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