-oxoquinolizines were introduced recently to overcome bacterial resistance to fluoroquinolones . They exhibit potent antibacterial activity against Gram-positive, Gram-negative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quinolone-resistant MRSA . Preliminary studies indicated that oxoquinolizines possess distinct activity and toxicity profiles as compared with their parent quinolones . In order to develop a potent antibacterial agent with the desired spectrum of activity, good tolerability, and balanced pharmacokinetic profile, we synthesized and evaluated a series of oxoquinolizines with various substituents at the C-8 position . Most compounds tested in this study demonstrated better activity against Gram-positive bacteria than ciprofloxacin and exhibited good susceptibility against ciprofloxacin- and methicillin-resistant S . aureus . While maintaining potent in vitro activity, several compounds showed improved in vivo efficacy over ABT-719 as indicated by the mouse protection test . As an example, the oral ED(50) values for the cis-3-amino-4-methylpiperidine analogue 3ss against S . aureus NCTC 10649M, S . pneumoniae ATCC 6303, and E . coli JUHL were 0 . 8, 2.0, and 1.4 mg/kg, compared to 3.0, 10.0, and 8.3 mg/kg for ABT-719 . The current study revealed that the steric and electronic environment, conformation, and absolute stereochemistry of the C-8 group are very important to the antibacterial profiles . Structural modifications of the C-8 group provide a useful means to improve the antibacterial activities, physicochemical properties, and pharmacokinetic profiles . Manipulation of the C-8 group also allows us to generate analogues with the desired spectrum of activity, such as analogues that are selective against respiratory pathogens.

J Heart Lung Transplant, 1999 Aug, 18(8), 764 - 8
Does the donor-recipient ABO blood group compatibility status predict subsequent lung transplantation outcomes?
Yu NC, Haug MT 3rd, Khan SU, Goormastic M, Hague LK, Mehta AC, Maurer JR.
BACKGROUND: The study was conducted to compare lung transplantation outcomes between ABO-identical (AI) and ABO-compatible (AC) recipients . METHODS: Charts of lung allograft recipients transplanted between February, 1990 and October, 1995 were reviewed . Standard triple-drug immunosuppression and general antimicrobial prophylaxis were provided . Surveillance spirometry was administered every three months . Flexible bronchoscopy (FB) with transbronchial biopsies (TBBs) were undertaken for clinical indications . Time to event analysis on acute (AR) and chronic (CR) rejection and actuarial survival were determined by Kaplan-Meier analysis . Cumulative curves were compared with a log rank test . Comparisons of age, maximum forced expiratory volume in one second (FEV1) in the single (SLT) and double (DLT) lung recipients, duration of intensive care unit and hospital stay were carried out using the Wilcoxon Rank Sum test . Gender, race, underlying diagnoses, cytomegalovirus (CMV) status and pulmonary reimplantation response (PRR) were compared by Chi-square or Fisher's exact test where appropriate . RESULTS: Of the 100 lung recipients (age = 42.5 +/- 13.4 years; M:F = 50:50), 64 were AI and 36 AC . Median follow-up was 22 (range = 0-78) months . Outcome did not differ significantly between the 2 groups in terms of intensive care unit and hospital stay, PRR incidence and grade, incidence and frequencies of AR, median time and grade of first AR, maximum FEV1 for SLT and DLT recipients, incidence of CR and survival at 12 months . CONCLUSIONS: As the donor supply remains limited, this could considerably simplify the logistics of future transplantation.

J AOAC Int, 1999 Sep-Oct, 82(5), 1071 - 6
Confirmatory test results on milk from commercial sources that tested positive by beta-lactam antibiotics screening tests; Moats WA; Fifty-four milk samples from commercial sources that tested positive for beta-lactam antibiotics were analyzed by a multiresidue liquid chromatographic (LC) procedure based on LC fractionation . Penicillin G and cephapirin were the beta-lactam antibiotics found most frequently . Some samples did not contain detectable beta-lactam antibiotics . In a few, the presence of a beta-lactam antibiotic was suspected because certain LC fractions tested positive for antimicrobial activity, which was no longer present in a replicate treated with beta-lactamase . However, the unknowns could not be identified by LC analysis.

Biochemistry, 1999 Sep 7, 38(36), 11700 - 10
A chemically synthesized version of the insect antibacterial glycopeptide, diptericin, disrupts bacterial membrane integrity; Winans KA et al.; Insects protect themselves against bacterial infection by secreting a battery of antimicrobial peptides into the hemolymph . Despite recent progress, important mechanistic questions, such as the precise bacterial targets, the nature of any cooperation that occurs between peptides, and the purpose of multiple peptide isoforms, remain largely unanswered . We report herein the chemical synthesis and preliminary mechanistic investigation of diptericin, an 82 residue glycopeptide that contains regions similar to two different types of antibacterial peptides . A revised, highly practical synthesis of the precursor N(alpha)-Fmoc-Thr(Ac(3)-alpha-D-GalNAc) allowed us to produce sufficient quantities of the glycopeptide for mechanistic assays . The synthetic, full-length polypeptide proved to be active in growth inhibition assays with an IC(50) of approximately 250 nM, a concentration similar to that found in the insect hemolymph . Biological analysis of diptericin fragments indicated that the main determinant of antibacterial activity lay in the C-terminal region that is similar to the attacin peptides, although the N-terminal segment, related to the proline-rich family of antibacterial peptides, augmented that activity by 100-fold . In all assays, activity appeared glycosylation independent . Circular dichroism of unglycosylated diptericin indicated that the peptide lacked structure both in plain buffer and in the presence of liposomes . Diptericin increased the permeability of the outer and inner membranes of Escherichia coli D22 cells, suggesting possible mechanisms of action . The ability to access glycopeptides of this type through chemical synthesis will facilitate further mechanistic studies.

Dev Comp Immunol, 1999 Sep, 23(6), 443 - 9
Oyster metallothionein as an oxyradical scavenger: implications for hemocyte defense responses; Anderson RS et al.; In order to better understand the interplay between metallothionein (MT) and reactive oxygen species (ROS) in oyster hemocytes, studies of the hydrogen peroxide (H2O2) scavenging properties of MT were carried out in a cell-free system . Mammalian MT is involved in protection against oxidative stress by virtue of its ability to scavenge free radicals; therefore, the H2O2 scavenging potentials of Crassostrea virginica and rabbit MTS were compared . Oyster and rabbit MTs showed similar dose-dependent suppression of H2O2-stimulated, luminol-augmented chemiluminescence (CL); the EC50 for CL (25 microM H2O2) was approximately 1.0 microM MT for both species . The interaction of ROS with MT in hemocytes could play a role in protection of the cells and surrounding tissues from oxidants associated with antimicrobial responses . Mobilization of bound zinc from MT by hemocyte-derived ROS may produce aberrant regulatory effects on various cellular processes . The data suggest that MT may be involved in immunoregulatory pathways in oyster hemocytes as a result of its ability to scavenge antimicrobial ROS.

J Dent Res, 1999 Sep, 78(9), 1518 - 24
Clonal infection with Actinobacillus actinomycetemcomitans following periodontal therapy; Ehmke B et al.; Mechanical debridement results in a shift of the bacterial composition in the periodontal pocket on the species level . It is unknown, however, whether a clonal change within a species could lead to the emergence of strains with different levels of virulence . Therefore, in the present study, the genetic variability of Actinobacillus actinomycetemcomitans was assessed and strains identified which were associated with periodontal disease progression following periodontal therapy, i.e., refractory periodontitis . Twenty adult patients with untreated periodontitis and subgingival colonization of A . actinomycetemcomitans were randomly assigned to receive full-mouth scaling alone or scaling with an adjunctive antimicrobial therapy . Both groups received supportive periodontal therapy at 3, 6, 9, 12, 18, and 24 months . Subgingival plaque samples were taken at every visit; venous blood was obtained at 24 months only . A . actinomycetemcomitans isolates were typed by the RAPD method, and antibody reactivity against outer membrane proteins was assessed by immunoblot analysis . Eleven distinct RAPD patterns were found in 18 patients completing the study . All patients harbored only one A . actinomycetemcomitans genotype, and within each patient this genotype persisted throughout the 24-month observation period . No differences in the expression of antibody reactivity against outer membrane proteins were found between strains isolated at baseline and at 24 months . Three genotypes were associated with reduced survival rates of teeth without probing attachment loss of 2 mm or more . The results indicated that (i) most patients harbored only one A . actinomycetemcomitans genotype; (ii) the genotype persisted following therapy; and (iii) only some genotypes were associated with refractory periodontitis.

J Am Vet Med Assoc, 1999 Oct 1, 215(7), 959 - 62, 946
Hypercalcemia associated with granulomatous disease in a cat; Mealey KL et al.; A 6-year-old cat was examined because of recurrence of a draining mass involving skin and subcutaneous tissues of the caudoventral aspect of the abdomen . Previous treatment included administration of antimicrobial drugs and corticosteroids and surgical excision . Atypical mycobacteria were seen during cytologic examination of biopsy specimens of the mass; Nocardia sp was cultured . While hospitalized, the cat developed hypercalcemia and was found to have high serum calcitriol concentrations . Treatment consisted of administration of ciprofloxacin and trimethoprim-sulfadiazine because of the infection and administration of sodium chloride solution, furosemide, and calcitonin because of the hypercalcemia . The cat recovered.

Rinsho Byori, 1999 Aug, 47(8), 754 - 66
{Multicenter evaluation of broth microdilution test, BrothMIC MTB, to determine minimum inhibitory concentrations (MICs) of antimicrobial agents for Mycobacterium tuberculosis--evaluation of interlaboratory precision and interpretive compatibility with agar proportion method}; Yamane N et al.; A newly developed microdilution antimycobacterial susceptibility test, BrothMIC MTB (Kyokuto Pharmaceutical Industrial Co., Ltd., Tokyo, Japan) to determine minimum inhibitory concentrations (MICs) was evaluated at multisites . The test method utilizes air-dried microplates containing serially diluted antimicrobial agents and the modified Middlebrook 7H9 broth . The eight antimycobacterial agents tested were rifampicin, isoniazid, ethambutol, streptomycin, kanamycin, levofloxacin, sparfloxacin and ciprofloxacin . The test plates were reconstituted by inoculation of 0.2 ml of cell suspensions (6 x 10(5) cells/ml) and were incubated at 36 degrees C in 5% to 10% CO2 . The growth endpoints were visually read after 7-day and 10-day incubations . The reproducibility was evaluated with the four reference strains of Mycobacterium tuberculosis, and were compared with the agar proportion method described in the National Committee for Clinical Laboratory Standards (NCCLS) M24-T . Of the 1,022 testings of the reference strains, 1,020 (99.8%) of the MICs read after 7-day incubation fell within 3 log2 dilutions . The growth endpoints read after 7-day and 10-day incubations gave equal MIC ranges for the respective agents . The results obtained by the BrothMIC MTB for 93 clinical isolates of M . tuberculosis compared well with those determined by the NCCLS method with 98% to 99% agreements, except for ethambutol . According to the comparative analysis with the agar proportion method, the interpretive MIC breakpoints to discriminate between the isolates susceptible and resistant against the respective agents were proposed . In conclusion, this newly developed microdilution test for M . tuberculosis is a practical, rapid, quantitative, nonradiometric alternative for the determination of MICs in clinical mycobacteriology laboratories.

J Antimicrob Chemother, 1999 Sep, 44 Suppl A, 37 - 46
Safety and tolerability of quinupristin/dalfopristin: administration guidelines; Rubinstein E et al.; The safety and tolerability of quinupristin/dalfopristin were assessed in both comparative and non-comparative trials (2298 quinupristin/dalfopristin-treated patients) . In comparative clinical trials, the most frequent systemic adverse events related to quinupristin/dalfopristin were nausea (4.6%), diarrhoea (2.7%), vomiting (2.7%) and skin rash (2.5%) . The comparator group showed similar rates, except that nausea was significantly more common (7.2%; P = 0.01) . In non-comparative trials, arthralgia and myalgia were reported most frequently but were reversible upon treatment discontinuation . The renal, inner ear, cardiovascular and central nervous systems were not implicated as significant target organs for toxicity . The most frequent local adverse events related to infusion of quinupristin/dalfopristin were inflammation, pain, oedema, infusion site reaction and thrombophlebitis . Results of laboratory tests while on therapy were comparable for quinupristin/dalfopristin and comparator groups, except that increases in conjugated bilirubin of >5 x the upper limit of normal were reported in 5.5% of quinupristin/dalfopristin recipients; increases in total bilirubin of >5 x the upper limit of normal occurred in 1.5% . Comparator recipients more frequently had increases in alanine aminotransferase and alkaline phosphatase . Quinupristin/dalfopristin inhibits the cytochrome P450 3A4-mediated metabolism of drugs including midazolam, nifedipine, terfenadine and cyclosporin . Therefore, plasma drug monitoring and/or dosage reduction of these agents is prudent . Concomitant administration of drugs that can prolong the electrocardiographic QTc interval should be avoided . Quinupristin/dalfopristin is visually and chemically compatible with commonly used drugs of various classes, but it is not compatible with sodium chloride solution and certain other drugs, including some antimicrobials . Therefore, when prescribing quinupristin/dalfopristin, clinicians should be aware of the potential for peripheral venous intolerance, arthralgias and myalgias, increases in conjugated bilirubin, interactions with drugs metabolized by the cytochrome P450 3A4 isoenzyme and certain physico-chemical incompatibilities . However, multiple studies have shown that the safety and tolerability of quinupristin/dalfopristin are generally favourable, and that it provides clear benefits to ill patients with severe gram-positive infections.

Vestn Otorinolaringol, 1999, (5), 27 - 9
{Low frequency ultrasound therapy in chronic suppurative otitis media}; Drachuk AI; A novel low-frequency ultrasound unit "Tonsillor-2" equipped with a device for treatment of middle ear diseases and a set of ultrasonic wave guides was employed in the treatment of 434 patients . A short-term response was achieved in 93% of the patients . Indications to and techniques of treatment of otitis media purulenta chronica (OMPC) are described . The method of low-frequency ultrasound therapy of OMPC can be used in monotherapy, in preoperative preparation, in postoperative management . Low frequency 25-27 kHz ultrasound is shown not to diminish antimicrobial drug activity.

J Immunol, 1999 Oct 15, 163(8), 4564 - 73
Ectosomes released by human neutrophils are specialized functional units; Hess C et al.; Here we show that human polymorphonuclear leukocytes (PMN) release ectosomes independently of complement attack during their activation both in vitro and at the site of inflammation in vivo . Patterns of biotinylated proteins on the surface of PMN and on PMN-derived ectosomes indicated a specific sorting of cell surface proteins into and out of ectosomes . Ectosomes expressed clusters of complement receptor 1 (CR1), which allowed them to bind efficiently to opsonized bacteria . Myeloperoxidase and human leukocyte elastase, both stored within the azurophilic granules of PMN, were found to colocalize on ectosomes with CR1 . Furthermore, myeloperoxidase colocalized with human leukocyte elastase . In contrast, not present on CR1-expressing ectosomes were CD63, a selective marker for the azurophilic granules, and CD14, which is located within the same granules and the secretory vesicles as CR1 . Of the other complement regulatory proteins expressed by PMN, only CD59 colocalized with CR1, while CD55 and CD46 were almost absent . Ectosomes released by activated PMN at the site of inflammation may function as a well organized element (ecto-organelle), designed to focus antimicrobial activity onto opsonized surfaces.

Clin Ther, 1999 Sep, 21(9), 1539 - 48
Efficacy of omeprazole plus two antimicrobials for the eradication of Helicobacter pylori in a Turkish population; Uygun A et al.; Omeprazole combined with 2 antimicrobials has been suggested as a first-line option for Helicobacter pylori eradication in recent years . However, controversy exists regarding the efficacy of this protocol . This open-label, prospective clinical study investigated the efficacy of omeprazole-based triple therapy for H pylori eradication in 518 patients with H pylori-positive functional dyspepsia with or without duodenal ulcer . Amoxicillin, macrolides (clarithromycin or roxithromycin), and nitroimidazoles (metronidazole, ornidazole, or tinidazole) were the antibiotics used in the study . Nonulcer patients were randomly assigned to 1 of 8 different treatment protocols and duodenal ulcer patients were randomly assigned to 1 of 4 different treatment protocols consisting of omeprazole (20 mg once daily for nonulcer patients, 20 mg twice daily for ulcer patients for 14 days) with a combination of 2 of the above antimicrobials (for 10 days) . H pylori infection was assessed by histologic findings and a rapid urease test before therapy and 4 weeks after therapy ended . Four hundred fifty-nine patients completed their regimens; 327 had functional dyspepsia (180 men, 147 women; median age, 39 years; range, 18 to 70 years) and 132 had ulcers (81 men, 51 women; median age, 40 years; range, 18 to 70 years) . Eradication of H pylori was achieved in 58.8% (270 of 459) of all patients, 58.1% (190 of 327) of nonulcer dyspeptic patients, and 60.6% (80 of 132) of duodenal ulcer patients . The eradication rate varied from 47.2% to 69.4% in different treatment protocols . There were no statistically significant differences in eradication rates in any treatment group . All drugs were generally well tolerated in all groups, and no patient discontinued treatment because of side effects . Therapy with omeprazole and 2 antimicrobials for H pylori had limited efficacy in a Turkish population . The reason for these results, which conflict with those of other studies, is not clear . Further investigations of regimens for the eradication of H pylori in our population are necessary.

FEBS Lett, 1999 Oct 1, 459(1), 115 - 8
Isolation and purification of a 316 Da preformed compound from strawberry (Fragaria ananassa) leaves active against plant pathogens; Filippone MP et al.; An antibiotic called fragarin showing activities against bacterial and fungal plant pathogens was isolated and purified by FPLC chromatography from the soluble fraction of strawberry leaves . The molecular weight value determined by mass spectrometry is 316 Da . Fragarin remains fully active after protease treatment or alkaline hydrolysis at 100 degrees C for 20 min . Biological and chemical analyses suggest that fragarin may be a new type of an antimicrobial preformed compound--phytoanticipin--and would constitute a primary non-specific barrier of strawberry defense.

Curr Opin Microbiol, 1999 Oct, 2(5), 475 - 82
What's new in the antibiotic pipeline; Lee VJ et al.; Many advances have recently been made in the development of chemotherapeutic agents for bacterial infections . As a consequence of problematic antimicrobial-resistant bacteria, research is now directed towards narrow-spectrum agents rather than broad-spectrum agents . Further, orally active agents have always been desirable, but today's cost-saving environment, in line with a desire to minimize treatment costs, values reduced administration costs and keeping patients out of the hospital . There has been a recent increase in research into orally active antibacterial agents, such as carbapenems and cephalosporins, and non-glycopeptide natural products.

J Pept Sci, 1999 Aug, 5(8), 374 - 8
Isolation and sequence analysis of new peptaibol, boletusin, from Boletus spp; Lee SJ et al.; A new peptaibol, boletusin, was isolated from the methanol extract of the fruiting body of the mushroom, Boletus spp . Sequential determination by positive FAB MS/MS showed that boletusin is a peptide consisting of 19 amino acids, with one acetylated N-terminus residue, phenylalanine, and a C-terminal amino alcohol, tryptophanol . This peptide showed antimicrobial activity against several Gram-positive bacteria.

J Med Chem, 1999 Sep 23, 42(19), 3899 - 909
Glycosylation of fluoroquinolones through direct and oxygenated polymethylene linkages as a sugar-mediated active transport system for antimicrobials; Jung ME et al.; We report herein the synthesis and biological testing of several glycosylated derivatives of some fluoroquinolone antibiotics . In particular, we have prepared several glycosylated derivatives of ciprofloxacin (2) in which the carbohydrate units are linked to the free secondary amine of the piperazine unit by: (a) no linker (e.g., a glycosylamine), (b) a beta-oxyethyl linker, and (c) a gamma-oxypropyl linker . Both glucose and galactose were used as carbohydrates so that six compounds of this type were prepared, e.g., no linker 4a,b, oxyethyl linker 5a,b, and oxypropyl linker 6a,b . In addition the aryl glycosides of glucose and galactose (7a,b) were prepared from the active 1-(4-hydroxyphenyl)fluoroquinolone (3.) The syntheses of the glycosylamines 4a,b involved the direct condensation of glucose and galactose with the hydrochloride salt of ciprofloxacin (2) . For the oxyalkyl-linked compounds, we first prepared the peracetylated omega-bromoalkyl glycopyranosides 14a,b and 15a,b and then coupled them to the allyl ester of ciprofloxacin (11) to give, after saponification to remove all of the esters, the desired fluoroquinolone carbohydrates 5a,b and 6a,b . The final series was prepared from 2,4,5-trifluorobenzoyl chloride (22) which gave 3 in four precedented steps . Coupling of 3 with the peracetylated glucosyl and galactosyl halides 12a,b and 26 afforded, after saponification, the desired aryl glycosides 7a,b . Six of these derivatives of ciprofloxacin-4a,b, 5a,b, and 6a,b-were subjected to microbiological screening . Of the six, compound 6a showed the highest activity . Since 6a would give the hydroxypropyl-substituted ciprofloxacin on hydrolysis and its activity is approximately 4-8 times less than that of ciprofloxacin (2), this implies that compound 6a is probably being actively transported . Thus preliminary results suggest that some of the compounds are stable in culture conditions and may be differentially transported by multiple resistant organisms . In some cases, the addition of a linker and a carbohydrate to ciprofloxacin lessens, but does not eliminate, antimicrobial activity.

Antimicrob Agents Chemother, 1999 Oct, 43(10), 2383 - 8
Beta-lactamase production in Prevotella intermedia, Prevotella nigrescens, and Prevotella pallens genotypes and in vitro susceptibilities to selected antimicrobial agents; Matto J et al.; The present study investigated the beta-lactamase production of 73 Prevotella intermedia, 84 Prevotella nigrescens, and 14 Prevotella pallens isolates and their in vitro susceptibilities to six antimicrobial agents . The P . intermedia and P . nigrescens isolates were recovered from oral and extraoral samples obtained from subjects in two geographic locations from 1985 to 1995 . The clonality of the beta-lactamase-positive and beta-lactamase-negative isolates and the clustering of the genotypes were studied by arbitrarily primed-PCR fingerprinting . beta-Lactamase production was detected in 29% of P . intermedia isolates, 29% of P . nigrescens isolates, and 57% of P . pallens isolates . No difference in the frequencies of beta-lactamase production by P . intermedia and P . nigrescens between isolates from oral and extraoral sites, between isolates obtained at different time periods, or between P . intermedia isolates from different geographic locations was observed . However, the P . nigrescens isolates from the United States were significantly more frequently (P = 0.015) beta-lactamase positive than those from Finland . No association between the genotypes and beta-lactamase production or between the genotypes and the sources of the isolates was found . The penicillin G MICs at which 90% of the isolates were inhibited were 8 microg/ml for P . intermedia, 8 microg/ml for P . nigrescens, and 16 microg/ml for P . pallens . For the beta-lactamase-negative isolates, the corresponding values were 0.031, 0.031, and 0.125 microg/ml, and for the beta-lactamase-positive isolates, the corresponding values were 16, 8, and 32 microg/ml . All isolates were susceptible to amoxicillin-clavulanate, cefoxitin, metronidazole, azithromycin, and trovafloxacin . The MICs of amoxicillin-clavulanate and cefoxitin were relatively higher for the beta-lactamase-positive population than for the beta-lactamase-negative population.

Br J Cancer, 1999 Oct, 81(3), 393 - 403
Proline-rich antimicrobial peptide, PR-39 gene transduction altered invasive activity and actin structure in human hepatocellular carcinoma cells; Ohtake T et al.; PR-39 is an endogenous proline-rich antimicrobial peptide which induces the synthesis of syndecan-1, a transmembrane heparan sulphate proteoglycan involved in cell-to-matrix interactions and wound healing . Previously, we revealed that the expression of syndecan-1 was reduced in human hepatocellular carcinomas with high metastatic potential and speculated that syndecan-1 played an important role in inhibition of invasion and metastasis . It is assumed that a modification of this process with PR-39 and syndecan-1 may result in a new strategy by which it can inhibit the invasion and metastasis . Therefore, we transduced a gene of PR-39 into human hepatocellular carcinoma cell line HLF, which shows a low expression of syndecan-1 and a high in vitro invasive activity, and examined whether this procedure could reduce the invasive activity of tumour cells . In two transfectants with PR-39 gene, the syndecan-1 expression was induced and the invasive activity in type I collagen-coated chamber was inhibited . Moreover, these transfectants showed the suppression of motile activity assayed by phagokinetic tracks in addition to the disorganization of actin filaments observed by a confocal imaging system . In contrast, five transfectants with syndecan-1 gene in the HLF cells revealed suppression of invasive activity but did not alter the motile activity and actin structures of the cell . These results suggest that PR-39 has functions involved in the suppression of motile activity and alteration of actin structure on human hepatocellular carcinoma cells in addition to the suppression of invasive activity which might result from the induction of syndecan-1 expression.

J Dent, 1999 Sep, 27(7), 517 - 22
Dynamic viscoelastic properties of antimicrobial tissue conditioners containing silver-zeolite; Ueshige M et al.; OBJECTIVES: The purpose of this study was to determine the effects of including the antimicrobial silver-zeolite (SZ) on the dynamic viscoelastic properties of various tissue conditioners . METHODS: The dynamic viscoelastic properties of five commercially available tissue conditioners: Visco-gel (VG), GC Soft-Liner (SL), FITT (FT), SR-Ivoseal (IV) and Shofu Tissue Conditioner (TC) containing SZ were evaluated after 1 and 28 days of water- and artificial saliva immersions with the use of complex modulus and loss tangent parameters . Values for these two parameters for each tissue conditioner were statistically analyzed by one- and two-way ANOVA and Bonferroni's test . RESULTS: Complex modulus and loss tangent values of TC were not significantly different among specimens containing 0, 2, 5 and 10 wt.%-SZ, respectively . In FT and TC containing 2 wt.%-SZ, these values were not significantly different between 1 and 28 days in both water- and saliva immersions . CONCLUSION: The results suggest that incorporating SZ does not affect TC's inherent dynamic viscoelastic properties, while the other tissue conditioners investigated may be found to have changed viscoelastic properties as a consequence of the inclusion of SZ.

Science, 1999 Oct 1, 286(5437), 113 - 7
Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense; Wilson CL et al.; Precursors of alpha-defensin peptides require activation for bactericidal activity . In mouse small intestine, matrilysin colocalized with alpha-defensins (cryptdins) in Paneth cell granules, and in vitro it cleaved the pro segment from cryptdin precursors . Matrilysin-deficient (MAT-/-) mice lacked mature cryptdins and accumulated precursor molecules . Intestinal peptide preparations from MAT-/- mice had decreased antimicrobial activity . Orally administered bacteria survived in greater numbers and were more virulent in MAT-/- mice than in MAT+/+ mice . Thus, matrilysin functions in intestinal mucosal defense by regulating the activity of defensins, which may be a common role for this metalloproteinase in its numerous epithelial sites of expression.

Pediatrics, 1999 Oct, 104(4 Pt 1), 961 - 4
Nocardia farcinica pneumonia in chronic granulomatous disease; Shetty AK et al.; Infection with Nocardia poses a diagnostic challenge in patients with chronic granulomatous disease (CGD) because the signs and symptoms are often nonspecific, delay in diagnosis is common, and invasive procedures are frequently required to obtain appropriate tissue specimens . We present the first reported case of N farcinica pneumonia in an adolescent with X-linked CGD . Differentiation of N farcinica from other members of N asteroides complex is important because of its propensity for causing disseminated infection and antimicrobial resistance . Physicians caring for patients with CGD should maintain a high index of suspicion for nocardiosis, especially in those receiving chronic steroid therapy . Early diagnosis remains critical for decreased morbidity and occasional mortality.

Gene Ther, 1999 May, 6(5), 737 - 48
Needle injection catheter delivery of the gene for an antibacterial agent inhibits neointimal formation; Nikol S et al.; Percutaneous transluminal coronary angioplasty is a routinely used non-surgical revascularization technique for patients with coronary artery disease . Up to 30% of patients undergoing coronary angioplasty develop a renarrowing of treated vessels, called restenosis . Smooth muscle cell proliferation is thought to be an important factor in restenosis; this leads to neointima formation and arterial lumen narrowing . Neointima may be reduced by the transfer of genes encoding proteins with antiproliferative effects . Cecropins are antimicrobial peptides with antiproliferative properties in mammalian cells . Cecropin A is one member of this family of peptides . In this article, a plasmid carrying the gene for the immature form, pre-pro-cecropin A, complexed with liposomes was locally delivered to perivascular tissue in a porcine arterial injury model using a needle injection catheter . Retention of the plasmid in the treated arteries was demonstrated at both 8 and 21 days following application . Transferred plasmid DNA was not detected in any other tissues analyzed . Pre-pro-cecropin A-specific transcripts could also be found in treated arteries . Balloon-injured vessels demonstrated significantly reduced neointima at 21 days in vessels treated with the pre-pro-cecropin A gene compared with neointimal area in those given a control gene (P < 0.05) . The needle injection catheter appears to be useful for local intravascular gene delivery . In vivo gene transfer of cecropins may be of therapeutic relevance in restenosis prevention by limiting cell proliferation.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 1999 Sep, 88(3), 273 - 6
Oral mucositis in myelosuppressive cancer therapy; Epstein JB et al.; Because the etiology of mucositis is multifactorial , approaches to prevention and management have also been multifactorial . Effective prevention and management of mucositis will reduce the pain and suffering experienced during cancer treatment . Oropharyngeal pain in cancer patients frequently requires systemic analgesics, adjunctive medications, physical therapy, and psychologic therapy in addition to oral care and topical treatments . Good oral hygiene reduces the severity of oral mucositis and does not increase the risk of bacteremia . Current approaches to management include frequent oral rinsing with saline or bicarbonate rinses, maintaining excellent oral hygiene, and using topical anesthetics and analgesics . Cryotherapy is a potential adjunctive approach in some cases . There are a number of approaches that appear to represent viable candidates for further study . Biologic response modifiers offer the potential for prevention and for acceleration of healing . Various cytokines will enter clinical trials in the near future; these offer the potential for reduction of epithelial cell sensitivity to the toxic effects of cancer therapy or for stimulation of repair of the damaged tissue . Other approaches include the use of medications to reduce exposure of the oral mucosa to chemotherapeutic drugs that are secreted in saliva . Antimicrobial approaches have met with conflicting results, little effect being seen with chlorhexidine and systemic antimicrobials in the prevention of mucositis in radiation patients . In patients with BMT and patients with leukemia, chlorhexidine may not be effective in preventing mucositis, although there may be reduction in oral colonization by Candida . Initial studies of topical antimicrobials that affect the gram-negative oral flora have shown reductions in ulcerative mucositis during radiation therapy but have not been assessed in leukemia/BMT . Among other approaches that require further study are low-energy lasers and anti-inflammatory medications . These approaches to management have undergone initial study, but additional investigation is needed to determine their effectiveness with respect to the prevention of mucositis and symptom management and to determine appropriate doses and frequencies of intervention . Current studies and our increasing understanding of the pathogenesis of oral mucositis will lead to new approaches to management and improved quality of life for these patients.

Am J Otol, 1999 Sep, 20(5), 561 - 7
Aspergillus mastoiditis in acquired immunodeficiency syndrome; Chen D et al.; OBJECTIVE: This study aimed to analyze the clinical presentation, diagnosis, management, and results of treatment in a series of three patients with acquired immunodeficiency syndrome (AIDS) in whom Aspergillus mastoiditis developed . This study also aimed to compare these aspects of Aspergillus mastoiditis in patients with AIDS with three additional cases present in the current literature . A classification system for fungal infections of the ear and temporal bone is proposed . STUDY DESIGN: The study design was a retrospective case review . SETTING: The study was conducted at multiple tertiary referral centers . PATIENTS: Three individuals with diagnosed AIDS and mastoiditis resulting from culture-proven Aspergillus were studied . INTERVENTION: Patients were treated with both medical and surgical methods including local and systemic antimicrobial/antifungal agents and mastoidectomy . MAIN OUTCOME MEASURES: These measures included return of facial nerve function, control/resolution of disease, and survival . RESULTS: All three patients in this series initially presented with otalgia and otorrhea and intact facial nerve function . Facial nerve paresis developed in all patients between 5 and 12 weeks after initial symptoms . Paresis uniformly improved or resolved after mastoidectomy . Two patients treated with systemic antifungal therapy and prompt surgical debridement after development of facial palsy had full resolution of infection . One patient had full recovery of facial paresis and the other had partial recovery . The third patient was lost to follow-up after initial treatment with antimicrobials and surgery and died 3 months later without a clear etiology . CONCLUSIONS: Aspergillus mastoiditis is an unusual infection in patients with AIDS . Because of its rarity, fungal mastoiditis in immunocompromised individuals can result in a significant delay in diagnosis and treatment . The decision between conservative antimicrobial therapy and aggressive surgical treatment also can present a therapeutic challenge in the management of these life-threatening infections, especially in patients with existing immunodeficiency and illness . Early surgical debridement followed by antimicrobial therapy may be life preserving in this patient population.

Vet Clin North Am Small Anim Pract, 1999 Sep, 29(5), 1261 - 74, ix
Treatment of severe orthopedic infections; Dernell WS; Severe infections are uncommon following orthopedic surgery, yet they can be frustrating for the veterinarian and owner to treat and can result in devastating consequences for the patient . This article reviews the common causes for postoperative infection, reviews established treatment, and introduces newer methods for treatment and control . A thorough understanding of the pathogenesis, application of appropriate diagnostic procedures, the institution of aggressive treatment regimens, with adherence to established principles, will often result in satisfactory outcomes even with severe orthopedic infections . For those more refractory to treatment, the use of newer treatment methods, specifically locally implantable materials for sustained release of antimicrobials can improve success in the treatment of these more difficult cases.

Infect Control Hosp Epidemiol, 1999 Sep, 20(9), 624 - 6
Infection and antimicrobial use in laparoscopic cholecystectomy; McGuckin M et al.; Retrospective chart review of 1,702 patients undergoing laparoscopic cholecystectomy (LC) revealed an overall infection rate of 2.3% and a surgical-site infection rate of 0.4% . Preoperative antimicrobial prophylaxis was received by 79% of patients, but only 33% of these received the agent within 1 hour or less prior to surgery . These facts suggest that antimicrobial prophylaxis may not be necessary for low-risk LC patients.

Infect Control Hosp Epidemiol, 1999 Sep, 20(9), 610 - 3
Surveillance of antimicrobial prophylaxis for surgical procedures; Vaisbrud V et al.; OBJECTIVE: To assess the practice of antimicrobial prophylaxis for surgical procedures in eight surgical departments in a 550-bed teaching hospital . METHODS: A list of all major procedures performed in our hospital, with recommendations for prophylaxis based upon the literature, has been distributed since 1993 and is updated periodically . The practice of surgical prophylaxis between January 1 and March 31, 1996, was examined by assessing four variables: (1) Did the particular procedure justify prophylaxis, and was it provided? (2) Was timing optimal, ie, within 1 hour prior to surgery? (3) Was the appropriate antimicrobial selected? (4) Was duration optimal, ie, < or =24 hours? RESULTS: During the study period, 2,117 operations were performed, of which 1,631 (77%) were reviewed . Sixty-six percent were clean surgery, 28% clean-contaminated, and 6% contaminated; 72% of procedures were elective, 28% emergencies . Of 1,631 operations requiring prophylaxis, 1,142 (70%) received it, 489 (30%) did not . Of 1,631 patients, 1,392 (85%) received appropriate care: 929 (67%) appropriately received prophylaxis, and 463 (33%) appropriately did not receive prophylaxis . Of 955 patients who received prophylaxis, 26 (3%) did so inappropriately . Of 1,142 patients who should have received prophylaxis, 213 (19%) did not receive it . Female gender, clean surgery, elective operations, and infrequently performed procedures were all significant indicators of inappropriately withheld prophylaxis (P<.001) . In addition, the rate of appropriately provided prophylaxis varied between departments from 71% to 97% (P<.001) . Assessment of the 929 procedures for which prophylaxis was justified and given revealed that 100% of patients received it on time, the choice of antimicrobial was appropriate in 95% of cases, and duration was < or =24 hours in 91% . CONCLUSIONS: Audits of surgical prophylaxis are expected to detect different errors in different institutions . Conducting audits of surgical prophylaxis probably should be part of the routine activity of infection control teams . Feeding the information back to surgeons could improve adherence to recommended guidelines and might contribute to reduced wound infection rates.

Comb Chem High Throughput Screen, 1998 Jun, 1(2), 73 - 87
A simple, inexpensive apparatus for performance of preparative scale solution phase multiple parallel synthesis of drug analogs . I . Preparation of a retrospective library of quinolone antiinfective agents; Frank KE et al.; A simple inexpensive apparatus is described consisting of conveniently commercially available components which is suitable for the solution phase multiple parallel synthesis of 24-72 analogs of drug-like molecules . The use of the apparatus is illustrated by preparation of a retrospective library of over 100 analogs of antimicrobial fluoroquinolones prepared in 0% to quantitative yields . Each analog was prepared in up to 150 mg quantity and each was analyzed by NMR and mass spectrometric techniques to verify its purity and identity.

Lett Appl Microbiol, 1999 Aug, 29(2), 130 - 5
In-vitro antimicrobial activity and chemical composition of Sardinian Thymus essential oils; Cosentino S et al.; Essential oils and their components are becoming increasingly popular as naturally occurring antimicrobial agents . In this work the chemical composition and the antimicrobial properties of Thymus essential oils and of their main components were determined . Three essential oils obtained from different species of Thymus growing wild in Sardinia and a commercial sample of Thymus capitatus oil were analysed . The essential oil components were identified by GC/MS analysis . The antimicrobial activity of the oils and components was determined against a panel of standard reference strains and multiple strains of food-derived spoilage and pathogenic bacteria, using a broth microdilution method . The GC/MS analysis showed that the major constituents of the oils were monoterpene hydrocarbons and phenolic monoterpenes, but the concentration of these compounds varied greatly among the oils examined . The results of the antimicrobial assay showed that essential oils extracted from Sardinian Thymus species have an antimicrobial activity comparable to the one observed in other thyme oils . It seems also confirmed that the antimicrobial properties of thyme essential oils are mainly related to their high phenolic content . Among the single compounds tested carvacrol and thymol turned out to be the most efficient against both reference strains and food-derived bacteria . The results of this study confirmed the possibility of using thyme essential oils or some of their components in food systems to prevent the growth of foodborne bacteria and extend the shelf-life of processed foods.

Trends Plant Sci, 1999 Oct, 4(10), 394 - 400
Flavonoids and isoflavonoids - a gold mine for metabolic engineering; Dixon RA et al.; Flavonoid-derived plant natural products have long been known to function as floral pigments for the attraction of insect pollinators, as signal molecules for beneficial microorganisms in the rhizosphere, and as antimicrobial defense compounds . New functions for flavonoid compounds continue to be found, particularly in plant-microorganism signaling, and there has been an explosion of interest in flavonoids and isoflavonoids as health-promoting components of the human diet . The flavonoid and isoflavonoid pathways are probably the best characterized natural product pathway in plants, and are therefore excellent targets for metabolic engineering . Manipulation of flavonoid biosynthesis can be approached via several strategies, including sense or antisense manipulation of pathway genes, modification of the expression of regulatory genes, or generation of novel enzymatic specificities by ra-tional approaches based on emerging protein structure data . In addition, activation tagging provides a novel approach for the discovery of uncharacterized structural and regulatory genes of flavonoid biosynthesis.

Carbohydr Res, 1999 Apr 30, 317(1-4), 19 - 28
Molecular, crystal and solution structure of a beta-cyclodextrin complex with the bromide salt of 2-(3-dimethylaminopropyl)tricyclo{3.3.1.1(3,7)}decan-2-ol, a potent antimicrobial drug; Perrakis A et al.; The pharmacological properties of a cyclomaltoheptaose (beta-cyclodextrin) series of adamantane-group-bearing compounds that exhibit potent antibacterial activity have been studied, both isolated and in complex with beta-cyclodextrins (betaCDs) . In this work, the structure of the bromide salt of 2-(3-dimethylaminopropyl)-tricyclo{3.3.1.1(3,7)}decan-2-ol(A DM-10) complexed with betaCD and ten water molecules was studied in the solid state by X-ray crystallography and in solution by NMR spectroscopy . X-ray crystallographic studies of the complex were performed both at room and cryogenic temperatures . The long aliphatic chain of ADM-10 adopts a single conformation at low temperature in contrast to what is observed at room temperature, where two side chain conformations are seen . Both NMR and X-ray crystallography studies indicate that the adamantane moiety of ADM-10 is buried in the betaCD cavity . Chemical shifts in NMR experiments can be explained on the basis of the crystal structure of the complex.

J Microbiol Immunol Infect, 1998 Dec, 31(4), 240 - 4
Serious complications in scrub typhus; Tsay RW et al.; Scrub typhus, a mite-transmitted zoonosis caused by Orientia tsutsugamushi, is a disease endemic to Taiwan . Serious complications in scrub typhus were more common in the past 4 years than reported previously . Between August 1993 and July 1997, 33 cases of scrub typhus were admitted at Tri-Service General Hospital . Symptoms and signs were: fever (100%), chills (39%), cough (24%), headache (21%), diarrhea (18%), dyspnea (18%), eschar (60%), adenopathy (33%), and rash (21%) . Nineteen percent (6/32) had obvious leukopenia (WBC < 4000/ mm3), 34% (11/32) had leukocytosis(WBC > 10,000/mm3) and 44% (14/32) had thrombocytopenia (platelet count < 100,000/mm3) . Elevation of aspartate aminotransferase (AST) and elevation of alanine aminotransferase (ALT) were 81% (26/32) and 75% (24/32), respectively . Serious complications included pneumonitis 36% (12/33), acute respiratory distress syndrome (ARDS) 15% (5/33), acute renal failure 9% (3/33), myocarditis 3% (1/33) and septic shock 3% (1/33) . One patient died of ARDS due to delay in diagnosis . Other patients recovered after appropriate antibiotic and intensive supportive treatments . Emerging virulent strains of O . tsutsugamushi in Taiwan might be biologically plausible . Scrub typhus should be considered in a patient with fever, varying degree of respiratory distress, particularly if there is an eschar or a history of environmental exposure in endemic areas . Prompt diagnosis, timely antimicrobial therapy and intensive supportive care are important for ARDS and other life-threatening complications.

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