Bactericidal

Gen Dent, 2000 Jan-Feb, 48(1), 54 - 60
Drug use for the pregnant or lactating patient; Haas DA et al.; The dental patient who is pregnant or lactating may require management involving the administration or prescription of drugs . The approach of completely avoiding all drugs may not permit appropriate treatment of the patient and most often is not warranted . This article reviews the current considerations in the use of drugs in the dental patient who is either pregnant or lactating . The safety of the local anesthetics, vasoconstrictors, analgesics, antimicrobials, and sedatives used in dentistry is discussed.

Planta Med, 2000 Dec, 66(8), 768 - 9
Antimicrobial triterpenoids from Licania heteromorpha; Braca A et al.; Six triterpenoids having a lupane and oleane skeleton were isolated from the leaves and young branches of Licania heteromorpha Bentham var . heteromorpha and were identified as: betulinic acid 1, alphitolic acid 2, 3 beta-O-trans-p-coumaroyl alphitolic acid 3, 3 beta-O-cis-p-coumaroyl alphitolic acid 4, 3 beta-O-trans-p-coumaroyl maslinic acid 5, 3 beta-O-cis-p-coumaroyl maslinic acid 6 . The antimicrobial activity of these compounds was evaluated in vitro on clinically isolated microorganisms employing a microdilution method . Compounds 2, 3, 5, and 6 showed antimicrobial activity on Gram-positive bacteria and yeasts, whereas none of the six triterpenoids were active against Gram-negative organisms.

Planta Med, 2000 Dec, 66(8), 687 - 93
Antioxidant and antimicrobial activity of Foeniculum vulgare and Crithmum maritimum essential oils; Ruberto G et al.; The essential oils obtained from Crithmum maritimum L . (marine fennel) and two samples of Foeniculum vulgare Miller (common fennel) were analysed by GC and GC-MS and assayed for their antioxidant and antibacterial activities . The antioxidant activity of the oils was evaluated by two lipid model systems: a modified thiobarbituric acid reactive species (TBARS) assay and a spectrophotometric detection of hydroperoxydienes from linoleic acid in a micellar system . The oils demonstrated antioxidant capacities, comparable in some cases to that of alpha-tocopherol and butylated hydroxytoluene (BHT), used as reference antioxidants . Concerning the antimicrobial tests the essential oils were assayed against twenty-five genera of bacteria, including animal and plant pathogens, food poisoning and spoilage bacteria . Oils from the two samples of F . vulgare showed a higher and broader degree of inhibition than that of C . maritimum.

J Pharm Belg, 2000 Nov-Dec, 55(6), 137 - 41
{Multiple bacterial resistance in daily practice}; Sternon J; Present and future solutions to the problem of bacterial multiple resistance involve physicians, patients and veterinarians . Their behaviour should evolve to take into account the medical and economical issues of antibiotic prescription . The clinical diagnosis requires a more rigorous assessment, based on bacteriological and rapid antigenic tests . Vaccination in both young people and the elderly, is an essential prophylactic tool, which is too often neglected . When a bacterial infection is suspected or proven, priority should be given to a targeted antimicrobial therapy with a bactericidal activity, in order to quickly eradicate pathogens . Therapies should be shorter and questionable antibioprophylaxis should also be avoided . A watch laboratory network should provide physicians with an adequate information on local bacterial resistance patterns on a regular basis, in order to allow them adjusting their prescription.

Inorg Chem, 2000 Jul 24, 39(15), 3301 - 11
Synthesis and characterization of water-soluble silver(I) complexes with L-histidine (H2his) and (S)-(-)-2-pyrrolidone-5-carboxylic acid (H2pyrrld) showing a wide spectrum of effective antibacterial and antifungal activities . Crystal structures of chiral helical polymers {Ag(Hhis)}n and ({Ag(Hpyrrld)}2)n in the solid state; Nomiya K et al.; Two water-soluble, silver(I) complexes showing a wide spectrum of effective antibacterial and antifungal activities, i.e., ({Ag(Hhis)}.0.2EtOH)2 (1; H2his = L-histidine) and {Ag(Hpyrrld)}2 (3; H2pyrrld = (S)-(-)-2-pyrrolidone-5-carboxylic acid) were prepared . In aqueous solution 1 and 3 were present as dimers, whereas in the solid state they were polymers . Crystallization of 1 by slow evaporation and/or vapor diffusion gave water-insoluble crystals of {Ag(Hhis)}n (2) showing modest antimicrobial activities . The complex 1 in the solid state is a polymer formed by intermolecular hydrogen-bonding interactions between dimeric {Ag(Hhis)}2 cores, while 2 is a different polymer without a core complex . X-ray crystallography revealed that 2 was a left-handed helical polymer consisting of a bent, 2-coordinate silver(I) atom bonding to the Namino atom of one Hhis- ligand and the N pi atom of a different Hhis- ligand . Of particular note is the fact that Ocarboxyl atoms do not participate in the coordination . X-ray crystallography also revealed that 3 was a left-handed helical polymer formed by self-assembly of dimeric {Ag(Hpyrrld)}2 cores with an intramolecular metal(I)-metal(I) interaction (Ag-Ag distance, 2.9022(7) A) . The FT-IR and the solid-state 13C and 15N NMR spectra showed that the dimeric core of 1 was formed through Ag-N bonds, while that of 3 was formed through Ag-O bonds . The molecular ions of 1 and 3 were detected by the positive-ion electrospray ionization (ESI) mass spectrometry . For 1-3, characterization by elemental analysis, TG/DTA, FT-IR, and variable-temperature solid-state 13C NMR and room-temperature 15N NMR measurements was performed, and for 1 and 3, that by solution molecular weight measurements and solution (109Ag, 1H, and 13C) NMR spectroscopies was also carried out . The antibacterial and antifungal activities of 1 and 3 were remarkable and comparable to those of the previous silver(I)-N-heterocycle complexes.

Methods Find Exp Clin Pharmacol, 2000 Sep, 22(7), 581 - 4
Effect of clarithromycin on the pharmacokinetics of carbamazepine in rhesus monkeys; Badyal DK et al.; Clarithromycin, an advanced-generation macrolide antimicrobial, is less prone to drug interactions as compared to erythromycin . Based on two case reports in which increased carbamazepine (CBZ) plasma concentrations were observed in patients receiving clarithromycin, a crossover multiple dose study was designed to find out the pharmacokinetic interaction between CBZ and clarithromycin in rhesus monkeys . CBZ (46 mg/kg/d) was administered to the monkeys alone and along with clarithromycin (20 mg/kg/d) . Blood samples were collected from 0-24 h . Plasma concentrations of CBZ were measured by HPLC technique . Pharmacokinetic data revealed an increase in plasma concentrations, AUC(0-24) and t1/2e of CBZ when coadministered with clarithromycin, but the increase was not statistically significant . These findings suggest careful administration and plasma monitoring of CBZ concentrations when coadministered with clarithromycin.

Avian Dis, 2000 Oct-Dec, 44(4), 963 - 7
Presence of fluoroquinolone-resistant coliforms in poultry litter; Hofacre CL et al.; Litter was collected from four turkey farms (eight houses) with a history of fluoroquinolone (FQ) treatment failure, 10 adult broiler breeder chicken farms (43 houses) with one having a history of FQ treatment, and 30 broiler chicken farms (110 houses) with 24 having a history of FQ treatment . In the turkey litter, the percentage of nalidixic acid-resistant (at 100 microg/ml) coliforms/total number of coliforms ranged from 0.6% to 61.9% . Two of the four farms had houses containing coliforms resistant to the two FQs, enrofloxacin (1 microg/ml) and sarafloxacin (1 microg/ml) . There was also multiple resistance to other antimicrobials on all four turkey farms (ampicillin, tetracycline, chloramphenicol, kanamycin) . The level of total coliforms from the adult broiler breeder litter was low, and there were no nalidixic acid-resistant isolates from any of the 10 farms . In the broiler chickens, 7 of 91 houses with a history of FQ usage contained coliforms resistant to nalidixic acid; however, 2 of the 19 houses on farms with no history of FQ usage had nalidixic acid-resistant coliforms . All of the broiler farms with nalidixic acid-resistant isolates were also resistant to the FQ sarafloxacin, whereas only 3 of the 24 treatment history farms and 1 of the no-treatment history farms exhibited enrofloxacin-resistant coliforms in the litter.

J Fam Pract, 2001 Jan, 50(1), 26 - 31
The common cold in patients with a history of recurrent sinusitis: increased symptoms and radiologic sinusitislike findings; Alho OP et al.; BACKGROUND: We evaluated whether the symptoms and signs and radiologic findings during a common cold are similar in patients who have and have not suffered from recurrent sinusitis . METHODS: We recruited 2 series of volunteer cases from February 1, 1996, to December 31, 1996 . Twenty-three adults who claimed to have suffered from recurrent sinusitis and 25 who had never had sinusitis were examined during the period of a self-diagnosed cold of 48 to 96 hours' duration and again after 21 days . Symptom scores were recorded, nasoendoscopy and computed tomography scans were performed, and viral and bacterial specimens were taken . RESULTS: The patients with a history of sinusitis had significantly higher symptom scores than the control patients (P=.04) and had radiologic sinusitislike changes more often (65% {15} vs 36% {9}; difference 29% {95% confidence interval, 2%-56%}; P=.04) . The viral etiology of the common cold (verified in 67% of the episodes) was similar in both groups . Pathogenic bacteria were isolated from the middle meatus in 24% (6) of the control patients and only 9% (2) of the sinusitis-prone patients (P=.15) . On the basis of the symptomatology, radiologic findings, and bacterial cultures only 2 patients in the sinusitis-prone group should have been treated with antimicrobials . CONCLUSIONS: Some patients are susceptible to both sinusitislike symptoms and radiologic findings during viral common colds . This may cause them to consult their physicians earlier and more often during viral colds, which may result in unnecessary antibiotic treatments . Nasopharyngeal bacteriological cultures may prove to be useful in ruling out bacterial sinusitis.

Am J Health Syst Pharm, 2001 Jan 1, 58(1), 41 - 50; quiz 51-3
Treatment strategies for recurrent oral aphthous ulcers; Barrons RW; The clinical features, etiology, and treatment of recurrent aphthous ulcers (RAU) are discussed . Aphthous ulcers are among the most common oral lesions in the general population, with a frequency of up to 25% and three-month recurrence rates as high as 50% . The ulcers, which usually occur on the nonkeratinized oral mucosa, can cause considerable pain and may interfere with eating, speaking, and swallowing . RAU is classified as minor, major, and herpetiform on the basis of ulcer size and number . The cause of RAU is idiopathic in most patients . The most likely precipitating factors are local trauma and stress . Other associated factors include systemic diseases and nutritional deficiencies, food allergies, genetic predisposition, immune disorders, the use of certain medications, and HIV infection . The primary goals of therapy for RAU are relief of pain, reduction of ulcer duration, and restoration of normal oral function . Secondary goals include reduction in the frequency and severity of recurrences and maintenance of remission . Topical medications, such as antimicrobial mouthwashes and topical corticosteroids, can achieve the primary goals but have not been shown to alter recurrence or remission rates . Systemic medications can be tried if topical therapy is ineffective . Levamisole has shown variable efficacy in reducing ulcer frequency and duration in patients with minor RAU . Oral corticosteroids should be reserved for severe cases of major RAU that do not respond to topical agents . Thalidomide is effective but, because of its toxicity and cost, should be used only as an alternative to oral corticosteroids . RAU can be effectively managed with a variety of topical and systemic medications.

Poult Sci, 2000 Dec, 79(12), 1857 - 60
Validation of thiosulfate for neutralization of acidified sodium chlorite in microbiological testing; Kemp GK et al.; At low pH, acidified sodium chlorite (ASC) has antimicrobial activity against a variety of foodborne contaminants . To evaluate the antimicrobial efficacy of ASC at specific time points posttreatment, it is necessary to halt the action of the disinfectant by removing residual chlorite or by increasing the pH . In this study, thiosulfate was investigated at varying concentrations for its effect on microbial survival and was investigated at a concentration of 0.1% in the presence of ASC for its effect on the antimicrobial and chemical activity of the test solution . Additionally, sodium thiosulfate was tested in two buffering systems, buffered peptone water (BPW) and Butterfield's phopshate buffer (BPB), for its ability to inactivate ASC chemistry . The results of this study show that, at a concentration of 0.1%, sodium thiosulfate has no deleterious effect on Escherichia coli survival and is effective in halting the antimicrobial action of ASC by eliminating the production of residual chlorite . The BPW alone and BPB in combination with thiosulfate were found to be effective inactivators of ASC chemistry.

Nihon Kokyuki Gakkai Zasshi, 2000 Nov, 38(11), 844 - 9
{Pulmonary Nocardia otitidiscaviarum infection in an immunocompetent host}; Matsuo K et al.; A rare case of pulmonary Nocardia otitidiscaviarum (N . otitidiscaviarum) was encountered in an immunocompetent host . A 74-year-old man was admitted to our hospital with a high fever and a productive cough . His chest radiograph and CT scan revealed infiltrative shadows in the right middle and lower lung fields . Although several antibiotics (third-generation cephalosporin, minocycline, imipenem) were administered, the fever and cough persisted, and C-reactive protein remained elevated . Repeated sputum cultures showed normal flora, so a transbronchial lung biopsy and bronchoalveolar lavage (BAL) were performed bronchoscopically at the right S5 . The BAL fluid contained acid-fast, branching filamentous structures . The microorganism was identified as N . otitidiscaviarum by the Research Center for Pathogenic Fungi and Microbial Toxicoses (Chiba University) . Trimethoprim-sulfamethoxazole was therefore administered, but the fever continued to rise daily, and C-reactive protein remained elevated . This isolated N . otitidiscaviarum showed resistance to multiple antimicrobial agents in vitro when examined by the disk diffusion method, and so, on the basis of the antibiogram, the patient was treated with clarithromycin (oral, 600 mg/day) plus amikacin (400 mg/day), which proved successful . Testing for pulmonary nocardiosis should be added to the differential diagnosis procedures for refractory pneumonia as an opportunistic infection and for community-acquired pneumonia.

Eur J Ophthalmol, 2000 Oct-Dec, 10(4), 286 - 92
Preoperative gentamicin eye drops and chlorhexidine solution in cataract surgery . Experimental and clinical results; Montan PG et al.; PURPOSE: 1) To evaluate the effects on the conjunctival flora of gentamicin ophthalmic eye drops 0.3%, given four times in 45 minutes, and a conjunctival rinse with 10 ml chlorhexidine 0.05% solution . 2) To investigate retrospectively the rate of endophthalmitis after cataract operations when these antimicrobials were applied preoperatively . METHODS: Seventy-six patients undergoing standard phacoemulsification operations were enrolled in the experimental part of the study . Cultures were taken preoperatively, 5 minutes after prophylaxis with either chlorhexidine or gentamicin . To assess the combined effects of chlorhexidine and gentamicin, cultures were taken after the cataract operation . Hospital charts were reviewed for cases of endophthalmitis in 1994 and 1995, when this prophylactic protocol was used at the St Erik's cataract surgery department . RESULTS: The conjunctival microflora was significantly suppressed by chlorhexidine rinsing alone (p = 0.001), while no other significant anti-bacterial effects were observed with the experimental prophylaxis . The endophthalmitis rate was 32/12 . 806 operations (0.25%) . CONCLUSIONS: Topical rinsing with chlorhexidine solution suppresses conjunctival flora in the short term . Combined topical chlorhexidine and gentamicin prophylaxis does not eliminate postoperative endophthalmitis caused by gram-positive bacteria.

J Inorg Biochem, 2001 Jan 1, 83(1), 7 - 16
Copper(II) complexes with phenoxyalkanoic acids and nitrogen donor heterocyclic ligands: structure and bioactivity; Dendrinou-Samara C et al.; The copper complexes with the phenoxyalkanoic acids MCPA, 2,4-D, 2,4,5-T and 2,4-DP in the presence of a nitrogen donor heterocyclic ligand, phen or bipyam, were prepared and characterized . Interaction of Cu(II) with phenoxyalkanoic acids and bipyam leads to dinuclear or uninuclear neutral complexes while in the presence of phen uninuclear neutral or cationic forms have been isolated . The crystal structure of bis(1,10-phenanthroline)(2-methyl-4-chloro-phenoxyacetato)copper(ll) chloride-methanol(1/1)-water(1/0.6), 1 has been determined and refined by least-squares methods using three-dimensional MoK, data . 1 crystallizes in space group P1, in a cell of dimensions a = 14.577(6)A, b = 1 1.665(5) A, c = 12.249(6) A, alpha = 98.38( 1)degrees, beta = 112.18( 1) degrees, gamma = 104.56(1 ) degrees, V= 1,798( 1) A3 and Z= 2 . The cyclic voltammograms of uninuclear cationic complexes in dmf exhibit an extra cathodic wave due to the chloride ion . The available evidence supports an increasing antimicrobial effeciency for the cationic complexes.

Ann Plast Surg, 2001 Jan, 46(1), 55 - 8
Actinomycosis of the frontal and parotid regions; Ermis I et al.; Cervicofacial actinomycosis still occurs infrequently and should be included in the differential diagnosis of neoplasms, and chronic suppurative and granulomatous lesions of the head and neck region . The authors present two cases of actinomycosis . Patient 1 was a 32-year-old man who was first seen with a firm, suppurative mass at his left frontal region . Patient 2 was a 36-year-old woman with an indurated mass at her left parotid area . Both patients were diagnosed histopathologically with cervicofacial actinomycosis, but each patient had a different clinical course and different response to antimicrobial and surgical treatments.

J Parasitol, 2000 Dec, 86(6), 1355 - 9
Effect of the antimicrobial peptide, D-hecate, on trichomonads; Mutwiri GK et al.; Tritrichomonas foetus and Trichomonas vaginalis are protozoan parasites that cause sexually transmitted diseases in cattle and humans, respectively . There is a need for new antimicrobial agents to treat or prevent trichomoniasis because there are currently no approved chemotherapeutic agents against T . foetus and resistance of T . vaginalis to metronidazole does occur . Therefore, we evaluated the effect of a novel antimicrobial peptide, D-hecate, on the viability of 6 isolates of T . foetus and T . vaginalis in vitro . Tritrichomonas foetus and T . vaginalis were grown to mid log phase (24 hr) or late log/stationary phase (48 hr) . Parasites at 10(6)/ml were mixed with equal volumes of D-hecate to final concentrations of 10 microM, 20 microM . and 40 microM of D-hecate . Controls had minimal essential medium (MEM) alone . The numbers of viable parasites were determined microscopically after 10, 20, and 30 min of incubation at 37 C with D-hecate or MEM . Our results show that D-hecate killed all 6 isolates of T . foetus and T . vaginalis evaluated . The killing effect was dependent on the concentration of the peptide, incubation time, and phase of growth of the parasites . Ultrastructural studies of parasites treated with 10 microM of D-hecate revealed extensive damage to the plasma membrane of most T . foetus and T . vaginalis cells, while a few cells were distorted but remained intact . D-Hecate may be a useful chemotherapeutic agent for the treatment of trichomoniasis.

Methods Inf Med, 2000 Dec, 39(4-5), 303 - 10
A data mining system for infection control surveillance; Brossette SE et al.; Nosocomial infections and antimicrobial resistance are problems of enormous magnitude that impact the morbidity and mortality of hospitalized patients as well as their cost of care . The Data Mining Surveillance System (DMSS) uses novel data mining techniques to discover unsuspected, useful patterns of nosocomial infections and antimicrobial resistance from the analysis of hospital laboratory data . This report details a mature version of DMSS as well as an experiment in which DMSS was used to analyze all inpatient culture data, collected over 15 months at the University of Alabama at Birmingham Hospital.

Nahrung, 2000 Dec, 44(6), 407 - 10
Improvement in the yield of lipophilized lysozyme by the combination with Maillard-type glycosylation; Liu S et al.; Hen egg white lysozyme was modified using the Maillard-type glycosylation method prior to the lipophilization with palmitic acid . The yield of lipophilized lysozyme significantly increased by the pre-glycosylation of the protein . The lipophilized lysozyme derivative was separated into two main fractions with different level of glycosylation . All fractions showed a strong antimicrobial activity against Gram-negative bacteria, Escherichia coli . The lipophilization of the lysozyme combined with glycosylation is a promising method for potential industrial applications of the lysozyme due to the enhanced antimicrobial activity and the improved yield.

Arzneimittelforschung, 2000 Dec, 50(12), 1115 - 9
New thiazolo{4,5-d}pyrimidine derivatives as potential antimicrobial agents; Urgun H et al.; In this study, by starting from ethyl 4-amino-2,3-dihydro-3-phenyl-2-thioxothiazole-5-carboxylate (1), three compounds having 2,3-dihydro-3-phenyl-5-mercapto-6-alkyl/phenyl-2-thioxothiazolo{4,5- d}pyrimidin-7(6H)-one (2a-c) structure and their 5-(4'-nonsubstituted/-substituted benzoylmethyl)thio derivatives (3a-l) were synthesized . The antimicrobial activities of the synthesized compounds were investigated against some bacteria and fungi using the microdilution method . 2,3-Dihydro-3,6-diphenyl-5-(4'-bromobenzoylmethyl)thio-2-thioxothiazolo {4,5-d}pyrimidin-7(6H) one (3k) possessing remarkable activity against Gram-positive bacteria and yeast like fungi was found to be the most active compound in this series.

Zentralbl Chir, 2000, 125 Suppl 2, 196 - 8
{Value of non-randomized prospective multicenter studies of perioperative antibiotic prophylaxis}; Hell K; Non-randomized prospective multicenter studies involving a large number of patients are often capable to prove effectiveness of perioperative antimicrobial prophylaxis in situations where it is not feasible to carry out highly sophisticated clinical trials due to limitations in logistical or financial resources . Furthermore, these studies tend to give a true picture of the daily work and procedures in hospitals, contrary to controlled trials in clinical research which might suffer of multitudes of restrictions and exclusions . Some non-randomized studies each involving more than 1,000 patients on antibiotic prophylaxis in colonic and biliary surgery as well as appendectomy are discussed and its usefulness demonstrated.

Med Clin North Am, 2001 Jan, 85(1), 79 - 114
Nosocomial pneumonia . Diagnostic and therapeutic considerations; Cunha BA; Many patients with presumed nosocomial pneumonia probably have infiltrates on the chest radiograph, fever, and leukocytosis resulting from noninfectious causes . Because of the high mortality and morbidity associated with nosocomial pneumonias, however, most clinicians treat such patients with a 2-week empiric trial of antibiotics . Before therapy is initiated, the clinician should rule out other causes of pulmonary infiltrates, fever, and leukocytosis that mimic a nosocomial pneumonia (e.g., pre-existing interstitial lung disease, primary or metastatic lung carcinomas, pulmonary emboli, pulmonary drug reactions, pulmonary hemorrhage, collagen vascular disease affecting the lungs, or congestive heart failure) . If these disorders can be eliminated from diagnostic consideration, a 2-week trial of empiric monotherapy is indicated . The clinician should treat cases of presumed nosocomial pneumonia as if P . aeruginosa were the pathogen . Although P . aeruginosa is not the most common cause of nosocomial pneumonia, it is the most virulent pulmonary pathogen associated with nosocomial pneumonia . Coverage directed against P . aeruginosa is effective against all other aerobic gram-negative bacillary pathogens causing hospital-acquired pneumonia . The clinician should select an antibiotic for empiric monotherapy that is highly effective against P . aeruginosa, has a good side-effect profile, has a low resistance potential, and is relatively inexpensive in terms of its cost to the institution . The preferred agents for empiric monotherapy for nosocomial pneumonia are cefepime, meropenem, and piperacillin . Single organisms are responsible for nosocomial pneumonia, not multiple pathogens . S . aureus rarely, if ever, causes nosocomial pneumonia but is mentioned frequently in studies based on cultures of respiratory tract secretions . S . aureus, unless accompanied by a necrotizing pneumonia with rapid cavitation within 72 hours, in the sputum indicates colonization rather than infection and should not be addressed therapeutically . Antibiotics associated with a high resistance potential should not be used as monotherapy or included in combination therapy regimens (i.e., ceftazidime, ciprofloxacin, imipenem, or gentamicin) . Combination therapy is more expensive than monotherapy and is indicated only when P . aeruginosa is extremely likely, based on its characteristic clinical presentation, or is proved by tissue biopsy . Therapy should not be based on respiratory secretion cultures regardless of technique . Optimal combination regimens include cefepime or meropenem plus levofloxacin or piperacillin or aztreonam or amikacin . Nosocomial pneumonias usually are treated for 14 days . Lack of radiographic or clinical response to appropriate empiric nosocomial pneumonia monotherapy after 14 days suggests an alternate diagnosis . In these patients, a tissue biopsy specimen should be obtained to determine the cause of the persistence of pulmonary infiltrates unresponsive to appropriate antimicrobial therapy.

Med Clin North Am, 2001 Jan, 85(1), 43 - 77
Community-acquired pneumonia . Diagnostic and therapeutic approach; Cunha BA; Optimal empiric therapy of CAP is with appropriate monotherapy (e.g., doxycycline, levofloxacin) . Combination therapy is problematic because of potential side effects and high cost . Empiric coverage should have a high degree of activity against both typical and atypical pathogens . The antibiotic selected should have an excellent side-effect profile and be relatively inexpensive . Clinicians should be selective in their choice of antibiotic for CAP and choose an antimicrobial that has little or no resistance potential, is relatively inexpensive, and permits i.v.-to-PO switch monotherapy.

Med Clin North Am, 2001 Jan, 85(1), 149 - 85
Antibiotic side effects; Cunha BA; Antibiotic side effects are approached best from an individual agent perspective rather than from a class-related standpoint . As this article indicates, with the exception of drug fevers and drug rashes, most antibiotic side effects are related to individual agents and not class side effects . Clinicians should view antimicrobial side effects as related to each organ system and be aware that more often a nonmicrobial medication is the explanation for the drug side effect rather than the antimicrobial . Nonantimicrobial medications are the most common cause of drug fever; among antimicrobials, beta-lactams and sulfonamides are the most common causes of drug-induced fevers . Antimicrobial side effects have important implications for the patient, legal and economic implications for the hospital, and medicolegal implications for the physician . Antibiotic side effects that prolong hospitalization in today's managed care environment have important economic implications . Clinicians should be familiar with the most common side effects of the most frequently used antimicrobials, to minimize the potential of having adverse reactions occur in patients . Most adverse events related to antimicrobials are reversible rapidly on cessation of the medication . Irreversible toxicities include aminoglycoside-induced ototoxicity, Stevens-Johnson syndrome, and toxicity secondary to nitrofurantoin . The most common acute fatal drug reactions include hypersensitivity reactions resulting in anaphylaxis or the Stevens-Johnson syndrome and fatal hepatic necrosis secondary to trovafloxacin . Clinicians should eliminate the use of drugs associated with chronic or fatal toxicities because multiple therapeutic alternatives exist for virtually every potential infection.

Med Clin North Am, 2001 Jan, 85(1), 133 - 47, vii
Antimicrobial therapy in the elderly; Rajagopalan S et al.; This article focuses on the special characteristics of infection in the elderly and provides an update of the principles of antibiotic selection, use of specific antibiotics, and empiric use of antimicrobials in the treatment of infectious diseases in this particularly vulnerable group . Antituberculous, antifungal, and antiviral agents are mentioned briefly; detailed information regarding these classes of agents in reference to aging can be found in standard reviews of antimicrobial therapy in the elderly.

Med Clin North Am, 2001 Jan, 85(1), 125 - 32
New uses of older antibiotics; Klein NC et al.; Despite the development of extended-spectrum penicillins, cephalosporins, and quinolones, the older antimicrobial agents, doxycycline, minocycline, TMP-SMX, clindamycin, and metronidazole, still play an important role in the treatment of infectious diseases . All of these older drugs are well absorbed by the oral route, attaining serum levels equivalent to those achieved by parenteral administration . The availability of generic forms of the older drugs reduces their cost . Besides traditional uses, some older drugs have become the preferred therapy for newly recognized infectious diseases . Doxycycline is the preferred drug for rickettsial tickborne diseases, ehrlichiosis and early Lyme disease . TMP-SMX is the preferred drug for I . belli and Cyclospora . Minocycline has been used to treat MRSA and MRSE infections . Clindamycin or metronidazole combined with a quinolone is an excellent oral regimen for polymicrobial infections . {table: see text}

Med Clin North Am, 2001 Jan, 85(1), 115 - 23, vii
Oral antibiotic treatment of infectious diseases; Sensakovic JW et al.; The use of antimicrobial agents (i.e., penicillins, cephalosporins, macrolides, aminoglycosides, tetracyclines, quinolones) have continued to grow at an astounding rate . Centers for Disease Control and Prevention estimates are of some 150 million prescriptions annually in the United States, amounting to some 50 millions pounds of antibiotics annually being used in the United States with some 15 to 17 million pounds being used in livestock and agriculture alone . These large numbers serve as indicators for caution and concern . Most oral antibiotics are prescribed for respiratory tract infections, more than half of which are probably viral, for which antimicrobials are not necessary . This overprescribing is noted at a time when increasing antimicrobial resistance is being recognized in hospital settings as well as in the community . The dilemma for the practitioner is to be able to use antibiotics efficaciously and prevent overusage and overprescribing.

Gastroenterol Clin North Am, 2000 Dec, 29(4), 895 - 902
Accurate diagnosis of Helicobacter pylori . 14C-urea breath test; Chey WD; The 14C-urea breath test is an accurate means of identifying the presence of H . pylori infection before and after antimicrobial therapy . Several issues, including out of office analysis, the need for a support structure to perform the test, concerns regarding radiation exposure, and inconsistent reimbursement, have slowed the widespread acceptance of the 14C-urea breath test in clinical practice . Despite these problems, the 14C-urea breath test is simple, rapid, and relatively inexpensive compared with the currently available version of the 13C-urea breath test . As such, the 14C-urea breath test provides an attractive, nonendoscopic means of identifying active H . pylori infection.

Gastroenterol Clin North Am, 2000 Dec, 29(4), 759 - 73, vii
How to treat Helicobacter pylori . First-line, second-line, and future therapies; Megraud F et al.; Numerous trials were performed in the 1990s to define the optimal therapy for Helicobacter pylori infections . The proposed proton-pump inhibitor (PPI)-based and ranitidine bismuth citrate (RBC)-based triple therapies led to satisfactory results . Their first drawback is cost, and, for this reason, many people worldwide cannot benefit from these regimens . Failures of first-line therapies essentially are because of antimicrobial resistance, which increases with the selection pressure resulting from the use of these drugs . Second-line treatments using antimicrobial agents for which H . pylori resistance is low or nonexistent are being tested to find alternatives to the quadruple therapy . There is a need for new drugs, which should be highly effective, nonselective of resistant strains, and without side effects, to improve current regimens . These drugs may be the results of postgenomic studies.

Cornea, 2001 Jan, 20(1), 112 - 6
Corneal co-infection with Scedosporium apiospermum and Acanthamoeba after sewage-contaminated ocular injury; Rumelt S et al.; PURPOSE: To describe a corneal co-infection with the fungus Scedosporium apiospermum and Acanthamoeba that result in spontaneous corneal perforation . METHODS: A 27-year-old man presented due to severe ocular pain in his left eye caused by a corneal ulcer . The patient was injured 7 days before presentation by metallic thread contaminated by sewage . Corneal scrapping and deep stromal biopsy were obtained and stained for microscopic evaluation with periodic acid-Schiff, Giemsa, and Gomori's methenamine silver stains . Samples were sent for aerobic and anaerobic bacterial and fungal cultures . RESULTS: Corneal biopsy and corneal scrapping showed viable Acanthamoeba cysts in the corneal stroma and S . apiospermum micelle, respectively . The fungal culture was sensitive to ketoconazole, miconazole, econasole, and traconazole . Devastating corneal perforation occurred despite aggressive antifungal and antiamoebic topical and systemic treatment initiated after diagnosis . The corneal button showed a necrotic tissue devoid of inflammatory cells and microorganisms . CONCLUSION: S . apiospermum and Acanthamoeba may co-infect immune privilege sites, such as the cornea, in immunocompetent hosts . Compromised corneal surface, e.g., after trauma by sewage-contaminated objects, may increase the susceptibility for such devastating coinfection . Prevention may be possible by use of protective eyewear by high-risk individuals . Treatment should be initiated promptly with broad-spectrum antimicrobial agents after ocular injury by sewage-contaminated objects . Repeated corneal cultures and biopsies, if the cultures are negative, are warranted . Corticosteroids should be withheld until the causative agents are identified and targeted treatment is initiated.

Am J Manag Care, 2000 Dec, 6(23 Suppl), S1202 - 10
Antibiotic kinetic and dynamic attributes for community-acquired respiratory tract infections; Nicolau DP; Factors, including the age of the treatment population, this population's multiple comorbidities, the greater severity of their illness, and the considerable change in the pathogens in their epidemiology and resistance patterns, affect the management of community-acquired respiratory tract infections in the outpatient setting . Moreover, outcome is affected by the host, etiologic agent, and the selection of the antimicrobial treatment . The challenge of selecting appropriate antimicrobial therapy is often at the discretion of the prescriber . The nature of respiratory tract infections and the relationship of antimicrobial therapy to the resolution of infection are described.

Am J Manag Care, 2000 Dec, 6(23 Suppl), S1178 - 88
Clinical choices of antibiotics: judging judicious use; Steinberg I; Scientific literature widely documents the current overuse of antibiotics but often does not address the issue of the judicious use of antibiotics . Multiple analyses of prescribing patterns consistently reveal inappropriate prescribing of antibiotics, even when the clinician is aware of appropriate antibiotic use . In addition to overprescribing antibiotics, providers frequently address therapy failures by switching to same-class antibiotic agents . Additional investigations report that prescribing of antibiotics at the first office visit tends to increase, rather than decrease, costs and has marginal impact on patient outcomes . Patient education interventions, delivered prior to illness, can significantly reduce inappropriate use of antibiotics and reverse resistance trends . A variety of developments in antimicrobial use and resistance and newer antibiotic and respiratory infection management strategies are discussed.

J Pharm Pharmacol, 2000 Nov, 52(11), 1355 - 9
Determination of the salivary retention of hexetidine in-vivo by high-performance liquid chromatography; McCoy CP et al.; The non-antibiotic antimicrobial agent hexetidine is widely used at a concentration of 0.1% w/v as an oral rinse to reduce the number of viable microorganisms within the oral cavity . However, following use, the available concentration of hexetidine in the oral cavity declines with time, thus compromising the resultant antimicrobial activity . It is, therefore, desirable to determine the persistence of the agent in the oral cavity by quantification of the drug concentration in saliva, thus enabling prediction of its antimicrobial activity in the oral environment . A rapid reverse-phase HPLC method was therefore developed and validated for hexetidine in aqueous solution (Oraldene) and in saliva samples collected from volunteers post-rinsing with 15 mL of hexetidine oral rinse for 30s . The HPLC assay was sufficiently sensitive to accurately detect hexetidine in saliva up to 25 min after in-vivo use of a commercial oral rinse . Furthermore, it was possible to detect hexetidine below the published minimum inhibitory concentrations (MICs) for a selection of microorganisms . From these data a first-order elimination rate constant of hexetidine from the oral cavity was determined post-rinsing in each of six volunteers . The validated HPLC assay method presented is useful for the assay of hexetidine in the oral cavity both at and below MICs . The first-order elimination rate constant shows significant variation between volunteers.

Int J Hematol, 2000 Oct, 72(3), 358 - 61
Necrotizing enterocolitis: experience of 27 cases from a single Korean institution; Choi JH et al.; Necrotizing enterocolitis (NEC) can involve any site in the gastrointestinal tract and is a fatal complication of immunosuppression . To characterize NEC, clinical and radiological characteristics were analyzed . A total of 27 cases of NEC were identified from January 1993 to August 1998, and medical records were reviewed . NEC was diagnosed by clinical and radiological criteria, and other mimicking conditions were excluded . Of the NEC cases, 22 (81.5%) occurred in patients with underlying hematologic malignancy . All patients complained of abdominal pain and fever at the time of inclusion . Escherichia coli was the most common pathogen identified . The most common finding by computed tomography was single-layered diffuse bowel wall thickening with variable density . Other findings were ascites, fascial thickening, pneumatosis, and mesenteric lymphadenopathy . Of the patients, 25 were treated with antimicrobials with or without recombinant hematopoietic growth factors, and 2 were treated with surgery because of perforation and profound bleeding . Among the 12 patients who died, NEC was the direct cause of death in 7 patients . In conclusion, computed tomography is an effective tool for early diagnosis of NEC . Bowel rest, broad-spectrum antimicrobials, and recombinant hematopoietic growth factors are important aspects of treatment . Surgery should be reserved for complicated cases.

Phytomedicine, 2000 Jun, 7(3), 239 - 43
Allylsulfide constituents of garlic volatile oil as antimicrobial agents; Avato P et al.; Six different mixtures of garlic distilled oils containing diallyl disulfide (DDS) and diallyl trisulfide (DTS), ranging from 1 to 51% and 88 to 38% respectively, have been assayed against a number of yeasts (C . albicans, C . tropicalis and B . capitatus), gram-positive bacteria (S . aureus and B . subtilis) and gram-negative bacteria (P . aeruginosa and E . coli) . Results obtained support a specific antifungal more than an antibacterial activity and implicate DDS as the active constituent . Incubation of garlic extracts made up of 1% DDS and 88% DTS resulted, in fact, in the absence of growth inhibition against all the tested microorganisms, whereas garlic oils with higher quantities of DDS showed significant inhibitory activity, increasing with the increase of DDS amount.

Can J Gastroenterol, 2000 Sep, 14(8), 676 - 80
Appropriateness of omeprazole prescribing in Quebec's senior population; Gregoire JP et al.; BACKGROUND: Prescribing omeprazole for the treatment of digestive disorders accounts for an important part of the costs in Quebec's drug benefit plan . In July 1993, the Quebec drug program listed omeprazole, with restriction, in its formulary . On January 1, 1994, this restriction was lifted; since then, omeprazole has been listed in the regular provincial formulary . OBJECTIVE: To describe the appropriateness of initial omeprazole prescribing in the ambulatory senior population of Quebec in the 27 months after being listed without restriction . SUBJECTS AND METHODS: A retrospective population-based cohort study was performed using prescription and medical services claims databases of the Quebec drug program . Data were extracted for elderly patients who received their first omeprazole prescription between July 1, 1994 and March 31, 1996 . RESULTS: Among the 47,140 first-time users of omeprazole identified, 7516 (15.9%) had had an endoscopy in the previous six months, 2308 (4.9%) were given an antimicrobial agent and omeprazole simultaneously, and 22,730 (48.2%) received omeprazole after prior use of an H2 receptor antagonist (H2RA) or a prokinetic drug . A total of 26,525 (56.3%) first-time users were prescribed omeprazole based on at least one of the three criteria listed above . Among these users, 729 (2.8%) received an H2RA concurrently with omeprazole . Altogether, 25,796 (54.7%) first-time users received omeprazole appropriately . CONCLUSIONS: Although reimbursement for omeprazole prescriptions has not been restricted in Quebec since January 1, 1994, it was prescribed appropriately for elderly patients in the majority of cases studied.

Int J Antimicrob Agents, 2000 Sep, 16(1), 25 - 9
Antimicrobial activities of levofloxacin, clarithromycin, and KRM-1648 against Mycobacterium tuberculosis and Mycobacterium avium complex replicating within Mono Mac 6 human macrophage and A-549 type II alveolar cell lines; Sato K et al.; The antimicrobial activities of levofloxacin, clarithromycin and KRM-1648 against Mycobacterium tuberculosis (MTB) and Mycobacterium avium complex (MAC) residing in Mono Mac 6 human macrophage-like cells (MM6-Mphis) and A-549 human type II alveolar epithelial cells (A-549 cells) were studied . We measured the antimicrobial activity of test drugs in terms of effects on the behaviour of intracellular organisms during a 7-day cultivation of MTB- or MAC-infected cells in the medium containing the drugs at Cmax doses . Microbicidal action of levofloxacin against intracellular MTB within A-549 cells was markedly less than its activity against the same organisms in MM6-Mphis . The same effect was also noted for the action of KRM-1648 against MAC organisms but this did not occur with clarithromycin . The MIC of KRM-1648 for MAC multiplying within A-549 cells was 32 times larger than that for MAC residing in MM6-Mphis . These findings indicate that MTB and MAC organisms replicating in the type II lung epithelial cells resist the action of certain antimycobacterial agents such as quinolones and rifamycin derivatives but not when the organisms are contained in macrophages . It appears that the antimicrobial action of certain drugs against intracellular mycobacteria is differentially manifested depending on the types of host cells, i.e . professional phagocytes (MM6-Mphis) or non-professional phagocytes (A-549cells), in which the organisms are contained.

Adv Ther, 2000 May-Jun, 17(3), 148 - 51
Effect of anti-infective ophthalmic solutions on corneal cells in vitro; Matsumoto S et al.; External ocular infections caused by susceptible strains of bacteria have recently been treated with potent broad-spectrum antimicrobial solutions . This study was conducted to compare the in vitro biologic effects of three anti-infective ophthalmic solutions (Ocuflox, Ciloxan, and Tobramycin) on rabbit corneal epithelial cell cultures . Epithelial cell layers from albino rabbit eyes were isolated and incubated in culture media for 9 days, following which the cultures were rinsed and treated with the anti-infective solutions . Ciloxan and Tobramycin caused extensive ethidium bromide staining of the corneal epithelial cell layer after 5, 10, and 15 minutes, indicating acute cell membrane damage . Ocuflox ophthalmic solution caused less ethidium bromide staining at all evaluated times and, therefore, less cell membrane damage than the comparator solutions.

Thorax, 2001 Feb, 56(2), 121 - 5
Leucocyte response and anti-inflammatory cytokines in community acquired pneumonia; Kolling UK et al.; BACKGROUND: In the host defence of the lung neutrophils (PMN) play a central role . Apart from antimicrobial properties, recent data indicate that PMN also exert anti-inflammatory effects by stimulation and release of cytokine antagonists such as interleukin-1 receptor antagonist (IL-1ra) . METHODS: Cytokine release from lipopolysaccharide stimulated whole blood was studied in 18 patients with community acquired pneumonia (CAP) and severe co-morbidities at admission and after 24 hours . Release of IL-1ra, interleukin-1beta (IL-1beta), tumour necrosis factor alpha (TNFalpha), soluble TNF receptor type I (sTNF-RI), and IL-8 was determined by ELISA . RESULTS: The mean (SD) leucocyte level at admission was 12.5 (4.1)/nl . There was a significant correlation between the release of anti-inflammatory cytokines such as IL-1ra and sTNF-RI and the leucocyte count at admission and after 24 hours . Additional in vitro experiments showed that co-incubation of peripheral blood mononuclear cells with autologous PMN led to a marked dose dependent increase in IL-1ra and sTNF-RI release . CONCLUSION: These results indicate that PMN may be responsible for the increase in anti-inflammatory cytokines in CAP . Strategies to increase neutrophil counts may exert beneficial effects, not only by augmenting the antimicrobial activity but also by modulating the inflammatory cytokine response.

Thorax, 2001 Feb, 56(2), 115 - 20
Role of bronchoalveolar lavage in immunocompromised patients with pneumonia treated with a broad spectrum antibiotic and antifungal regimen; Hohenadel IA et al.; BACKGROUND: In a retrospective study the value of bronchoalveolar lavage (BAL) in the diagnosis of pneumonia was investigated in 95 immunocompromised patients suffering from haematological disorders and receiving a regimen of broad spectrum antibiotics and antifungal agents (BSAR) . METHODS: With the exception of four afebrile patients, all had fever, raised C reactive protein (CRP) levels, and new infiltrates visible on chest radiography . All patients underwent BAL to identify the organism causing the pneumonia and surveillance cultures were performed regularly for pathogens at different sites . Following classification of the isolates, patients with positive cultures were subdivided into two groups, pathogenic or contaminated . We investigated whether relevant pathogens were cultured only from the BAL fluid and whether they were susceptible to BSAR . RESULTS: Although 77 of the 95 patients were thrombocytopenic, bleeding during BAL occurred in only 15% of all patients . Ten days after the procedure the fever improved in 88% of patients, radiographic findings improved in 71%, and CRP levels improved in 75% of patients; 22% of patients died within 28 days . Pathologically relevant isolates were found in 65% of all patients . Respiratory pathogens were detected only in the BAL fluid of 29 of the 95 patients (35% Gram positive species, 40% Gram negative species, 11% Mycobacterium, 11% fungi, and 3% cytomegalovirus) . In 16 of these 29 patients (55%) the pathogens cultured only from the BAL fluid were resistant to treatment . Pathogens detected only in the BAL fluid were not susceptible to a standard broad spectrum antibiotic and antifungal regimen including teicoplanin, ceftriaxon, tobramycin, and amphotericin B in 12 of the 29 patients (41%) . CONCLUSIONS: Our data suggest that 12 patients were treated with broad spectrum antimicrobial agents which were not directed at the appropriate organism on in vitro sensitivity tests without BAL . BAL is a relatively safe procedure in the diagnosis of pneumonia, supplying important information in immunocompromised patients as well as in immunocompromised patients receiving BSAR.

Am J Physiol Cell Physiol, 2001 Feb, 280(2), C296 - 302
Cryptdin-3 induces novel apical conductance(s) in Cl- secretory, including cystic fibrosis, epithelia; Merlin D et al.; Opening of anion-conductive pathways in apical membranes of secretory cells lining mucosal surfaces is a critical step in salt and water secretion and, thus, hydration of sites including airway and intestine . In intestine, Paneth cells are positioned at the base of the secretory gland (crypt) and release defensin peptide, in mice termed cryptdins, into the crypt lumen . Because at least some defensins have been shown to form anion-conductive channels in phospholipid bilayers, we tested whether these endogenous antimicrobial peptides could act as soluble inducers of channel-like activity when applied to apical membranes . To directly evaluate the possibility of cryptdin-3-mediated apical anion conductance (G(ap)), we have utilized amphotericin B to selectively permeabilize basolateral membranes of electrically tight monolayers of polarized human intestinal secretory epithelia (T84 cells), thus isolating the apical membrane for study . Cryptdin-3 induces G(ap) that is voltage independent (deltaG(ap) = 1.90 +/- 0.60 mS/cm2) and exhibits ion selectivity contrasting to that elicited by forskolin or thapsigargin (for cryptdin-3, Cl- = gluconate; for forskolin and thapsigargin, Cl- >> gluconate) . We cannot exclude the possibility that the macroscopic current induced by cryptdin could be the sum of cation and Cl- currents . Cryptdin-3 induces a current in basolaterally permeabilized epithelial monolayers derived from airway cells harboring the deltaF508 mutation of cystic fibrosis (CF; deltaG(ap) = 0.80 +/- 0.06 mS/cm2), demonstrating that cryptdin-3 restores anion secretion in CF cells; this occurs independently of the CF transmembrane conductance regulator channel . These results support the idea that cryptdin-3 may associate with apical membranes of Cl--secreting epithelia and self-assemble into conducting channels capable of mediating a physiological response.

J Am Geriatr Soc, 2001 Jan, 49(1), 85 - 90
Interventions to prevent pneumonia among older adults; Yamaya M et al.; Pneumonia is a common cause of death in older people . Antimicrobial drugs do not prevent pneumonia and, because of increasingly resistant organisms, their value in curing infection will become more limited . Establishing new strategies to prevent pneumonia through consideration of the mechanisms of this devastating illness is essential . The purpose of this review is to discuss how pneumonia develops in older people and to suggest preventive strategies that may reduce the incidence of pneumonia among older adults . Aspiration of oropharyngeal bacterial pathogens to the lower respiratory tract is one of the most important risk factors for pneumonia; impairments in swallowing and cough reflexes among older adults, e.g., related to cerebrovascular disease, increase the risk for the development of pneumonia . Thus, strategies to reduce the volumes and pathogenicity of aspirated material should be pursued . For example, since both swallowing and cough reflexes are mediated by endogenous substance P, pharmacologic therapy using angiotensin-converting enzyme inhibitors, which decrease substance P catabolism, may improve both reflexes and result in the lowering of the risk of pneumonia . Similarly, since the production of substance P is regulated by dopaminergic neurons in the cerebral basal ganglia, treatment with dopamine analogs or potentiating drugs such as amantadine (and, of course, prevention of cerebral vascular disease, which can result in basal ganglia strokes) should affect the incidence of pneumonia . The purpose of this review is to consider promising pharmacologic treatments as methods of preventing pneumonia in older adults and to review other proven strategies, e.g., infection control and cerebrovascular disease prevention that will lessen the incidence of pneumonia.

Cell Microbiol, 2001 Feb, 3(2), 115 - 23
Helicobacter pylori-mediated transcriptional regulation of the human beta-defensin 2 gene requires NF-kappaB; Wada A et al.; Human beta-defensin 2 (hBD-2) is an antimicrobial peptide involved in host defence against bacterial infection in epithelial tissues . Its levels are dramatically increased after bacterial infection . The involvement of NF-kappaB in Helicobacter pylori-mediated induction of hBD-2 promoter activity was examined . A luciferase reporter plasmid containing the hBD-2 promoter extending from -2110 base pairs to -1 was transiently expressed in MKN45 cells, and promoter activity was determined after incubation with H . pylori for 6 h . Deletion or mutation of the NF-kappaB site at -208 abolished activation of the hBD-2 promoter . Only H . pylori strains carrying a cag pathogenicity island (PAI) induced activation of the NF-kappaB site of the hBD-2 promoter gene . By gel retardation analyses, H . pylori increased NF-kappaB binding to hBD-2 promoter gene sequences . Supershift analysis demonstrated that whereas H . pylori activated NF-kappaB p65-p65 and p50-p50 homodimers, and the p65-p50 heterodimer of NF-kappaB, only the p65-p65 homodimer bound to the NF-kappaB site of the hBD-2 promoter . Thus, specific NF-kappaB proteins are important cis-elements for induction of hBD-2 gene transcription by H . pylori.

Ann Intern Med, 2001 Feb 20, 134(4), 298 - 314
Antibiotic resistance in the intensive care unit; Kollef MH et al.; Antimicrobial resistance has emerged as an important determinant of outcome for patients in the intensive care unit (ICU) . This is largely due to the administration of inadequate antimicrobial treatment, which is most often related to bacterial antibiotic resistance . In addition, the escalating problem of antimicrobial resistance has substantially increased overall health care costs . This increase is a result of prolonged hospitalizations and convalescence associated with antibiotic treatment failures, the need to develop new antimicrobial agents, and the implementation of broader infection control and public health interventions aimed at curbing the spread of antibiotic-resistant pathogens . Intensive care units are unique because they house seriously ill patients in confined environments where antibiotic use is extremely common . They have been focal points for the emergence and spread of antibiotic-resistant pathogens . Effective strategies for the prevention of antimicrobial resistance in ICUs have focused on limiting the unnecessary use of antibiotics and increasing compliance with infection control practices . Clinicians caring for critically ill patients should consider antimicrobial resistance as part of their routine treatment plans . Careful, focused attention to this problem at the local ICU level, using a multidisciplinary approach, will have the greatest likelihood of limiting the development and dissemination of antibiotic-resistant infections.

Chem Biol, 2001 Jan, 8(1), 17 - 31
Energetic, structural, and antimicrobial analyses of beta-lactam side chain recognition by beta-lactamases; Caselli E et al.; BACKGROUND: Penicillins and cephalosporins are among the most widely used and successful antibiotics . The emergence of resistance to these beta-lactams, most often through bacterial expression of beta-lactamases, threatens public health . To understand how beta-lactamases recognize their substrates, it would be helpful to know their binding energies . Unfortunately, these have been difficult to measure because beta-lactams form covalent adducts with beta-lactamases . This has complicated functional analyses and inhibitor design . RESULTS: To investigate the contribution to interaction energy of the key amide (R1) side chain of beta-lactam antibiotics, eight acylglycineboronic acids that bear the side chains of characteristic penicillins and cephalosporins, as well as four other analogs, were synthesized . These transition-state analogs form reversible adducts with serine beta-lactamases . Therefore, binding energies can be calculated directly from K(i) values . The K(i) values measured span four orders of magnitude against the Group I beta-lactamase AmpC and three orders of magnitude against the Group II beta-lactamase TEM-1 . The acylglycineboronic acids have K(i) values as low as 20 nM against AmpC and as low as 390 nM against TEM-1 . The inhibitors showed little activity against serine proteases, such as chymotrypsin . R1 side chains characteristic of beta-lactam inhibitors did not have better affinity for AmpC than did side chains characteristic of beta-lactam substrates . Two of the inhibitors reversed the resistance of pathogenic bacteria to beta-lactams in cell culture . Structures of two inhibitors in their complexes with AmpC were determined by X-ray crystallography to 1.90 A and 1.75 A resolution; these structures suggest interactions that are important to the affinity of the inhibitors . CONCLUSIONS: Acylglycineboronic acids allow us to begin to dissect interaction energies between beta-lactam side chains and beta-lactamases . Surprisingly, there is little correlation between the affinity contributed by R1 side chains and their occurrence in beta-lactam inhibitors or beta-lactam substrates of serine beta-lactamases . Nevertheless, presented in acylglycineboronic acids, these side chains can lead to inhibitors with high affinities and specificities . The structures of their complexes with AmpC give a molecular context to their affinities and may guide the design of anti-resistance compounds in this series.

Thorax, 2001 Mar, 56(3), 223 - 7
Similarities and differences in lectin cytochemistry of laryngeal and tracheal epithelium and subepithelial seromucous glands in cases of sudden infant death and controls; Paulsen FP et al.; BACKGROUND: It has been speculated that non-specific defence mechanisms of the epithelium and subepithelial seromucous glands play a role in the larynx and lungs in cases of sudden infant death . METHODS: The larynx and trachea from five children who had died of sudden infant death (SID) syndrome and five control cases of comparable age were compared for the presence of lectin binding sites (12 different lectins tested) . RESULTS: The secretory product of mucin producing cells contained carbohydrates including galactose and sialic acids . Binding sites for fucose and N-acetyl-galactosamine were only present in some of the specimens and distribution revealed no correlation between cases of SID and controls . Epithelial cells and serous cells of seromucous glands contained binding sites for sialic acid in cases of SID and controls . Moreover, binding sites for mannose were detected in these cells but were only present in SID cases . The difference between the SID and control groups as to the presence/expression of concanavalin A was highly significant . CONCLUSIONS: It is suggested that mucus hypersecretion in SID occurs in response to bacterial toxins or viral infection and is not specific . The different binding sites for mannose in cases of SID and controls could indicate differences in the production of antimicrobial peptides . A disturbed expression pattern of antimicrobial peptides in children who later succumb to SID could be responsible for an imbalance of the local microflora with a higher density of microorganisms on the mucosa . Further studies are required to elucidate the pattern of expression of antimicrobial peptides in subsequent SID victims.

Hum Mol Genet, 2001 Mar 1, 10(5), 445 - 56
Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes; Lawrance IC et al.; To elucidate the biological dysregulation underlying two forms of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), we examined global gene expression profiles of inflamed colonic tissue using DNA microarrays . Our results identified several genes with altered expression not previously linked to IBD . In addition to the expected upregulation of various cytokine and chemokine genes, novel immune function-related genes such as IGHG3, IGLL2 and CD74, inflammation-related lipocalins HNL and NGAL, and proliferation-related GRO genes were over-expressed in UC . Certain cancer-related genes such as DD96, DRAL and MXI1 were differentially expressed only in UC . Other genes over-expressed in both UC and CD included the REG gene family and the calcium-binding S100 protein genes S100A9 and S100P . The natural antimicrobial defensin DEFA5 and DEFA6 genes were particularly over-expressed in CD . Overall, significant differences in the expression profiles of 170 genes identified UC and CD as distinct molecular entities . The genomic map locations of the dysregulated genes may identify novel candidates for UC and CD genetic susceptibility.

Antimicrob Agents Chemother, 2001 Mar, 45(3), 786 - 8
Antimicrobial susceptibility of Ehrlichia phagocytophila; Horowitz HW et al.; Human granulocytic ehrlichiosis is a recently described disease caused by an obligate intracellular gram-negative organism recently named Ehrlichia phagocytophila . To expand our knowledge of the susceptibility of E . phagocytophila, we tested six New York State isolates for susceptibility to 12 antimicrobials using an HL-60 cell culture system . All of the isolates were susceptible to doxycycline (MIC, < or =0.125 microg/ml; minimum bactericidal concentration {MBC}, 0.125 to 0.5 microg/ml), rifampin (MIC, < or =0.125 microg/ml; MBC, < or =0.125 microg/ml), ofloxacin (MIC, < or =2 microg/ml; MBC, < or =2 microg/ml), levofloxacin (MIC, < or =1 microg/ml; MBC, < or =1 microg/ml), and trovafloxacin (MIC, < or =0.032 microg/ml; MBC, < or =0.032 microg/ml) . Isolates were uniformly resistant to amoxicillin, ceftriaxone, erythromycin, azithromycin, clarithromycin, and amikacin . For one strain, the MBC of chloramphenicol was < or =8 microg/ml . These data suggest that quinolone antibiotics and rifampin may be alternative agents for patients with intolerance to tetracyclines.

Antimicrob Agents Chemother, 2001 Mar, 45(3), 768 - 75
Novel scintillation proximity assay for measuring membrane-associated steps of peptidoglycan biosynthesis in Escherichia coli; Chandrakala B et al.; We have developed a novel, high-throughput scintillation proximity assay to measure the membrane-associated steps (stages 2 and 3) of peptidoglycan synthesis in Escherichia coli . At least five enzymes are involved in these two stages, all of which are thought to be essential for the survival of the cell . The individual enzymes are difficult to assay since the substrates are lipidic and difficult to isolate in large quantities and analysis is done by paper chromatography . We have assayed all five enzymes in a single mixture by monitoring synthesis of cross-linked peptidoglycan, which is the final product of the pathway . E . coli membranes are incubated with the two sugar precursors, UDP-N-acetyl muramylpentapeptide and UDP-{(3)H}-N-acetylglucosamine . The radiolabel is incorporated into peptidoglycan, which is captured using wheat germ agglutinin-coated scintillation proximity assay beads . The assay monitors the activity of the translocase (MraY), the transferase (MurG), the lipid pyrophosphorylase, and the transglycosylase and transpeptidase activities of the penicillin-binding proteins . Vancomyin, tunicamycin, nisin, moenomycin, bacitracin, and penicillin inhibit the assay, and these inhibitors have been used to validate the assay . The search for new antimicrobial agents that act via the late stages of peptidoglycan biosynthesis can now be performed in high throughput in a microtiter plate.

Clin Infect Dis, 2001 Feb 15, 32(4), 660 - 1 Epub 2001 Feb 07.
Nocardia asteroides native valve endocarditis; Watson A et al.; A 39-year-old man with a history of injection drug abuse was given a diagnosis of Nocardia asteroides native aortic valve endocarditis, and he required valve replacement therapy, despite having received potent antimicrobial therapy . This is the first reported proven case of native valve endocarditis due to Nocardia species.

Clin Infect Dis, 2001 Feb 15, 32(4), 605 - 11 Epub 2001 Feb 07.
Role of clinical microbiology laboratories in the management and control of infectious diseases and the delivery of health care; Peterson LR et al.; Modern medicine has led to dramatic changes in infectious diseases practice . Vaccination and antibiotic therapy have benefited millions of persons . However, constrained resources now threaten our ability to adequately manage threats of infectious diseases by placing clinical microbiology services and expertise distant from the patient and their infectious diseases physician . Continuing in such a direction threatens quality of laboratory results, timeliness of diagnosis, appropriateness of treatment, effective communication, reduction of health care-associated infections, advances in infectious diseases practice, and training of future practitioners . Microbiology laboratories are the first lines of defense for detection of new antibiotic resistance, outbreaks of foodborne infection, and a possible bioterrorism event . Maintaining high-quality clinical microbiology laboratories on the site of the institution that they serve is the current best approach for managing today's problems of emerging infectious diseases and antimicrobial agent resistance by providing good patient care outcomes that actually save money.

Clin Infect Dis, 2001 Feb 15, 32(4), 546 - 51 Epub 2001 Feb 09.
Low infectious morbidity after intensive chemotherapy and autologous peripheral blood progenitor cell transplantation in the outpatient setting for women with breast cancer; Chandrasekar PH et al.; Autologous peripheral blood progenitor cell (PBPC) transplantation is increasingly employed in the outpatient setting, yet data on early complications following PBPC transplantation are scant . We evaluated 105 women with high-risk primary or metastatic breast cancer who were treated at a single institution during 1996--1997 . The mean duration of neutropenia (absolute neutrophil count, <500 cells/mm(3)) was 7.5 days . Twenty-nine percent of women remained afebrile throughout the neutropenic period . Of the remaining 71%, most (64 of 75) had fever of unknown origin . Infections, mostly of mild severity, occurred in 34% of women; these infections included bacteremia due to gram-positive organisms, catheter site infection, cellulitis, pneumonia, oral candidiasis, herpes simplex virus infection, and vaginitis . Fifty percent of PBPC transplant recipients required hospital admission, usually because of persistent fever; the mean duration of hospitalization was 3 days . No deaths or serious adverse events occurred . Such reduced infectious morbidity may be a consequence of minimal oral and/or gastrointestinal mucositis associated with the conditioning regimen and broad-spectrum antimicrobial prophylaxis used for this patient population.

Toxicol Appl Pharmacol, 2001 Feb 15, 171(1), 20 - 6
Human alveolar macrophage responses to air pollution particulates are associated with insoluble components of coarse material, including particulate endotoxin; Soukup JM et al.; Inhalation of particulate matter in the ambient air has been shown to cause pulmonary morbidity and exacerbate asthma . Alveolar macrophage (AM) are essential for effective removal of inhaled particles and microbes in the lower airways . While some particles minimally effect AM function others inhibit antimicrobial activity or cause cytokine and growth factor production leading to inflammation and tissue remodeling . This study has investigated the effects of water soluble (s) and insoluble (is) components of Chapel Hill, North Carolina ambient particulate matter in the size ranges 0.1-2.5 microm (PM2.5) and 2.5-10 microm (PM10) diameter, on human AM IL-6, TNFalpha, and MCP-1 cytokine production and host defense mechanisms including phagocytosis and oxidant production . Cytokines were found to be induced by isPM10 to a much higher extent (>50-fold) than sPM10, which in turn stimulated production better than isPM2.5, while sPM2.5 was inactive . Previous studies have indicated that endotoxin (ETOX) is a component of sPM10 responsible for cytokine production . Here, it is shown that inhibition of isPM10-induced cytokine production was partially achieved with polymyxin B and LPS-binding protein (LBP), but not with a metal chelator, implicating ETOX as a cytokine-inducing moiety also in isPM10 . In addition to inducing cytokines, exposure to isPM10, but not the other PM fractions, also inhibited phagocytosis and oxidant generation in response to yeast . This inhibition was ETOX independent . The decrease in host defenses may be the result of apoptosis in the AM population, which was also found to be specifically caused by isPM10 . These results show that the functional capacity of AM is selectively modulated by insoluble components of coarse PM, including the biocontaminant ETOX.

Exp Eye Res, 2001 Mar, 72(3), 289 - 99
Ocular pharmacokinetics in rabbits using a novel dual probe microdialysis technique; Macha S et al.; Ocular infections involve delicate internal structures of the eye that often require treatment with antimicrobial agents . A major constraint to the study of ocular drug absorption from systemic administration is the inaccessibility of the vitreous for continuous serial sampling . A novel dual probe microdialysis technique has been employed in our laboratory, which will enable the delineation of complete ocular pharmacokinetics of a drug . New Zealand albino rabbits weighing 2--2.5 kg were used . The animals were kept under anesthesia throughout the experiment . A concentric probe was implanted in the vitreous chamber about 3 mm below the corneal scleral limbus . Simultaneously a linear probe was implanted in the anterior chamber across the cornea . Intraocular pressure (IOP) was measured using Schiotz tonometer . The total protein concentrations in the aqueous and vitreous humors were determined using the Bio-Rad protein assay method . The aqueous and vitreous elimination kinetics of fluorescein were studied after intravitreal and systemic administrations over a period of 10 hr . Microdialysis technique was also compared to the conventional direct sampling technique by determining the intravitreal kinetics of fluorescein . Results suggest that IOP reverted to normal within 2 hr after the implantation of the probes . The increase in the vitreal total protein concentration was not significantly different from the baseline . The increase in the aqueous total protein concentration was less than five times the basal concentration throughout the experiment . The blood-aqueous and blood-retinal barrier integrity was delineated by determining the permeability index for fluorescein and were found to be 9.48 +/- 4.25% and 1.99 +/- 0.66% for the anterior and vitreous chamber, respectively . The rate constant of penetration of fluorescein into the anterior chamber was found to be 8.48 +/- 1.33 x 10(-2) min(-1), which was significantly higher than into the vitreous i.e . 4.34 +/- 2.82 x 10(-2) min(-1) . The terminal elimination rate constant of fluorescein from the anterior chamber (1.48 +/- 0.79 x 10(-2) min(-1)) was found to be similar to that of the plasma terminal elimination rate constant (1.57 +/- 0.25 x 10(-2) min(-1)), but significantly higher than from the vitreous (3.0 +/- 0.7 x 10(-3) min(-1)) . The terminal vitreal elimination rate constant of fluorescein after intravitreal administration was found to be similar by both microdialysis (3.98 +/- 0.6 x 10(-3) min(-1)) and direct sampling (4.38 +/- 1.4 x 10(-3) min(-1)) techniques . In case of direct sampling technique the area under the vitreous concentration-time curve was higher compared to that obtained by the microdialysis technique . There was no breakdown of the blood ocular barriers as shown by a very small change in the intraocular fluid protein concentrations . This was also confirmed by the fluorescein kinetics, which were in accordance with the previous studies . IOP data suggests that the intraocular fluid dynamics were not affected and the animals stabilized within 2 hr after the implantation of the probes . Fluorescein data suggests that the vitreous compartment is surrounded by a tighter barrier compared to the anterior chamber . This technique appears to be more sensitive, reproducible and requires only one animal for the determination of entire ocular pharmacokinetic profile .

Int J Infect Dis, 2000, 4(3), 140 - 7
Genetic diversity and evidence for acquired antimicrobial resistance in Mycobacterium tuberculosis at a large hospital in South India; Harris KA Jr et al.; OBJECTIVE: To assess genetic diversity and drug resistance of Mycobacterium tuberculosis isolates collected at Christian Medical College Hospital (CMCH), Vellore, India, between July 1995 and May 1996 . MATERIALS AND METHODS: Isolates were subjected to IS6110-based restriction fragment length polymorphism (RFLP) analysis and tested for resistance to isoniazid, rifampin, ethambutol, streptomycin, and pyrazinamide, and DNA from selected strains was sequenced in regions associated with drug resistance . RESULTS: One hundred and one M . tuberculosis isolates were collected from 87 patients with pulmonary tuberculosis . Charts of 69 patients were reviewed for history of tuberculosis illness and treatment . DNA from 29 strains was sequenced in katG, rpoB, and gyrA, and sometimes pncA regions . Analysis by RFLP revealed a high degree of genetic diversity, with no identifiable clusters of infection . Of the strains tested, 51% were resistant to at least one antibiotic, and 43% were resistant to more than one drug . There was a high rate of resistance observed in patients whose charts indicated a history of improperly administered tuberculosis treatment, whereas little drug resistance was observed in patients never previously treated for tuberculosis . Sequencing of genes associated with drug resistance revealed several previously unreported mutations in resistant strains . CONCLUSIONS: This analysis suggests that the cases of tuberculosis in the sample are largely reactivation of long-standing infections and that the drug resistance among patients in CMCH is largely acquired or secondary rather than attributable to the spread of drug-resistant strains.

Infect Immun, 2001 Mar, 69(3), 1402 - 8
Salivary histatin 5 is an inhibitor of both host and bacterial enzymes implicated in periodontal disease; Gusman H et al.; One of the salient features of periodontitis and gingivitis is the increase in the levels of bacterial and host-derived proteolytic enzymes in oral inflammatory exudates . This study evaluated the potential of histatin 5, a 24-residue histidine-rich salivary antimicrobial protein, to inhibit these enzymes . Using biotinylated gelatin as a substrate, histatin 5 was found to inhibit the activity of the host matrix metalloproteinases MMP-2 and MMP-9 with 50% inhibitory concentrations (IC50s) of 0.57 and 0.25 microM, respectively . To localize the domain responsible for this inhibition, three peptides containing different regions of histatin 5 were synthesized and tested as inhibitors of MMP-9 . Peptides comprising residues 1 to 14 and residues 4 to 15 of histatin 5 showed much lower inhibitory activities (IC50, 21.4 and 20.5 microM, respectively), while a peptide comprising residues 9 to 22 showed identical activity to histatin 5 against MMP-9 . These results point to a functional domain localized in the C-terminal part of histatin 5 . To evaluate the effect of histatin 5 on bacterial proteases, a detailed characterization of histatin 5 inhibition of gingipains from Porphyromonas gingivalis was carried out using purified Arg- and Lys-specific enzymes . Kinetic analysis of the inhibition of the Arg-gingipain revealed that histatin 5 is a competitive inhibitor, affecting only the Km with a K(i) of 15 microM . In contrast, inhibition of Lys-gingipain affected both the Km and Vmax, suggesting that both competitive and noncompetitive competitive processes underlie this inhibition . The inhibitory activity of histatin 5 against host and bacterial proteases at physiological concentrations points to a new potential biological function of histatin in the oral cavity.

Expert Opin Investig Drugs, 2001 Feb, 10(2), 321 - 9
Granulysin: a novel antimicrobial; Kumar J et al.; Granulysin is a novel lytic molecule produced by human cytolytic T-lymphocytes (CTLs) and natural killer (NK) cells . It is active against a broad range of microbes, including Gram-positive and -negative bacteria, parasites and Mycobacterium tuberculosis . It is functionally related to other antibacterial peptides, like defensins and magainins, but is structurally distinct . It has structural similarity to porcine NK-lysin and to amoebapores made by Entamoeba histolytica . Synthetic peptides derived from granulysin have differential activity against eukaryotic cells and bacteria . Selective bactericidal peptides may have therapeutic roles as novel antibiotics.

Expert Opin Investig Drugs, 2001 Feb, 10(2), 309 - 20
Antimicrobial properties of porphyrins; Stojiljkovic I et al.; A large number of natural and synthetic porphyrins of diverse chemical compositions and characteristics can be isolated from nature or synthesised in the laboratory . Antimicrobial and antiviral activities of porphyrins are based on their ability to catalyse peroxidase and oxidase reactions, absorb photons and generate reactive oxygen species (ROS) and partition into lipids of bacterial membranes . Light-dependent, photodynamic activity of natural and synthetic porphyrins and pthalocyanines against Gram-positive and Gram-negative bacteria has been well demonstrated . Some non-iron metalloporphyrins (MPs) possess a powerful light-independent antimicrobial activity that is based on the ability of these compounds to increase the sensitivity of bacteria to ROS or directly produce ROS . MPs mimic haem in their molecular structure and are actively accumulated by bacteria via high affinity haem-uptake systems . The same uptake systems can be used to deliver antibiotic-porphyrin and antibacterial peptide-porphyrin conjugates . Haemin, the most well known natural porphyrin, possesses a significant antibacterial activity that is augmented by the presence of physiological concentrations of hydrogen peroxide or a reducing agent . Natural and synthetic porphyrins have relatively low toxicity in vitro and in vivo . The ability for numerous chemical modifications and the large number of different mechanisms by which porphyrins affect microbial and viral pathogens place porphyrins into a group of compounds with an outstanding potential for discovery of novel agents, procedures and materials active against pathogenic microorganisms.

Curr Infect Dis Rep, 2001 Feb, 3(1), 50 - 58
Preparation of the HIV-infected Traveler to the Tropics; Karp CL; Pre-travel advice and planning can help the HIV-infected traveler minimize the unavoidable risks of tropical travel . Issues to cover: the diagnosis, staging, and stabilization of HIV infection and its sequelae; adequacy of the supply of medications currently used; optimal sources of medical care in planned destinations; potential HIV-related legal restrictions on travel; special risks associated with the medical geography of the traveler's route and planned activities; the need to avoid food-, water-, and vector-borne diseases; any appropriate vaccination, chemoprophylaxis, and antimicrobial agents; and arrangement for adequate medical follow-up upon the traveler's return.

Pediatr Infect Dis J, 2001 Jan, 20(1), 98 - 101; discussion 120-2
Historical perspective on the use of otic antimicrobial agents; Myer CM 3rd; Treatment of otorrhea has been described in the literature since 1500 BC . A multitude of therapeutic options have been described, including the use of astringents, antiseptics, alcohol, benzoin and various powders . Since the middle of the 20th century, antibiotic usage has been promoted as the most effective means of therapy . Until recently none of the agents that were used was found to be safe for middle ear use . Since 1990 there have been publications describing the safety and efficacy of fluoroquinolone drops for acute and chronic otorrhea . This article details the transition from treatment of otorrhea with nonspecific means to an era of antimicrobial therapy based on sound scientific evidence.

Pediatr Infect Dis J, 2001 Jan, 20(1), 1 - 5
Compliance issues related to the selection of antibiotic suspensions for children; Steele RW et al.; OBJECTIVE: To evaluate the palatability, cost and other compliance issues as variables in the selection of antibiotic suspensions for children . METHODS: Eighty-six physicians and health care personnel randomly sampled amoxicillin (used as a standard for comparison) and 11 other antibiotics, evaluating them in categories of appearance, smell, texture, taste and aftertaste . Overall scoring was then adjusted for cost, duration of therapy and dosing intervals . RESULTS: Overall taste (palatability) ranking of antibiotics, highest to lowest, was as follows: loracarbef, cefdinir, cefixime, azithromycin, ciprofloxacin, trimethoprim-sulfamethoxazole, clarithromycin, trimethoprim, amoxicillin/clavulanate, cefpodoxime and cefuroxime . Overall rating of antibiotics was greatly influenced by other compliance variables, in order of their impact: cost; duration of therapy (5 vs . 10 days); and dosing intervals . Cost was not judged to be a major factor by most participants unless antibiotic expense was >$50.00 for treatment of otitis media in our hypothetical 2-year-old, 13-kg child . Taking all variables into consideration, final ranking from highest to lowest was azithromycin, cefdinir, loracarbef, cefixime, amoxicillin, trimethoprim-sulfamethoxazole, cefpodoxime, trimethoprim, clarithromycin, ciprofloxacin, cefuroxime and amoxicillin/clavulanate . CONCLUSIONS: Variables related to compliance for families filling antibiotic prescriptions and children taking these products are important in the selection of antimicrobial therapy . Because final assessment is likely to vary considerably among health care personnel, decisions must be made on an individual basis.

Nat Med, 2001 Feb, 7(2), 174 - 9
T-cell release of granulysin contributes to host defense in leprosy; Ochoa MT et al.; A novel mechanism by which T cells contribute to host defense against microbial pathogens is release of the antimicrobial protein granulysin . We investigated the role of granulysin in human infectious disease using leprosy as a model . Granulysin-expressing T cells were detected in cutaneous leprosy lesions at a six-fold greater frequency in patients with the localized tuberculoid as compared with the disseminated lepromatous form of the disease . In contrast, perforin, a cytolytic molecule that colocalizes with granulysin in cytotoxic granules, was expressed at similar levels across the spectrum of disease . Within leprosy lesions, granulysin colocalized in CD4+ T cells and was expressed in CD4+ T-cell lines derived from skin lesions . These CD4+ T-cell lines lysed targets by the granule exocytosis pathway and reduced the viability of mycobacteria in infected targets . Given the broad antimicrobial spectrum of granulysin, these data provide evidence that T-cell release of granulysin contributes to host defense in human infectious disease.

Nat Med, 2001 Feb, 7(2), 167 - 73
Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum; Surolia N et al.; The antimicrobial biocide triclosan {5-chloro-2-(2,4-dichlorophenoxy)phenol} potently inhibits the growth of Plasmodium falciparum in vitro and, in a mouse model, Plasmodium berghei in vivo . Inhibition of {14C}acetate and {14C}malonyl-CoA incorporation into fatty acids in vivo and in vitro, respectively, by triclosan implicate FabI as its target . Here we demonstrate that the enoyl-ACP reductase purified from P . falciparum is triclosan sensitive . Also, we present the evidence for the existence of FabI gene in P . falciparum . We establish the existence of the de novo fatty acid biosynthetic pathway in this parasite, and identify a key enzyme of this pathway for the development of new antimalarials.

Rev Soc Bras Med Trop, 2000 Nov-Dec, 33(6), 609 - 12
{Brain abscess caused by Nocardia sp in immunosuppressed patient}; Barata CH et al.; Patient with autoimmune haemolytic anaemia and thrombocytopenic purpura (Evans Syndrome), treated with immunosuppressive therapy (prednisone and azathioprine) developed brain abscess unresponsive to antimicrobial therapy, in spite of its 23 days duration . Diagnosis could be possible after recover secretion of peribulbar abscess and maintenance of this material over seven days in incubation.

Echocardiography, 1998 Jul, 15(5), 489 - 492
Spontaneous Echo Contrast in Purulent Pericardial Effusion due to Non-Gas-Forming Organisms; Hung MJ et al.; We present the case of a 55-year-old man who developed massive pericardial effusion with tamponade within a 5-day period . During transthoracic two-dimensional echocardiographic examination, spontaneous echo contrast was visualized in pericardial effusion . A diagnosis of polymicrobial pyopericarditis was made when urgent pericardiocentesis revealed a significantly foul odor and purulent fluid that grew a culture of aerobes . After surgical drainage and appropriate antimicrobial therapy, this patient's pyopericarditis resolved . It was suggested that spontaneous echo contrast in pericardial effusion could be induced by non-gas-forming pyogenic cells.

Acta Crystallogr D Biol Crystallogr, 2001 Feb, 57(Pt 2), 306 - 9
Identification of many crystal forms of Aspergillus nidulans dehydroquinate synthase; Nichols CE et al.; Extensive crystallization trials of Aspergillus nidulans dehydroquinate synthase, a potential novel target for antimicrobial drugs, in complexes with different ligands have resulted in the identification of nine crystal forms . Crystals of unliganded DHQS, binary complexes with either the substrate analogue, carbaphosphonate or the cofactor NADH, as well as the ternary DHQS-carbaphosphonate-cofactor complex, were obtained . The ternary complex crystallizes from ammonium sulfate and CoCl(2) in space group P2(1)2(1)2, with unit-cell parameters a = 133.8, b = 86.6, c = 74.9 A . The binary carbaphosphonate complex crystallizes from PEG 6000 in space group P2(1)2(1)2(1), with a = 70.0, b = 64.0, c = 197.6 A, and the binary cofactor complex crystallizes from PEG 3350 and sodium potassium tartrate in space group P2(1), with a = 83.7, b = 70.4, c = 144.3 A, beta = 89.2 degrees . DHQS in the absence of ligands crystallizes in space group P2(1), with a = 41.0, b = 68.9, c = 137.7 A, beta = 94.8 degrees . Each of these crystal forms are suitable for high-resolution structure determination . Structures of a range of DHQS-ligand complexes will be of value in the structure-based design of novel antimicrobial drugs.

Acta Crystallogr D Biol Crystallogr, 2001 Feb, 57(Pt 2), 263 - 5
Crystallization and preliminary crystallographic studies of an antimicrobial protein from Pharbitis nil; Ha SC et al.; An antimicrobial protein from seeds of Pharbitis nil (Pn-AMP) which shows an antifungal activity towards several agriculturally important plant pathogens has been crystallized in the presence of equimolar N-acetylglucosamine with sodium citrate as precipitant . The crystal belongs to the hexagonal space group P6(1)22 (or P6(5)22), with unit-cell parameters a = b = 29.33 (5), c = 133.44 (12) A . Native data were collected using a crystal at 100 K to a resolution of 1.78 A.

Curr Med Chem, 2001 Mar, 8(4), 371 - 84
Adverse reactions to fluoroquinolones . an overview on mechanistic aspects; De Sarro A et al.; This review focuses on the most recent research findings on adverse reactions caused by quinolone antibiotics . Reactions of the gastrointestinal tract, the central nervous system (CNS) and the skin are the most often observed adverse effects . Occasionally major events such as phototoxicity, cardiotoxicity, arthropathy and tendinitis occur, leading to significant tolerability problems . Over the years, several structure-activity and side-effect relationships have been developed, in an effort to improve overall antimicrobial efficacy while reducing undesirable side-effects . In this article we review the toxicity of fluoroquinolones, including the newer derivatives such levofloxacin, sparfloxacin, graepafloxacin and the 7-azabicyclo derivatives, trovafloxacin and moxifloxacin . A special attention is given to new data on mechanistic aspects, particularly those regarding CNS effects . In recent years extensive in vivo and in vitro experiments have been performed in an attempt to explain the neurotoxic effects of quinolones sometimes observed under therapeutic conditions . However, the molecular target or receptor for such effects is still not exactly known . Several mechanisms are thought to be responsible . The involvement of gamma-aminobutyric acid (GABA) and excitatory amino acid (EAA) neurotransmission and the kinetics of quinolones distribution in brain tissue are discussed . In addition, quinolones may interact with other drugs--theophylline and nonsteroidal antiflammatory drugs (NSAID(s))--in producing CNS effects This article provides information about the different mechanisms responsible of quinolones interaction with NSAID(s), methylxanthines, warfarin and antiacids.

Curr Med Chem, 2001 Feb, 8(3), 305 - 16
Excessive matrix metalloproteinase activity in diabetes: inhibition by tetracycline analogues with zinc reactivity; Ryan ME et al.; Diabetes mellitus in rats is characterized by excessive activity of several matrix metalloproteinases (MMPs), notably collagenase(s) and gelatinase(s), in skin, gingiva, and other tissues . A number of tetracyclines (TCs), both antimicrobial compounds as well as chemically modified non-antimicrobial TC analogues (CMTs) are known to possess potent inhibitory activity against these enzymes . Three conventional antimicrobial TCs and six CMTs were used in this study . In vitro, doxycycline was shown to possess higher inhibitory capacity (i.e . lower IC(max)) against diabetic rat skin collagenase than either minocycline or tetracycline HCl . Addition of excess zinc partially reversed the proteinase inhibition by TCs . In vivo, using rats made diabetic with streptozotocin (STZ), oral administration of various TCs led to decreased weight loss and substantial reductions in the activity of both skin collagenase and skin gelatinase (primarily MMP-9, 92 kDa) without affecting blood glucose . Using an in vitro spectrophotometric technique, the Zn(++) reactivity of several CMTs was assessed and found to be positively related to the potency of these compounds as MMP inhibitors . One particular CMT (CMT-5, pyrazole analogue), which is neither antimicrobial nor capable of binding metal cations, did not inhibit the MMPs . TCs have potential utility in management of diabetic complications mediated by excessive activity of MMPs.

Curr Med Chem, 2001 Feb, 8(3), 295 - 303
A combination of subtherapeutic doses of chemically modified doxycycline (CMT-8) and a bisphosphonate (clodronate) inhibits bone loss in the ovariectomized rat: a dynamic histomorphometric and gene expression study; Ramamurthy N et al.; Recent studies have demonstrated that tetracyclines can reduce bone loss in the ovariectomized (OVX) rat model of osteoporosis . In the current study, a non-antimicrobial, chemically modified doxycycline (CMT-8), alone or in combination with a bisphosphonate (Clodronate), was evaluated in this model . Forty-two, 6month old, female rats were randomly assigned to the following groups, (6/ group): a) sham/vehicle, b) OVX/vehicle; c) OVX/1 mg/day CMT-8; d) OVX/2 mg/day CMT-8, e) OVX/1 mg/week Clodronate; and f) OVX/1 mg/day CMT-8 + 1 mg/week Clodronate, CMT-8 was administered by oral gavage, Clodronate injected S/C . Following sham surgery or OVX, the rats were treated for 90 days with CMT-8 or vehicle alone, injected at three different times with fluorochrome labels, the rats were sacrificed, and the tibiae excised for analysis by dynamic bone histomorphometry . Femurs were aseptically removed and analyzed for collagen, collagenase and osteopontin mRNAs by Northern and dot blot analysis . As expected, OVX decreased trabecular bone volume (BV/TV by 73.8% vs . sham p<.01), and also reduced trabecular thickness, numbers, and increased spacing . Bone loss in the OVX animals was partially prevented with either 2 mg/day CMT-8 or 1 mg/wk Clodronate (p<.01), while the 1 mg/day CMT-8 had no effect . Interestingly, the efficacy of the combination therapy of CMT-8 and Clodronate was significantly better than either treatment by itself, maintaining bone mass and structural indices at levels identical to sham values . OVX rats mRNA for collagen, collagenase and osteopontin were elevated indicating high-turnover bone loss . Only COMBO therapy significantly reduced the collagenase and osteopontin mRNA . In summary, CMT-8 mono-therapy (2 mg) alone partially inhibited bone loss in this animal model of osteoporosis . However, 1 mg/day (CMT-8) monotherapy had no effect on bone loss or bone mRNA levels and when combined with Clodronate, interacted to increase efficacy . Thus, a combination of a suboptimal dose of CMT-8 and a bisphosphonate appears to increase the amount of bone by suppressing resorption in a model of osteoporosis.

Curr Med Chem, 2001 Feb, 8(3), 271 - 9
Cytotoxic activity and inhibition of tumor cell invasion by derivatives of a chemically modified tetracycline CMT-3 (COL-3); Lokeshwar BL et al.; Tetracyclines such as chlortetracycline and doxycycline with antimicrobial activity were reported to possess cytostatic and cytotoxic activity against mammalian tumor cells, often at high doses . Non-antimicrobial chemically modified tetracyclines (CMTs), with limited systemic toxicity but with significant tumor cell toxicity and antimetastatic activity, are attractive for long term treatment for cancer . We recently reported one such CMT, 6-deoxy,6-demethyl 4-dedimethylamino tetracycline (CMT-3) is a potent anti-tumor and anti-metastatic drug . Here we report on the anti-cell proliferation and anti-invasive activity of five nitro derivatives of CMT-3 (CMT-3N).All the five CMT-3Ns (CMT-302, CMT-303, CMT-306, CMT-308 and CMT-316) inhibited in vitro cell proliferation of prostate cancer cells . The 50% growth inhibition concentration (IC(50)) of CMT-3Ns was similar to that of CMT-3 . Although CMT-3 was by far the most potent anti-cell proliferation drug, all CMT-3Ns except CMT-303 and CMT-308 had similar anti-cell proliferation activity (IC(50): 2.5 -5.7 microg/ml) . IC(50)s for CMT-303 and CMT-308 were approximately 8.1 and -12.4 microg/ml, respectively . Activity against tumor cell invasion was tested in vitro using the Matrigel invasion assay . All CMT-3Ns had similar anti- invasive activity . While cytotoxic activity of CMT-3 was strongly associated with cell death-effector caspase activation, mitochondrial permeablization and apoptosis, the CMT-3Ns weakly induced apoptosis and did not activate Caspase-3 . However, the CMT-3Ns were able to induce mitochondrial permeabilization . This dichotomous mechanism of cytotoxic activity of CMTs may have significance in their selection for clinical application.

Curr Med Chem, 2001 Feb, 8(3), 257 - 60
CMT-3, a non-antimicrobial tetracycline (TC), inhibits MT1-MMP activity: relevance to cancer; Lee HM et al.; Tetracyclines (TCs) and their non-antimicrobial analogs (CMTs) have therapeutic potential to inhibit tissue destructive disease processes, such as cancer invasion and metastasis, by inhibiting certain matrix metalloproteinases . Enhanced matrix metalloproteinase-2 (MMP-2; gelatinase A) activity has been correlated to cancer invasiveness, and membrane type MMP (MT1-MMP) expressed by tumor cells is involved in localizing and activating pro-MMP-2, a pathway believed to mediate cancer induced tissue breakdown . CMT-3 (6-demethyl, 6-deoxy, 4-dedimethylamino TC) has been shown to experimentally suppress prostate cancer, colon adenocarcinoma and melanoma invasiveness in cell culture and to inhibit tumor growth and metastasis in vivo and was used in the current in vitro study . Confluent MT1-MMP transfected COS-1 cells were harvested, washed thoroughly, subjected to N(2) cavitation and cell membrane enriched fractions were isolated by sequential centrifugations . This MT1-MMP preparation exhibited (i) pro-MMP-2 activating activity as shown by molecular weight shift of this gelatinase from 72 kDa to 62 kDa using gelatin zymography, and (ii) the ability to degrade both {(3)H-methyl} gelatin and casein at 37 degrees C . Adding CMT-3 at final concentrations of 5--20microM inhibited MT1-MMP gelatinolytic and caseinolytic activity, blocked MT1-MMP activation of pro-MMP-2, and decreased invasiveness (using the Matrigel system) of HT-1080 fibrosarcoma cells . The inhibition of MT1-MMP by CMT-3 may partially explain the inhibition of cancer cell -mediated tissue breakdown and invasiveness by this non-antimicrobial tetracycline analog.

Curr Med Chem, 2001 Feb, 8(3), 243 - 52
The lipophilicity, pharmacokinetics, and cellular uptake of different chemically-modified tetracyclines (CMTs); Liu Y et al.; CMTs are analogs of tetracyclines, which are chemically modified to eliminate their antimicrobial efficacy but which retain their inhibitory activity against matrix metalloproteinases . These compounds have been found to inhibit connective tissue breakdown in animal models of diseases such as periodontitis, arthritis and cancer . Because CMTs exhibit different in vivo efficacy in these various models of disease, the current study compared their pharmacokinetics and other properties as follows: Adult male Sprague-Dawley rats were administered by oral gavage a single dose of 5mg of different CMTs suspended in 1 ml 2% carboxymethyl-cellulose, and blood samples were collected from 1-48 hours after dosing . The sera were extracted, then analyzed by HPLC using a C-18 reverse-phase column . The results showed that the peak concentrations (C(max)) in rat sera 1-12 hours after oral administration of CMTs -1, -2,-3, -4,-5,-6,-7,-8 and doxycycline were 5.5, 0.7, 4.6, 6.2, 0.8, 0.7, 9.0 (note: the 3 peaks detected for CMT-7 were combined), 15.0 and 0.9 microg/ml, respectively . Their in vivo half-lives (t(1/2)) were 11, 5, 22, 11, 32, 15, 37, 38, and 17 hours, respectively . Of the anticollagenase CMTs tested, CMT-8 showed the greatest C(max) and t(1/2)values, followed by CMTs-3, -1, -4, and perhaps -7; CMTs-2, -5, and -6 exhibited much lower levels in serum . The relative lipophilicities of the 8 CMTs and doxycycline were tested by examining their extractability in octanol . The results showed that CMT-2, -5, and -6 had the lowest partition coefficients using this organic solvent, while CMT-3 was the most lipophilic . The lipophilicity of the different CMTs was also positively correlated (r(2)=0.767, P<0.05) to peak serum concentrations (C(max)), but not to their serum half-lives (r(2)=0.25,P=0.49) . This property of the different CMTs was also found to be positively correlated to their ability to enter into human whole blood cells in vitro (r2=0.95, P<0.001) . Since CMT-8, as well as CMTs-3 and -1, consistently exhibited the greatest in vivo efficacy in animal models of tissue breakdown, this may reflect, at least in part, their favorable pharmacokinetics and tissue uptake.

Curr Med Chem, 2001 Feb, 8(3), 237 - 42
Biologic properties of non-antibiotic, chemically modified tetracyclines (CMTs): a structured, annotated bibliography; Greenwald R et al.; The first paper reporting on a potentially important medical property of a non-antimicrobial tetracycline appeared in 1987 . Since then, a literature of over 75 papers has supported the therapeutic potential of this class of compounds . In this review, this literature is grouped and organized with commentary on the data which has been published to date . The biomedical applicability of these discoveries obviously covers a wide range of medical conditions and clearly justifies their continued development.

Am J Otolaryngol, 2001 Jan-Feb, 22(1), 19 - 32
Nitric oxide in the nasal airway: a new dimension in otorhinolaryngology; Djupesland PG et al.; The discovery that the gas nitric oxide (NO) is an important signaling molecule in the cardiovascular system earned its Nobel prize in 1998 . NO has since been found to play important roles in a variety of physiologic and pathophysiologic processes in the body including vasoregulation, hemostasis, neurotransmission, immune defense, and respiration . The surprisingly high concentrations of NO in the nasal airway and paranasal sinuses has important implications for the field of otorhinolaryngology . NO provides a first-line defense against micro-organisms through its antiviral and antimicrobial activity and by its upregulation of ciliary motility . Nasal treatments such as polypectomy, sinus surgery, removal of hypertrophic adenoids and tonsils, and treatment of allergic rhinitis may alter NO output and, therefore, the microbial colonization of the upper airways . Nasal surgery aimed at relieving nasal obstruction may do the same but would also be expected to improve pulmonary function in patients with asthma and upper airway obstruction . NO output rises in a number of conditions associated with chronic airway inflammation, but not all of them . Concentrations are increased in asthma, allergic rhinitis, and viral respiratory infections, but reduced in sinusitis, cystic fibrosis, primary ciliary dysfunction, chronic cough, and after exposure to tobacco and alcohol . Therefore, NO, similar to several other inflammatory mediators, probably subserves different functions as local conditions dictate . At present, it seems that the measurement of NO in the upper airway may prove valuable as a simple, noninvasive diagnostic marker of airway pathologies . The objective of this review is to highlight some aspects of the origin, physiology, and functions of upper airway NO, and to discuss the particular methodological problems that result from the complex anatomy.

N Engl J Med, 2001 Jan 18, 344(3), 205 - 11
Acute pharyngitis; Bisno AL; The primary care physician needs to identify those patients with acute pharyngitis who require specific antimicrobial therapy and to avoid unnecessary and potentially deleterious treatment in the large majority of patients who have a benign, self-limited infection that is usually viral . In most cases, differentiating between these two types of infection can be accomplished easily if the physician considers the epidemiologic setting, the history, and the physical findings, plus the results of a few readily available laboratory tests . When antimicrobial therapy is required, the safest, narrowest-spectrum, and most cost-effective drugs should be used . Despite agreement on these principles by expert advisory committees, data from national surveys of ambulatory care indicate that antimicrobial agents continue to be prescribed indiscriminately for upper respiratory infections.

Chest, 2001 Feb, 119(2 Suppl), 412S - 418S
Guidelines and critical pathways for severe hospital-acquired pneumonia; Fiel S; Hospital-acquired pneumonia (HAP) is associated with high morbidity and mortality . Early, appropriate, and adequate empiric therapy can increase the chance of survival . In 1995, the American Thoracic Society provided guidelines for the initial treatment of immunocompetent HAP patients, which is one of the principal HAP management approaches available to physicians today . However, these guidelines have several important limitations, including a lack of recommendations for duration of therapy and no recognition of newer drugs such as cefepime, trovafloxacin, and meropenem . Furthermore, they fail to distinguish among similar compounds (ie, beta-lactam/beta-lactamase inhibitor combinations) or to recommend specific antibiotics . The clinician using these guidelines needs to address local patterns of antimicrobial resistance, especially in ICUs . Effective computerized antibiotic management programs that incorporate information on local patterns of antimicrobial resistance can assist physicians in empiric therapy decision making, improve patient quality of care, and reduce medical costs.

J Hosp Infect, 2000 Dec, 46(4), 304 - 8
Virucidal efficacy of a combination of 0.2% peracetic acid and 80% (v/v) ethanol (PAA-ethanol) as a potential hand disinfectant; Wutzler P et al.; The formulation PAA-ethanol, consisting of 0.2% paracetic acid (PAA) and 80% ethanol, was tested for its virucidal activity on the enveloped vaccinia virus and papova virus SV 40 and the non-enveloped adenovirus type 2 and poliovirus type 1 . All test viruses were inactivated by PAA-ethanol within an exposure time of 1 minute, as measured by a log(10)reduction of 4 in virus titres . It was shown that poliovirus type 1 can be inactivated by PAA-ethanol within 1 min, whilst for the aqueous 0.2% PAA solution, an exposure time of 5 min is necessary . As shown by electron microscopic observation, the structure of virus particles was completely destroyed by 0.2% PAA within 15 min.The broad antimicrobial spectrum including a high virucidal activity, short exposure time and no toxic or allergenic decomposition products are favourable prerequisites for the medical use of PAA-ethanol and it warrants further investigation as a hand disinfectant .

J Cell Physiol, 2001 Mar, 186(3), 380 - 6
Altered macrophage-like functions of preadipocytes in inflammation and genetic obesity; Cousin B et al.; We recently demonstrated that preadipocytes exhibit functional features of macrophages, such as phagocytosis and anti-microbial activity, suggesting that preadipose cells could play a role in the inflammatory process or immune response . The aim of this study was to compare these functions of both macrophages and cells from stroma-vascular fraction (SVF) of the adipose tissue in two different situations, obesity and inflammation, characterized by alterations in immune responsiveness . We demonstrated that ob/ob mice exhibited strong decrease in antimicrobial activity of both macrophages and SVF . This defect is compensated in SVF, at least in part, by an enhancement of phagocytosis that does not seem to be due to an increased macrophage number . In vitro leptin treatment of SVF and macrophages from obese mice did not restore their immune defects . Thioglycollate treatment of lean and obese mice induced an inflammatory process that led to an increase in macrophage activity in both strains . This stimulation also observed in SVF from lean mice is not present in obese ones . This work demonstrated that SVF immune functions could be modified in different pathological situations such as inflammation and obesity and sustained the new physiological role of preadipocytes in these processes .

Oral Microbiol Immunol, 2001 Feb, 16(1), 10 - 5
Incidence of beta-lactamase production and antimicrobial susceptibility of anaerobic gram-negative rods isolated from pus specimens of orofacial odontogenic infections; Kuriyama T et al.; The incidence of beta-lactamase production in anaerobic gram-negative rods isolated from 93 pus specimens of orofacial odontogenic infections and the antimicrobial susceptibility of these isolates against 11 antibiotics were determined . A total of 191 anaerobic gram-negative rods were isolated from the specimens . Beta-lactamase was detected in 35.6% of the black-pigmented Prevotella and 31.9% of the nonpigmented Prevotella . However, no strains among the other species isolated produced beta-lactamase . Ampicillin, cefazolin and cefotaxime showed decreased activity as regards beta-lactamase-positive Prevotella strains, whereas the activity of ampicillin/sulbactam, cefmetazole, and imipenem continued to be effective against such strains . All tested beta-lactam antibiotics were effective against Porphyromonas and Fusobacterium . Erythromycin showed decreased activity against nonpigmented Prevotella and Fusobacterium . Clindamycin, minocycline and metronidazole were powerful antibiotics against which anaerobic gram-negative rods could be tested . The present study showed that beta-lactamase-positive strains were found more frequently in the Prevotella strains than in any of the other species of anaerobic gram-negative rods . The effectiveness of adding sulbactam to ampicillin was demonstrated, as well as the difference in cephalosporin activity against beta-lactamase-positive strains.

J Pept Res, 2001 Jan, 57(1), 59 - 67
Biological activities of retro and diastereo analogs of a 13-residue peptide with antimicrobial and hemolytic activities; Subbalakshmi C et al.; The biological activities of synthetic retro and diastereo analogs of PKLLKTFLSKWIG (SPFK), a 13-residue peptide with antimicrobial and hemolytic activities, have been investigated . Retro peptides with C-terminal acid and amide exhibited antibacterial activities comparable with those of SPFK . Their hemolytic activities were, however, only marginally lower . The diastereo analog with C-terminal acid was not antibacterial and was weakly hemolytic . Amidation of this analog could restore antibacterial activity . Both retro analogs were unordered in aqueous medium but had a propensity for a helical structure in trifluoroethanol . However, diastereo analogs were unordered in both aqueous medium and trifluoroethanol . Thus, reversing the sequence in a short amphiphilic peptide may not always result in the selective loss of biological activity such as hemolytic activity . Also, introduction of enantiomeric amino acids in a short peptide to generate a diastereomer may result in loss of structure as well as antimicrobial and hemolytic activities, unless compensated by an increase in positive charges.

J Invest Dermatol, 2001 Jan, 116(1), 12 - 22
Serial analysis of gene expression in differentiated cultures of human epidermal keratinocytes; Jansen BJ et al.; Keratinocyte gene expression was surveyed more comprehensively than before, by means of serial analysis of gene expression . A total of 25,694 tags derived from expressed mRNA, were analyzed in a model for normal differentiation and in a model where cultured keratinocytes were stimulated for a prolonged period of time with tumor necrosis factor-alpha, thus mimicking aberrant differentiation in the context of cutaneous inflammation . Serial analysis of gene expression revealed many transcripts derived from unknown genes and a large number of genes that are not known to be expressed in keratinocytes; furthermore, these data provide quantitative information about the relative abundance of transcripts, allowing the identification of differentially expressed genes . A major part of the identified transcripts accounted for genes involved in energy metabolism and protein synthesis . A large proportion of all transcripts (6%) corresponded to genes associated with terminal differentiation and barrier formation . Another highly expressed functional group of genes (2% of all transcripts) corresponded to proteins involved in host protection such as antimicrobial proteins and proteinase inhibitors . Three of these genes were not known to be expressed in keratinocytes, and some were upregulated after prolonged tumor necrosis factor-alpha exposure . Our data on expressed genes in keratinocytes are consistent with the known function of human epidermis, and provide a first step to generate a transcriptome of human keratinocytes.

J Clin Periodontol, 2001 Feb, 28(2), 157 - 61
A study to assess the plaque inhibitory action of a new zinc citrate toothpaste formulation; Moran J et al.; BACKGROUND, AIMS: Zinc-citrate-containing toothpastes have previously been suggested to be of value at inhibiting plaque and gingival inflammation . Present formulations have included triclosan which is thought to contribute major antibacterial/antiplaque effects . Alternative antimicrobial agents and other ingredients such as oils could help to produce equally effective formulations . The aim of this study was to determine whether zinc citrate toothpastes containing bromochlorophene and a triglyceride oil (1% and 8%) could inhibit de novo plaque formation . METHODS: Toothpaste slurry rinses were used over a 96-h period by 24 volunteers, whilst omitting all other oral hygiene procedures . For comparative purposes, a conventional commercial fluoride control toothpaste was also used in this triple cross-over double blind study . RESULTS: After 24 and 48 h, there were no statistically significant differences in plaque between the 2 test pastes and the control paste, whether assessed using a plaque index or plaque area . After 96 h, however, a significant reduction in plaque score of 10.6% and 24.2%) in plaque area (both p < 0.001) was found for the zinc citrate/1% oil toothpaste compared to the control paste . In addition, at 96 h, the 8% oil toothpaste significantly reduced plaque score compared to the control paste by 4.3% (p = 0.029) . CONCLUSIONS: These findings would appear to warrant further investigation into the potential value of the zinc citrate/bromochlorophene/triglyceride formulation at inhibiting both plaque and gingival inflammation.

J Clin Periodontol, 2001 Feb, 28(2), 146 - 56
Adjunctive treatment with subantimicrobial doses of doxycycline: effects on gingival fluid collagenase activity and attachment loss in adult periodontitis; Golub LM et al.; OBJECTIVES: The therapeutic effects of doxycycline and other tetracyclines in the treatment of periodontitis involve, at least in part, mechanisms that are unrelated to their antimicrobial activity . Previous clinical studies have shown that doxycycline administered orally, at doses below those needed for antimicrobial efficacy, to human subjects with adult periodontitis resulted in significantly reduced collagenase activity in gingival crevicular fluid (GCF) and in extracts of inflamed gingival tissues . The purpose of the present study was to identify clinically effective dosing regimens using subantimicrobial dose doxycycline (SDD) as an adjunctive therapy in patients with adult periodontitis . MATERIAL AND METHODS: A total of 75 adult men and women qualified for enrollment into the three-part, placebo-controlled, double-blind, parallel-group study . Patients were stratified based on repeatedly exhibiting pathologic levels of periodontal attachment (ALv) and GCF collagenase activity at several appointments prior to baseline . Patients were administered a scaling and prophylaxis, then 1 of 5 treatment schedules for 12 weeks (part I), followed by a 12-week period of no drug therapy (part II), a second scaling and prophylaxis, and 12 additional weeks of treatment (part III) . Primary determinants of efficacy included reductions in GCF collagenase activity and changes in relative ALv . RESULTS: 66 patients completed the 1st 12 weeks (part I) of the 3-part, 36-week study; 51 patients completed the entire 36-week study . From baseline to week 12 (part I), treatment with specially formulated SDD capsules (20 mg) 2x daily (1 x every 12 h) for up to 12 weeks was shown to significantly reduce GCF collagenase activity and to improve ALv, effects not seen in patients treated with placebo . Continuous drug therapy over the 12-week treatment period was needed to maintain and maximize the reduction in GCF collagenase and the improvement in ALv . Improvements in periodontal disease parameters occurred without the emergence of doxycycline-resistant micro-organisms . In patients administered an "on-off-on" regimen of SDD over 36 weeks (parts I-III), essentially no attachment loss occurred in patients receiving the highest of these SDD regimens (20 mg 2x daily during part I and 20 mg 1 x daily in part III), whereas patients administered placebo capsules experienced a mean attachment loss of approximately 0.8 mm at the 24- and 36-week time periods . CONCLUSIONS: Doxycycline administered at subantimicrobial doses led to improvements in disease parameters, with no apparent side effects, and appears to have significant potential as an oral adjunctive therapy in the long-term management of adult periodontitis.

Eur J Biochem, 2001 Feb, 268(3), 703 - 12
Analogs of the antimicrobial peptide trichogin having opposite membrane properties; Epand RF et al.; Four analogs of the antimicrobial peptide trichogin GA IV were studied . Their sequences are as follows: GT, n-octanoyl-Aib-Gly-Leu-Aib-Gly-Gly-Leu-Aib-Gly-Ile-Leu-OMe; ST, n-octanoyl-Aib-Ser-Leu-Aib-Ser-Ser-Leu-Aib-Ser-Ile-Leu-OMe; BT, n-octanoyl-Aib-Ser(tBu)-Leu-Aib-Ser(tBu)-Ser(tBu)-Leu-Aib-Ser(tBu)-Ile-Leu-OMe; and DT, n-octanoyl-Aib-Ser(tBu)-Leu-Aib-Ser(tBu)-Ser(tBu)-Leu-Aib-Ser(tBu)-Ile-Leu-Aib-Ser(tBu)-Leu-Aib-Ser(tBu)-Ser(tBu)-Leu-Aib-Ser(tBu)-Ile-Leu-OMe . The trichogin GA IV differs from GT only in the nature of the C-terminal residue, being a 1,2 aminoalcohol (leucinol) in the case of the parent peptide . Compared with GT, ST has an increased amphiphilicity . In contrast, BT has little amphiphilicity being composed only of hydrophobic amino acids . DT is an octanoylated head-to-tail dimer of BT . We show that BT and DT lower the bilayer-to-hexagonal phase transition temperature (T(H)) of dipalmitoleoylphosphatidylethanolamine, indicating that the peptides promote negative curvature . These two peptides, composed of only hydrophobic amino acids, have their bulkier groups on one face of the helix, suggesting that they may penetrate membranes at an oblique angle . In contrast, GT and ST, like trichogin itself, increase TH, promoting positive curvature . These peptides have contrasting membrane lytic activities . Whereas DT and BT did not produce leakage of aqueous contents, GT and ST, like trichogin, did cause rapid leakage . The leakage activity with liposomes also correlates with the greater potency of GT and ST, compared with the hydrophobic analogs, in their hemolytic and bacteriostatic action . ST has greater lytic ability than GT in liposomal leakage as well as hemolysis . We also measured the rate of peptide-promoted lipid mixing as an indication of membrane fusion . BT produced lipid mixing only with large unilamellar vesicles enriched with dioleoylphosphatidylethanolamine; ST did not produce lipid mixing, as its apparent reduction of energy transfer proved to be artifactual . Quasi-elastic light scattering of large unilamellar vesicles was also carried out after adding ST and BT . Peptide BT, but not ST, was able to aggregate large unilamellar vesicles . Thus, one of the properties of BT that leads to the induction of lipid mixing is that it is able to aggregate vesicles, placing the bilayers in juxtaposition . Thus, the two pairs of peptides, BT and DT vs GT and ST, exhibit contrasting behaviour with respect to a number of membrane biophysical properties . This occurs despite the fact that the chemical structures of the peptides are rather similar . Such distinct behavior is also reflected in their hemolytic and bacteriostatic actions.

Eur J Biochem, 2001 Jan, 268(2), 443 - 9
Involvement of Rel factors in the expression of antimicrobial peptide genes in amphibia; Miele R et al.; Genes coding for antimicrobial peptides in amphibia reveal a remarkably high number of structural motifs for response elements, previously identified in the genes of insect antimicrobial peptides and in those of the mammalian acute phase response . This study focuses on the functional analysis of the bombinin gene promoter in a Drosophila blood cell line, and the identification of kappaB-binding factors in skin secretions of the frog Bombina orientalis . Transfection experiments demonstrated that the bombinin gene promoter was activated in a lipopolysaccharide-dependent manner, and that insect Rel factors target specific sequences in the amphibian gene promoter . After bathing frogs in bacteria, their skin secretions contained kappaB-specific binding complexes, indicating that Rel factors are crucial components in the response against gram-negative bacteria in this species . These results suggest that a common ancestral control mechanism governs the expression of the first line host-defence from insects to vertebrates.

Clin Microbiol Infect, 2000 Feb, 6(2), 94 - 8
Antimicrobial susceptibility profile of soil isolates of Nocardia asteroides from Kuwait; Khan Z et al.; OBJECTIVES: To find the antimicrobial susceptibility profile of 42 soil isolates of Nocardia asteroides against 14 antimicrobial agents representing beta-lactams, aminoglycosides, ciprofloxacin, minocycline, erythromycin and third generation cephalosporins . METHODS: The antimicrobial susceptibility was determined by the disk diffusion method using Mueller-Hinton agar medium . A homogeneous suspension giving an inoculum of 106-108 CFU/mL was used to streak the plates . The zone of inhibition was read after 36-48 h of incubation at 37 degrees C . RESULTS: All the soil isolates of N . asteroides were susceptible to amikacin, imipenem and tobramycin . Susceptibility to cephalosporins was quite variable; 86% of the isolates were susceptible to cefotaxime, 57% to ceftriaxone and 40% to cefamandole . Fifty-seven per cent of the isolates showed intermediate susceptibility to cefamandole, 33% to ceftriaxone and 5% to cefotaxime . Ninety-three per cent of the isolates were resistant to sulfamethoxazole alone or in combination with trimethoprim . CONCLUSIONS: The study reports a wide variation in the antimicrobial susceptibility profile of soil isolates of N . asteroides originating from a single geographical area . Of interest is the finding that over 90% of N . asteroides isolates were resistant to sulfamethoxazole without any previous exposure to this drug . This may have serious therapeutic implications as sulphonamides or the combination of trimethoprim-sulfamethoxazole is the therapy of choice for nocardiosis . Demonstration of resistance to beta-lactam antibiotics may be attributed to the presence of beta-lactamases which was detectable in > 90% of the soil strains of N . asteroides . The study underscores the importance of antimicrobial susceptibility testing for clinical isolates of Nocardia since individual strains show considerable differences in their susceptibility patterns necessitating therapeutic adjustments.

Insect Biochem Mol Biol, 2001 Mar 1, 31(3), 257 - 62
Serine proteases as mediators of mosquito immune responses; Gorman MJ et al.; Serine proteases regulate several invertebrate defense responses, including hemolymph coagulation, antimicrobial peptide synthesis, and melanization of pathogen surfaces . These processes require the presence of serine proteases in the hemolymph where they can rapidly activate immune pathways in response to pathogen detection . Hemolymph coagulation in the horseshoe crab is controlled by several serine proteases, including two that are pathogen recognition molecules and two in the clip domain family of serine proteases . The antimicrobial peptide synthesis and melanization pathways include clip domain proteases as well as other, uncharacterized serine proteases . We have identified five serine proteases from the hemolymph of the mosquito, Anopheles gambiae . One, Sp22D, is a large protease with potential pathogen binding domains . Sp22D is expressed in three tissues that have immune functions (midgut epithelium, fat body, and hemocytes), and its transcript abundance increases after immune challenge . Sp14A, Sp14D1, and Sp14D2 are clip domain serine proteases that are similar to enzymes with presumed roles in melanization or antimicrobial peptide synthesis . They undergo changes in transcript abundance in response to infection with bacteria or malaria parasites, and they reside in a chromosomal region that has been associated with melanization of parasites . Sp18D, also a clip domain protease, is similar to a Manduca protease with a likely role in immunity, but immune challenge does not affect its mRNA abundance.

J Ethnopharmacol, 2001 Feb, 74(2), 181 - 7
Nitric oxide production by murine peritoneal macrophages in vitro and in vivo treated with Phyllanthus tenellus extracts; Ignacio SR et al.; Phyllanthus spp . are used traditionally for the treatment of viral, bacterial and parasitic infections . Macrophages may play a central role in innate and adaptive response against several infections . Nitric oxide (NO) can be induced during macrophage activation and may exert antimicrobial activity inhibiting the replication of several viruses or parasites . In the present study, we investigated the immunomodulatory role, both in vitro and in vivo, of aqueous extracts of fresh and dried Phyllanthus tenellus as well as an acetone/water extract of the dried plant . NO production by mouse peritoneal macrophages was detected in culture supernatants . Our results demonstrated that: (1) in vitro, a concentration of 100 microg/ml fresh extract stimulated significantly (P< or =0.05) NO production in all assays and the optimal production was achieved at 48-h incubation; (2) 10 and 50 mg/kg fresh extract injected twice intraperitonealy primed macrophages in vivo . Priming was detected by in vitro addition of a second stimulus with 100 microg/ml extract of the fresh plant . Thus, P . tenellus was able to pre-activate macrophages in vivo, and induce full activation in vitro . Further studies should be carried out to better evaluate the optimal dose schedules in terms of time/response for obtaining antiviral or other antimicrobial activity without host damage.

Int J Parasitol, 2001 Jan, 31(1), 29 - 37
Elevated anti-parasitic activity in peripheral blood monocytes and neutrophils of cattle infected with Babesia bovis; Court RA et al.; The innate immune response to bovine Babesia bovis infection in vivo has not previously been established . We used assays measuring phagocytosis and oxidative burst to investigate the immune response because they are indicative of the innate antimicrobial capacity of monocytes and neutrophils . Monocyte and neutrophil phagocytosis is thought to be non-specific in nature and so the phagocytosis of either opsonised Zymosan or Escherichia coli was used to indicate the non-specific phagocytic capacity of monocytes and neutrophils ex vivo . The kinetics of both phagocytic and oxidative burst activity in monocytes and neutrophils were followed twice weekly from pre-inoculation (day 0) through to 31 days after inoculation . Peripheral blood monocytes were found to display a pronounced oxidative burst, but a suppressed capacity to phagocytose during a primary infection . On the other hand, neutrophils exhibited an increased phagocytic capacity and reduced oxidative activity during a primary infection . These findings identified considerable antimicrobial activity evident in peripheral blood monocytes and neutrophils from cattle exposed to B . bovis as a primary exposure . This elevated antimicrobial activity was coincident with the time that parasite numbers peaked in the circulation and occurred prior to parasite clearance . These results suggest that peripheral blood monocytes and neutrophils are active mediators in the innate immune response to a primary B . bovis.

Int J Antimicrob Agents, 2001 Feb, 17(2), 151 - 4
Antimicrobial activity and postantibiotic effect of flurithromycin against Helicobacter pylori strains; Fera MT et al.; The minimal inhibitory concentrations (MIC) of flurithromycin on 49 clinical isolates of Helicobacter pylori was investigated . The MICs were determined using an agar dilution technique . Flurithromycin inhibited the growth of H . pylori strains with MIC(50) and MIC(90) values of 0.156 and 0.625 mg/l, respectively . The postantibiotic effects (PAE) were studied on ten strains, by exposure of the bacteria to flurithromycin at five and ten times MIC for 1 or 2 h . Regrowth was determined by measuring the viable counts after drug removal by a 10(3) dilution procedure . All PAEs increased as a function of concentration and time of exposure . The mean duration of PAEs varied between 1.5 and 6 h . These data are encouraging since macrolides play a key role in the clinical treatment of H . pylori infections, and the strong PAE caused by flurithromycin may contribute to the in vivo efficacy of this drug.

Int J Antimicrob Agents, 2001 Feb, 17(2), 137 - 42
Effect of antimicrobial apomyoglobin 56-131 peptide on liposomes and planar lipid bilayer membrane; Mak P et al.; The horse apomyoglobin 56-131 peptide is a convenient object for studies on the recently discovered antimicrobial activities of haem-binding protein fragments called haemocidins . The purpose of this study was to determine the effect of this peptide on planar lipid bilayer membranes and on liposomes of different lipid compositions . Micromolar concentrations of the apomyoglobin 56-131 fragment disrupt phosphatidylserine/phosphatidylethanolamine planar lipid bilayers without discrete conductance changes . The observed detergent-like action is dependent on peptide concentration; the lower amount of peptide resulted in longer bilayer lifetime . The cholesterol has an inhibitory effect on peptide-induced liposome lysis as shown by calcein release from liposomes . Additionally, there was considerable lytic activity on liposomes formed from anionic lipids of the sort found in bacterial membranes . Circular dichroism (CD) experiments showed that the peptide had a disordered structure in aqueous solutions and folds gradually to form helices in both membrane-mimetic trifluoroethanol solutions as well as in liposome suspensions . The features of the apomyoglobin 56-131 fragment that are similar to the cationic antimicrobial peptides acting in a 'carpet-like' manner are discussed.

Insect Biochem Mol Biol, 2001 Feb, 31(2), 129 - 37
Immune response of Drosophila melanogaster to infection with the flagellate parasite Crithidia spp; Boulanger N et al.; Insects are able to recognize invading microorganisms and to mount an immune response to bacterial and fungal infections . Recently, the fruitfly Drosophila melanogaster has emerged as a promising invertebrate model to investigate innate immunity because of its well-characterized genetics . Insects are also vectors of numerous parasites which can trigger an immune response . We have investigated the interaction of Drosophila melanogaster with the flagellate protozoan Crithidia spp . We show that a per os parasitic infection triggers the synthesis of several antimicrobial peptides . By reverse phase HPLC and mass spectrometry, peptides were shown to be present in the hemolymph and not in the gut tissue, suggesting the presence of immune messengers between the site of the infection, namely the gut, and the fat body, the main site of synthesis for antimicrobial peptides . Interestingly, we have identified one molecule which is specifically induced in the hemolymph after infection with Crithidia, but not with bacteria, suggesting that Drosophila can discriminate between pathogens . When flagellates were injected into the hemolymph, a low synthesis of antimicrobial peptides was observed together with phagocytosis of parasites by circulating hemocytes . The data presented here suggest that Drosophila-Crithidia spp . represents an interesting model to study host defense against protozoan parasites.

Fitoterapia, 2001 Jan, 72(1), 62 - 4
Phytochemical and antimicrobial study of Chukrasia tabularis leaves; Nagalakshmi MA et al.; Successive petroleum ether, benzene, chloroform, ethyl acetate and methanol extracts of Chukrasia tabularis leaves were tested for their phytochemical constituents, antibacterial and antifungal activity . The ethyl acetate and methanol extracts were found to be most effective against most of the tested organisms.

Fitoterapia, 2001 Jan, 72(1), 59 - 61
Antimicrobial activity of the heartwood of Taxus baccata; Erdemoglu N et al.; The ethanolic extract of Taxus baccata heartwood showed significant activity against selected gram-negative bacteria and against five out of nine tested fungi.

Fitoterapia, 2001 Jan, 72(1), 54 - 6
Phytochemical and antimicrobial studies on Butyrospermum paradoxum; Ogunwande IA et al.; The methanolic extracts of the leaves, stem bark, root bark, fruits and seeds kernels of Butyrospermum paradoxum have been evaluated for their phytochemical constituents, antibacterial and antifungal properties.

Vaccine, 2000 Dec 8, 19 Suppl 1, S96 - 9
Acute otitis media in the era of effective pneumococcal conjugate vaccine: will new pathogens emerge?
Pelton SI.
The immunogenicity of pneumococcal conjugate vaccine (PCV) in young infants and its serotype-specific efficacy in otitis media (OM) results in a modest reduction in total episodes of OM and a more substantial reduction in disease due to the most frequent pneumococcal serotypes . Since PCV will only prevent disease due to the most common serotypes, concerns about potential changes in the microbiology of OM have emerged . Insight into potential changes can be obtained from reviewing middle ear and nasopharyngeal isolates from studies of antimicrobial prophylaxis and bacterial polysaccharide immune globulin for prevention of OM and PCV for prevention of invasive pneumococcal disease, respectively . In children receiving PCV, a shift in serotypes of SP colonizing the nasopharynx has been observed . Since non-vaccine serotypes are already present in the community as the etiology of acute purulent OM, it is predictable that these non-vaccine serotypes will become more common especially in children less than two years of age.

Vaccine, 2000 Dec 8, 19 Suppl 1, S17 - 25
Cell biology of tubotympanum in relation to pathogenesis of otitis media - a review; Lim DJ et al.; The sterility of the eustachian tube and tympanic cavity of normal individuals is maintained not only by the adaptive immune system, but also by the mucociliary system and the antimicrobial molecules of innate immunity . Mucin production and periciliary fluid homeostasis are essential for normal mucociliary function and dysfunction of this system is an important risk factor for otitis media . The secreted antimicrobial molecules of the tubotympanum include lysozyme, lactoferrin, beta defensins, and the surfactant proteins A and D (SP-A, SP-D) . Defects in the expression or regulation of these molecules may also be the major risk factor for otitis media.

Vaccine, 2000 Dec 8, 19 Suppl 1, S2 - 8
The burden of otitis media; Klein JO; Otitis media is the most frequent reason that children go to the doctor for illness . In developing countries, where children have limited access to medical care, suppurative complications of otitis media (OM) are frequent and permanent hearing loss results . In developed countries, the most common morbidity of OM is conductive hearing loss due to middle ear effusion . Infants with severe and recurrent OM and persistent middle ear effusion are at risk for problems in behavior and development of speech, language and cognitive abilities . Parent stress is frequent . The cost of otitis media is large (>$5 billion in the United States) . Selection and spread of multi-drug resistant bacterial pathogens arising from extensive use of antimicrobial agents for OM is a problem for management of all diseases due to the pathogens . The incidence and severity of OM may diminish with introduction of new bacterial and viral vaccines.

Exp Gerontol, 2001 Jan, 36(1), 141 - 57
An analysis of parotid salivary gland function with desipramine and age in female NIA Fischer 344 rats; Koller MM et al.; Cyclic antidepressants are still a dominating group of psychotherapeutic drugs used in the treatment of depression . Dry mouth is one of their major side effects . In this study we analyzed the effects of the long-term administration of the tricyclic antidepressant desipramine and the reversibility of this treatment following a 15-day washout period on different parameters in parotid gland function in aging rats . We hypothesized that glandular function would be decreased, and recovery delayed with age . Drug treatment affected body weight, glandular weight, DNA synthesis, and the concentration of soluble and structural membrane proteins . Surprisingly, parotid flow rate was increased with desipramine in all ages . While the concentration of secreted proteins was generally decreased with treatment, total proteins secreted were quite stable . SDS/PAGE analysis revealed prominent changes with desipramine . Amylase activity was depressed with treatment, but only low residual cellular enzyme activity was detected in the glandular supernatant . Therefore, a secretory impairment with desipramine was excluded . The content of the antimicrobial proteins peroxidase and lysozyme was increased with desipramine in all age groups . Most parameters measured revealed delayed recovery with age . These data indicate that the tricyclic antidepressant desipramine has profound effects on parotid gland function, accented with age.

Biochem Biophys Res Commun, 2001 Jan 19, 280(2), 522 - 5
Inhibition of hBD-3, but not hBD-1 and hBD-2, mRNA expression by corticosteroids; Duits LA et al.; Intensive use of corticosteroids may be accompanied by increased susceptibility to infections; hence, we investigated the effects of dexamethasone on the expression of antimicrobial peptides, termed human beta-defensins (hBD), by cultured bronchial epithelial cells and mononuclear phagocytes . The results revealed that dexamethasone inhibited the (stimulated) expression of mRNA for hBD-3, but not hBD-1 and hBD-2 by these epithelial cells . Dexamethasone did not affect the (stimulated) mRNA expression of hBD-1 and hBD-2 by mononuclear phagocytes, whereas these cells did not express hBD-3 mRNA .

Biochem Biophys Res Commun, 2000 Dec 29, 279(3), 961 - 4
A protease inhibitor of the Kunitz family from skin secretions of the tomato frog, Dyscophus guineti (Microhylidae); Conlon JM et al.; Norepinephrine-stimulated skin secretions of the tomato frog, Dyscophus guineti, contained a trypsin inhibitor whose primary structure was established as: SPAEVCF LPK(10) ESGLCRARAL(20) RYYYDRGDGK(30) CEEFIYGGCG(40) GNGNNY KSLL(50) TCKISCE . This amino acid sequence identifies the peptide as a member of the Kunitz/bovine pancreatic trypsin inhibitor (BPTI) family and demonstrates that selective evolutionary pressure has acted to conserve those domains in the molecule (corresponding to positions 12-18 and 34-39 in BPTI) that interact with trypsin . Extracellular proteases produced by pathogenic microorganisms play important roles in facilitating invasion of the host and broad spectrum antimicrobial activity of BPTI has been described . Cationic, amphipathic alpha-helical antimicrobial peptides of the magainin type, important in the defense strategy of several species of frog, were not detected in the skin secretions . We speculate, therefore, that synthesis of a proteinase inhibitor in the skin of the tomato frog may be a component of an alternative strategy of this animal to defend itself against microorganisms.

Exp Parasitol, 2000 Dec, 96(4), 249 - 56
Standardization of the physicochemical parameters to assess in vitro the beta-hematin inhibitory activity of antimalarial drugs; Parapini S et al.; Intraerythrocytic plasmodia form hemozoin as a detoxification product of hemoglobin-derived heme . An identical substance, beta-hematin (BH), can be obtained in vitro from hematin at acidic pH . Quinoline-antimalarials inhibit BH formation . Standardization of test conditions is essential for studying the interaction of compounds with this process and screening potential inhibitors . A spectrophotometric microassay of heme polymerization inhibitory activity (HPIA) (Basilico et al., Journal of Antimicrobial Chemotherapy 42, 55-60, 1998) previously reported was used to investigate the effect of pH and salt concentration on BH formation . The yield of BH formation decreased with pH . Moreover, under conditions used in the above HPIA assay (18 h, 37 degrees C, pH = 2.7), several salts including chloride and phosphate inhibited the process . Aminoquinoline drugs formulated as salts (chloroquine-phosphate, primaquine-diphosphate), but not chloroquine-base, also inhibited the reaction . Interference by salts was highest at low pH and decreased at higher pH (pH 4) . Here, we describe different assay conditions that eliminate these problems (BHIA, beta-hematin inhibitory activity) . By replacing hematin with hemin as the porphyrin and NaOH solution with DMSO as solvent, the formation of BH was independent of pH up to pH 5.1 . No interference by salts was observed over the pH range 2.7-5.1 . Dose-dependent inhibition of BH formation was obtained with chloroquine-base, chloroquine-phosphate, and chloroquine-sulfate at pH 5.1 . Primaquine was not inhibitory . The final product, characterized by solubility in DMSO, consists of pure BH by FT-IR spectroscopy . The BHIA assay (hemin in DMSO, acetate buffer pH 5 +/- 0.1, 18 h at 37 degrees C) is designed to screen for those molecules forming pi-pi interactions with hematin and thus inhibiting beta-hematin formation .

J Surg Res, 2001 Feb, 95(2), 85 - 91
Taurine attenuates LPS-induced rolling and adhesion in rat microcirculation; Egan BM et al.; BACKGROUND: Adhesion of polymorphonuclear leukocytes (PMN) to endothelial cells and subsequent transendothelial migration are an early key events in the inflammatory response and play an important part in the pathogenesis of septic shock, contributing to vascular and tissue injury . Taurine (2-aminoethanesulfonic acid) is a sulphur-containing beta amino acid . It is a known antioxidant, possesses antimicrobial properties, and has previously been shown to be protective to the endothelium both in vivo and in vitro . The aim of this study was to determine if pretreatment with taurinewould attenuate the lipopolysaccharide (LPS)-induced increase in leukocyte-endothelial interactions and microvascular permeability during endotoxemia . MATERIALS AND METHODS: Male Sprague-Dawley rats (300-350 g) were randomized into three groups: (1) Control, (2) LPS, and (3) LPS + Taurine groups . Taurine was administered orally as a 4% solution . Endotoxemia was induced using Escherichia Coli endotoxin (Serotype 0.55 B5)-15 mg/kg via a slow intravenous infusion . Using mesenteric postcapillary venules (28-32-microm diameter) the number of adherent and migrated leukocytes and their rolling velocity were measured by intravital microscopy at baseline and subsequently at 10, 30, 60, and 90 min post administration of LPS . RESULTS: Following administration of LPS there was a reduction in leukocyte rolling velocity at 30, 60 and 90 min . This was accompanied by a significant increase in the number of adherent leukocytes at 10, 30, 60 and 90 min . Transendothelial migration was significantly increased at 90 min . Taurine significantly attenuated the LPS-induced reduction in leukocyte rolling velocity at 10 and 30 min and the number of adherent leukocytes at all time points . Taurine also attenuated the LPS-induced increase in transendothelial migration at 90 min . CONCLUSIONS: These results demonstrate that taurine ameliorates endotoxin-induced leukocyte-endothelial cell interactions associated with sepsis, thereby suggesting that taurine may have a therapeutic role in the preventionof endothelial damage in sepsis .

J Immunol, 2001 Feb 1, 166(3), 1912 - 20
The hamster as a model of human visceral leishmaniasis: progressive disease and impaired generation of nitric oxide in the face of a prominent Th1-like cytokine response; Melby PC et al.; Active human visceral leishmaniasis (VL) is characterized by a progressive increase in visceral parasite burden, cachexia, massive splenomegaly, and hypergammaglobulinemia . In contrast, mice infected with Leishmania donovani, the most commonly studied model of VL, do not develop overt, progressive disease . Furthermore, mice control Leishmania infection through the generation of NO, an effector mechanism that does not have a clear role in human macrophage antimicrobial function . Remarkably, infection of the Syrian hamster (Mesocricetus auratus) with L . donovani reproduced the clinicopathological features of human VL, and investigation into the mechanisms of disease in the hamster revealed striking differences from the murine model . Uncontrolled parasite replication in the hamster liver, spleen, and bone marrow occurred despite a strong Th1-like cytokine (IL-2, IFN-gamma, and TNF/lymphotoxin) response in these organs, suggesting impairment of macrophage effector function . Indeed, throughout the course of infection, inducible NO synthase (iNOS, NOS2) mRNA or enzyme activity in liver or spleen tissue was not detected . In contrast, NOS2 mRNA and enzyme activity was readily detected in the spleens of infected mice . The impaired hamster NOS2 expression could not be explained by an absence of the NOS2 gene, overproduction of IL-4, defective TNF/lymphotoxin production (a potent second signal for NOS2 induction), or early dominant production of the deactivating cytokines IL-10 and TGF-beta . Thus, although a Th1-like cytokine response was prominent, the major antileishmanial effector mechanism that is responsible for control of infection in mice was absent throughout the course of progressive VL in the hamster.

Biophys J, 2001 Jan, 80(1), 331 - 46
Voltage-dependent insertion of alamethicin at phospholipid/water and octane/water interfaces; Tieleman DP et al.; Understanding the binding and insertion of peptides in lipid bilayers is a prerequisite for understanding phenomena such as antimicrobial activity and membrane-protein folding . We describe molecular dynamics simulations of the antimicrobial peptide alamethicin in lipid/water and octane/water environments, taking into account an external electric field to mimic the membrane potential . At cis-positive potentials, alamethicin does not insert into a phospholipid bilayer in 10 ns of simulation, due to the slow dynamics of the peptide and lipids . However, in octane N-terminal insertion occurs at field strengths from 0.33 V/nm and higher, in simulations of up to 100 ns duration . Insertion of alamethicin occurs in two steps, corresponding to desolvation of the Gln7 side chain, and the backbone of Aib10 and Gly11 . The proline induced helix kink angle does not change significantly during insertion . Polyalanine and alamethicin form stable helices both when inserted in octane and at the water/octane interface, where they partition in the same location . In water, both polyalanine and alamethicin partially unfold in multiple simulations . We present a detailed analysis of the insertion of alamethicin into the octane slab and the influence of the external field on the peptide structure . Our findings give new insight into the mechanism of channel formation by alamethicin and the structure and dynamics of membrane-associated helices.

Anesth Analg, 2001 Feb, 92(2), 442 - 7
An evaluation of the Gram stain in protected bronchoalveolar lavage fluid for the early diagnosis of ventilator-associated pneumonia; Duflo F et al.; We investigated the usefulness and reliability of the Gram stain value versus quantitative cultures in the early diagnosis of ventilator-associated pneumonia (VAP) using the protected bronchoalveolar lavage (PBAL) . One hundred four mechanically ventilated patients (age = 52 +/- 19; SAPS II = 38 +/- 15) with a strong suspicion of VAP were consecutively included . One hundred sixteen PBAL were performed and mini-bronchoalveolar lavage were analyzed using the Gram stain standard method and the conventional quantitative culture technique . VAP diagnosis was based on a positive quantitative culture of mini-bronchoalveolar lavage fluid (cutoff > or = 10(3) CFU/mL) . A final diagnosis of VAP was established in 67 patients and there was no infection in 49 cases . Regarding detection of bacteria using the Gram stain, we found a sensitivity of 76.2%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 75.4% . There was a good agreement with the final diagnosis (kappa statistic 0.73; concordance 86.2%) . The degree of qualitative agreement between Gram stain and quantitative cultures was analyzed in the VAP group: the correlation was complete in 39% (26 of 67 VAP), partial in 28% (19 of 67 VAP) and there was no correlation in 33% (22 of 67 VAP) . We conclude that despite its overall "good agreement," the Gram stain is of limited use for the rapid diagnosis of VAP and unreliable for the early adaptation of empirical antimicrobial therapy when using the noninvasive PBAL procedure.

Sex Transm Infect, 2001 Feb, 77(1), 58 - 62
Is Mycoplasma hominis a vaginal pathogen?
Arya OP, Tong CY, Hart CA, Pratt BC, Hughes S, Roberts P, Kirby P, Howel J, McCormick A, Goddard AD.
OBJECTIVE: To evaluate the role of Mycoplasma hominis as a vaginal pathogen . DESIGN: Prospective study comprising detailed history, clinical examination, sexually transmitted infection (STI) and bacterial vaginosis screen, vaginal swabs for mycoplasmas and other organisms, follow up of bacterial vaginosis patients, and analysis of results using SPSS package . SETTING: Genitourinary medicine clinic, Royal Liverpool University Hospital . PARTICIPANTS: 1200 consecutive unselected new patients who had not received an antimicrobial in the preceding 3 weeks, and seen by the principal author, between June 1987 and May 1995 . MAIN OUTCOME MEASURES: Relation of M . hominis isolation rate and colony count to: (a) vaginal symptoms and with the number of polymorphonuclear leucocytes (PMN) per high power field in the Gram stained vaginal smear in patients with a single condition--that is, candidiasis, bacterial vaginosis, genital warts, chlamydial infection, or trichomoniasis, as well as in patients with no genital infection; (b) epidemiological characteristics of bacterial vaginosis . RESULTS: 1568 diagnoses were made (the numbers with single condition are in parenthesis) . These included 291 (154) cases of candidiasis, 208 (123) cases of bacterial vaginosis, 240 (93) with genital warts, 140 (42) chlamydial infections, 54 (29) cases of trichomoniasis, and 249 women with no condition requiring treatment . M . hominis was found in the vagina in 341 women, but its isolation rates and colony counts among those with symptoms were not significantly different from those without symptoms in the single condition categories . There was no association between M . hominis and the number of PMN in Gram stained vaginal smears whether M . hominis was present alone or in combination with another single condition . M . hominis had no impact on epidemiological characteristics of bacterial vaginosis . CONCLUSION: This study shows no evidence that M . hominis is a vaginal pathogen in adults.

Microbiology, 2001 Feb, 147(Pt 2), 403 - 10
Genetic manipulation of 6-phosphofructo-1-kinase and fructose 2,6-bisphosphate levels affects the extent to which benzoic acid inhibits the growth of Saccharomyces cerevisiae; Pearce AK et al.; The mechanisms by which the weak acid preservative benzoic acid inhibits the growth of Saccharomyces cerevisiae have been investigated . A reduction in the pyruvate kinase level, which decreases glycolytic flux, did not increase the sensitivity of yeast to benzoic acid . However, a decrease in 6-phosphofructo-1-kinase (PF1K), which does not affect glycolytic flux, did increase sensitivity to benzoic acid . Also, resistance was increased by elevating PF1K levels . Hence, resistance to benzoic acid was not dependent upon optimum glycolytic flux, but upon an adequate PF1K activity . Benzoic acid was shown to depress fructose 2,6-bisphosphate levels in YKC14, a mutant with low PF1K levels . This effect was partially suppressed by overexpressing constitutively active 6-phosphofructo-2-kinase (Pfk26(Asp644)) or by inactivating fructose-2,6-bisphosphatase (in a Deltafbp26 mutant) . The inactivation of PF2K (in a Deltapfk26 Deltapfk27 mutant) increased benzoic acid sensitivity . Therefore, the antimicrobial effects of benzoic acid can be relieved, at least in part, by the genetic manipulation of PF1K or fructose 2,6-bisphosphate levels.

J Clin Microbiol, 2001 Feb, 39(2), 769 - 71
Sterilization of Mycobacterium tuberculosis Erdman samples by antimicrobial fixation in a biosafety level 3 laboratory; Schwebach JR et al.; Incomplete sterilization of Mycobacterium tuberculosis Erdman cultures followed 1 h of incubation in low concentrations of glutaraldehyde (0.5 and 1.0%) or azide . In contrast, 2.5% glutaraldehyde, paraformaldehyde (2 or 4%), Vesphine IIse or 5% formalin sterilized these samples after 1 h . These results suggest caution in removing fixed M . tuberculosis samples from biosafety level 3.

J Antimicrob Chemother, 2001 Feb, 47(2), 233 - 7
Antibiotic prescribing knowledge of National Health Service general dental practitioners in England and Scotland; Palmer NO et al.; The inappropriate use of antibiotics has contributed to the worldwide problem of antimicrobial resistance . Information on the knowledge, understanding and training of dental practitioners in the use of antibiotics in clinical practice is scarce . This study assessed the level of knowledge of general dental practitioners and the need for educational initiatives . An anonymous postal questionnaire was sent to National Health Service dental practitioners working in 10 Health Authorities in England (1544) and four Health Boards in Scotland (672) . Each correct answer to the questionnaire was given a score of one mark; there were 84 questions . The scores for each section of the questionnaire were compared . Responses were received from 1338 (60.4%) of practitioners, of whom 22.1% had attended postgraduate courses in the previous 2 years on antibiotic prescribing . Practitioners who had attended courses had a significantly greater knowledge of antibiotic use (P < 0.05) than those who had not . There was no significant difference in knowledge between all age groups under 60 years of age . There were significant differences in knowledge between dentists practising in English Health Authorities and Scottish Health Boards (P < 0.01) . Knowledge was good for clinical signs that are indicators for prescribing antibiotics and for a number of non-clinical factors, e.g . patient expectation . Knowledge of therapeutic prescribing for commonly presenting clinical conditions and prophylactic prescribing for medically compromised patients, however, was generally poor . This study has shown that an urgent review of dental undergraduate and postgraduate education in antibiotic prescribing is required . Provision of prescribing guidelines may improve knowledge and encourage the appropriate use of antibiotics in clinical dental practice.

J Antimicrob Chemother, 2001 Feb, 47(2), 191 - 3
Antibiotic susceptibility of Kingella kingae isolates from respiratory carriers and patients with invasive infections; Yagupsky P et al.; The antimicrobial drug susceptibilities of 145 isolates of Kingella kingae to eight antibiotics were determined by the disc diffusion method . In addition, penicillin MICs were determined by the Etest . Study isolates included 37 from blood, 34 from the skeletal system and 74 from respiratory carriers . All isolates were beta-lactamase negative and susceptible to erythromycin, gentamicin, chloramphenicol, tetracycline and ciprofloxacin . A single isolate exhibited resistance to trimethoprim-sulphamethoxazole, and 56 (38.6%) were resistant to clindamycin . The penicillin MIC(50) was 0.023 mg/L and the MIC(90) was 0.047 mg/L . The distribution of MIC values did not differ according to the site of isolation.

J Antimicrob Chemother, 2001 Feb, 47(2), 129 - 40
Evidence to support the rationale that bacterial eradication in respiratory tract infection is an important aim of antimicrobial therapy; Dagan R et al.; Clinical outcome is dependent upon antibiotic-mediated bacterial eradication in a number of infections . However, in respiratory tract infections, the need for bacterial eradication has been controversial . Clinical data are now available that support the need for active bacterial eradication in otitis media . This may also be the case for other respiratory tract infections . An increase in antimicrobial resistance reduces the probability of achieving eradication . Conversely, failure to eradicate bacteria may promote the emergence and dissemination of antimicrobial-resistant clones . Pharmacokinetic/pharmacodynamic parameters can be used to predict the bacteriological efficacy of antimicrobial therapy . In conclusion, the aim of antimicrobial therapy in respiratory tract infections should be the eradication of the infecting organism.

Invest Ophthalmol Vis Sci, 2001 Feb, 42(2), 318 - 20
Group II PLA(2) content of tears in normal subjects; Saari KM et al.; PURPOSE: To determine the concentration of group II phospholipase (PL) A(2), an antimicrobial molecule, in tears of normal subjects in different age and sex groups . METHODS: PLA(2) content of tears was measured in 122 healthy volunteers with ages ranging from 20 to 89 years (mean, 49.5 years) by a time-resolved fluoroimmunoassay using a polyclonal rabbit antibody to recombinant human PLA(2) . RESULTS: The mean concentration of PLA(2) in tears was 54.5 +/- 33.9 microg/ml . It was highest in the age group 20 to 29 years (81.6 +/- 32.0 microg/ml), and a decrease of concentration occurred with an increase of age . PLA(2) values were statistically significantly lower in the age group 60 to 69 years (P = 0.0013) and 70 years or more (P = 0.0001) than in the age group 20 to 29 years . There were no statistically significant differences in PLA(2) content of tears between the genders in any age group (P = 0.798) . CONCLUSIONS: The results indicate that tears contain a high concentration of PLA(2) and that PLA(2) levels decrease with an increase of age and/or reflex tear component of the sample analyzed.

Circulation, 2001 Jan 23, 103(3), 351 - 6
Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment; Gieffers J et al.; BACKGROUND: Recovery of the intracellular bacterium Chlamydia pneumoniae from atherosclerotic plaques has initiated large studies on antimicrobial therapy in coronary artery disease . The basic concept that antibiotic therapy may eliminate and prevent vascular infection was evaluated in vitro and in vivo by examining the antibiotic susceptibility of C pneumoniae in circulating human monocytes, which are thought to transport chlamydiae from the respiratory tract to the vascular wall . METHODS AND RESULTS: Blood monocytes (CD14+) from 2 healthy volunteers were obtained before and after oral treatment with azithromycin or rifampin and then inoculated with a vascular C pneumoniae strain and continuously cultured in the presence of the respective antibiotic . Progress of infection and chlamydial viability was assessed by immunogold-labeling and detection of C pneumoniae-specific mRNA transcripts . Circulating monocytes from patients undergoing treatment with experimental azithromycin for coronary artery disease were examined for C pneumoniae infection by cell culture . Antibiotics did not inhibit chlamydial growth within monocytes . Electron microscopy showed development of chlamydial inclusion bodies . Reverse transcription-polymerase chain reaction demonstrated continuous synthesis of chlamydial mRNA for 10 days without lysis of the monocytes . The in vivo presence of viable pathogen not eliminated by azithromycin was shown by cultural recovery of C pneumoniae from the circulating monocytes of 2 patients with coronary artery disease . CONCLUSIONS: C pneumoniae uses monocytes as a transport system for systemic dissemination and enters a persistent state not covered by an otherwise effective antichlamydial treatment . Prevention of vascular infection by antichlamydial treatment may be problematic: circulating monocytes carrying a pathogen with reduced antimicrobial susceptibility might initiate reinfection or promote atherosclerosis by the release of proinflammatory mediators.

Clin Microbiol Rev, 2000 Apr, 13(2), 167 - 95
Applications of flow cytometry to clinical microbiology; Alvarez-Barrientos A et al.; Classical microbiology techniques are relatively slow in comparison to other analytical techniques, in many cases due to the need to culture the microorganisms . Furthermore, classical approaches are difficult with unculturable microorganisms . More recently, the emergence of molecular biology techniques, particularly those on antibodies and nucleic acid probes combined with amplification techniques, has provided speediness and specificity to microbiological diagnosis . Flow cytometry (FCM) allows single- or multiple-microbe detection in clinical samples in an easy, reliable, and fast way . Microbes can be identified on the basis of their peculiar cytometric parameters or by means of certain fluorochromes that can be used either independently or bound to specific antibodies or oligonucleotides . FCM has permitted the development of quantitative procedures to assess antimicrobial susceptibility and drug cytotoxicity in a rapid, accurate, and highly reproducible way . Furthermore, this technique allows the monitoring of in vitro antimicrobial activity and of antimicrobial treatments ex vivo . The most outstanding contribution of FCM is the possibility of detecting the presence of heterogeneous populations with different responses to antimicrobial treatments . Despite these advantages, the application of FCM in clinical microbiology is not yet widespread, probably due to the lack of access to flow cytometers or the lack of knowledge about the potential of this technique . One of the goals of this review is to attempt to mitigate this latter circumstance . We are convinced that in the near future, the availability of commercial kits should increase the use of this technique in the clinical microbiology laboratory.

Eur J Gastroenterol Hepatol, 1999 May, 11(5), 481 - 3
HTLV-I infection and the low prevalence of Helicobacter pylori infection in Japan; Walker M; HTLV-I retrovirus infection and Helicobacter pylori infection are common in Japan; however a report in this issue shows a significantly low prevalence of H . pylori in patients infected with HTLV-I . The reasons for this may be due to differences in genetic susceptibility of the infections, the gastric milieu in HTLV-I being unable to support H . pylori, or because antimicrobial therapy in HTLV-I infection has eradicated H . pylori in this susceptible population . Similarities between HIV-1, another retroviral infection, and the prevalence of H . pylori are noted.

Rehabil Nurs, 1999 Nov-Dec, 24(6), 232 - 3
Management of antibiotic-resistant organisms in the rehabilitation setting; Flynn ER; Preventing the spread of infection is a team effort . Development and use of rehabilitation-based infection control practices for control of ARO nosocomial infections must be a priority for rehabilitation research . Ongoing infection control surveillance of ARO presence, along with monitoring of resistance patterns, equips infection control practitioners with scientific data to identify appropriate barriers for use in the rehabilitation setting . Modification of antimicrobial usage may offer hope for reversing some of the damage done . With the assistance of physicians, infection control practitioners, laboratory personnel and others, we can prevent the spread of these dangerous organisms.

Biochem Biophys Res Commun, 2000 Apr 13, 270(2), 437 - 41
Nitric oxide inhibits cruzipain, the major papain-like cysteine proteinase from Trypanosoma cruzi; Venturini G et al.; Nitric oxide (NO) is a pluripotent regulatory molecule showing, among others, an antiparasitic activity . Moreover, NO inhibits cysteine proteinase action by nitrosylating the Cys catalytic residue . In the present study, the inhibitory effect of the substrate N-alpha-benzyloxycarbonyl-L-phenylalanyl-L-arginine-(7-amino-4-methyl coumarin) and of NO on the catalytic activity of cruzipain, the major papain-like cysteine proteinase from Trypanosoma cruzi (the hemoflagellate protozoan parasite which causes the American trypanosomiasis), is reported . In particular, NO-donors S-nitroso-glutathione (GSNO), (+/-)-(E)-4-ethyl-2-{(E)-hydroxyimino}-5-nitro-3-hexenamide (NOR-3), 3-morpholinosydnonimine (SIN-1), S-nitroso-acetyl-penicillamine (SNAP), and sodium nitroprusside (SNP) dose-dependently inhibited cruzipain, this effect being likely attributable to the S-nitrosylation of the Cys25 catalytic residue . These results were analyzed in parallel with those concerning the inhibitory effect of the substrate and of NO on the catalytic activity of falcipain, the cruzipain-homologous cysteine proteinase from Plasmodium falciparum . The modulation of the cruzipain and falcipain activity by NO may be relevant in developing new strategies against T . cruzi and P . falciparum in human host . As a whole, the NO-mediated S-nitrosylation of pathogenic viral, bacterial, fungal, and parasitic cysteine proteinases may represent a general mechanism of antimicrobial and antiparasitic host defences .

Dent Today, 1998 Oct, 17(10), 102 - 6, 108-9
Modulation of the host response in the treatment of periodontitis; Golub LM et al.; Periodontitis has two distinct but interconnected etiologic components: periodontopathic bacteria adjacent to the periodontal tissues, and host-mediated connective tissue-destructive responses to the specific causative bacteria and their metabolic products . Although past and existing therapies have focused primarily on the causative microbial challenge, the host component of periodontal destruction has recently been intensely studied . New treatment strategies that focus on attenuating destructive host responses are emerging . Host modulatory agents, when used adjunctively, may enhance clinical therapeutic responses and make these responses more predictable in the susceptible host . The ongoing development of safe, effective pharmacotherapies that specifically target host response mechanisms, and the introduction of such pharmacotherapies as adjuncts to traditional, antimicrobial interventions may represent a new, integrated approach in the long-term treatment and management of this chronic disease.

J Agric Food Chem, 2000 Dec, 48(12), 6435 - 8
Antimicrobial residue detection in chicken yolk samples following administration to egg-producing chickens and effects of residue detection on competitive exclusion culture (PREEMPT) establishment; McReynolds JL et al.; Competitive exclusion (CE) cultures may offer alternatives to antimicrobial agents for disease prophylaxis in poultry . To avoid potential transfer of antibiotic resistance, safe and effective CE cultures must, by necessity, be highly sensitive to antimicrobial residues . The following studies evaluated the effect of maternal administration of selected antibiotics on the establishment of a licensed CE culture, PREEMPT . Selected antibiotics were administered to actively laying hens for a period of 7 days (experiment 1) or 9 days (experiment 2) in drinking water {sulfadimethoxine (0.05%), enrofloxacin (0.005%), and tylosin tartrate (0.05%)} or feed (sulfadimethoxine with ormetoprim, 250 ppm) . In experiment 1, fertile eggs were collected daily and subjected to bioassay for detectable antimicrobial residues in yolk . Antimicrobial residues were not detected during the 7 days of treatment or the subsequent 3 days following cessation of treatment in the control, sulfadimethoxine, sulfadimethoxine with ormetoprim, or tylosin treatment groups . However, detectable residues were observed in eggs derived from enrofloxacin-treated hens on days 6 and 7 during antibiotic administration and also on days 2 and 3 post-antibiotic administration . In experiment 2, antimicrobial residues were also only detected in yolks from hens treated with enrofloxacin . Residue detection occurred on days 2-6 of antibiotic administration, on day 9 of antibiotic administration, on days 1-3 post-antibiotic administration, and also on day 7 post-antibiotic administration . A subset of eggs from each experimental group, corresponding to days 2-6 of antibiotic administration, days 4-6 post-antibiotic administration, and days 14-16 post-antibiotic administration, were pooled for incubation, and chicks hatched from these pools of fertile eggs were treated with PREEMPT at hatch . When 48-h cecal propionate concentrations were used as an index of culture establishment, reduced (P < 0.05) efficacy was observed only in chicks derived from enrofloxacin-treated hens at either collection period . Although several antibiotics do not appear to produce detectable egg residues or interfere with CE culture establishment, these data suggest that chicks derived from enrofloxacin-treated hens may not be candidates for safe and effective CE culture treatment.

Gut, 2001 Feb, 48(2), 176 - 85
Human defensin 5 is stored in precursor form in normal Paneth cells and is expressed by some villous epithelial cells and by metaplastic Paneth cells in the colon in inflammatory bowel disease; Cunliffe RN et al.; BACKGROUND AND AIMS: Intestinal epithelial cell derived antimicrobial peptides of the defensin family may play a major role in host defence against microorganisms . Our aims were to (i) isolate, characterise, and investigate the processing of human defensin 5 (HD-5) in normal Paneth cells and (ii) investigate expression of HD-5 in active inflammatory bowel disease (IBD) . METHODS: Antiserum raised against chemically synthesised putative mature HD-5 was used for immunohistochemistry and purification of HD-5 from extracts of normal terminal ileal crypts . RESULTS: In normal and Crohn's disease terminal ileum, HD-5 immunoreactivity was seen in Paneth cells and in some villous epithelial cells . Normal colonic mucosa did not express HD-5 but HD-5 immunoreactivity was seen in cells in the colonic crypt region of many IBD samples . N-terminal amino acid sequence analysis of HD-5 purified from normal terminal ileal Paneth cells consistently showed the predicted sequence of the precursor form of the peptide . Following stimulation of isolated intact normal terminal ileal crypts, a truncated form of HD-5, with the N-terminal sequence GEDNQLAIS, was detected in the supernatant . CONCLUSIONS: (i) HD-5 is present only in the precursor form in normal terminal ileal Paneth cells and is processed to the mature form during and/or after secretion, (ii) some villous epithelial cells express HD-5, and (iii) HD-5 is expressed by metaplastic Paneth cells in the colon in IBD.

Ann Rheum Dis, 2001 Feb, 60(2), 133 - 9
Increased peripheral T cell reactivity to microbial antigens and collagen type II in rheumatoid arthritis after treatment with soluble TNFalpha receptors; Berg L et al.; OBJECTIVE: Peripheral T cells from patients with rheumatoid arthritis (RA) are hyporesponsive when stimulated with antigen or mitogen in vitro, possibly owing to increased production of proinflammatory cytokines such as tumour necrosis factor alpha (TNFalpha) . This study sought to find out if and how RA T cell reactivity is affected during treatment with etanercept (Enbrel), a soluble TNFalpha receptor . METHODS: Heparinised blood was collected from patients with RA at baseline, after four and eight weeks of etanercept treatment, and from healthy controls . After density separation spontaneous production of interferon gamma (IFNgamma), TNFalpha, interleukin 6 (IL6), and IL10 by peripheral blood mononuclear cells (PBMC) was detected by ELISPOT . For detection of T cell reactivity, PBMC were stimulated in vitro with mitogen (phytohaemagglutinin (PHA)), microbial antigens (purified protein derivative (PPD), influenza), or an autoantigen, collagen type II (CII) . Supernatants were analysed for IFNgamma and IL2 content by enzyme linked immunosorbent assay (ELISA) . RESULTS: In RA the number of cells spontaneously producing IFNgamma was significantly increased after four, but not eight weeks' treatment with etanercept . T cell reactivity, as measured by IFNgamma production to PPD, influenza, and CII was significantly increased after four and sustained after eight weeks' treatment, whereas IFNgamma production induced by PHA remained unchanged . TNFalpha production was significantly higher in patients with RA than in controls and did not change during etanercept treatment . CONCLUSION: Treatment of patients with RA with etanercept may lead to increased peripheral T cell reactivity both to microbial antigens and to self antigens such as CII . These findings indicate that TNFalpha blockade may not only suppress but also stimulate certain aspects of antimicrobial immune defence and autoimmunity.

Med Clin North Am, 2000 Nov, 84(6), 1431 - 46
Antimicrobial pharmacodynamics; Ambrose PG Jr et al.; The ultimate goal of antimicrobial therapy is to provide the best possible outcomes for patients . For this to occur, the clinician should be cognizant of many clinical, microbiologic, pharmacologic, and epidemiologic data as well as fundamental pharmacodynamic concepts . An understanding of pharmacodynamic principles is essential; it forms the scientific basis for the design of dosing strategies that maximize clinical efficacy and minimize toxicity . In the 1990s, data accumulated from in vitro models of infection, animal models of infection, healthy volunteer studies, and clinical trials that have expanded knowledge on how drugs best kill microorganisms . This knowledge has enabled clinicians to establish the best modes of antibiotic administration to maximize the killing of microorganisms and to optimize clinical outcomes.

Med Clin North Am, 2000 Nov, 84(6), 1357 - 89, v
Monotherapy versus combination therapy for bacterial infections; Bouza E et al.; The authors discuss the latest findings regarding the use of one or more antimicrobial drugs for a variety of infections . They offer suggestions for treatment based on a host of considerations, including the synergy and antagonism of specific drugs, type of infection, potential toxicities, and cost.

Dermatol Clin, 2001 Jan, 19(1), 1 - 21
Systemic antibiotic agents; Sadick NS; Understanding the breadth of systemic antimicrobial agents available for use by the dermatologist and their associated side-effect profiles and drug interactions allows the clinician to offer patients optimal care in the management of cutaneous infectious disease.

Minerva Chir, 2000 Sep, 55(9), 599 - 605
{Antibiotic prophylaxis in the surgical treatment of inguinal hernia: need or habit?}; Barreca M et al.; BACKGROUND: Prophylactic antibiotics are recommended for clean-contaminated and selected contaminated surgery . In clean surgery antibiotics are suggested if the operation involves the insertion of prosthetic devices and a potential infection is expected to cause serious morbidity or mortality . Inguinal hernia repair is a clean operation, infections are rare; they can usually be cured without removing the prosthesis and recurrence is uncommon even after removal of the mesh . Aim of the study is to evaluate whether the lack of antimicrobial prophylaxis increases the risk of postoperative infections in patients treated for groin hernia, compared to those treated with prophylaxis . METHODS: One hundred and forty-eight patients underwent inguinal hernia repair with mesh: 64 patients (43%) received 2 g cefotaxime by intravenous bolus about 30 minutes before the operation, 84 patients (57%) did not receive any antimicrobic prophylaxis . Mean follow-up was 13 months (range 1-31 months) for both groups . RESULTS: We did not observe any major complication . Among both groups, no patient had developed infection at one week and one month after surgery . CONCLUSIONS: In personal experience, any advantage in terms of prevention of infections with antibiotic prophylaxis in patients operated on for groin hernia has been observed . A review of the literature showed no general agreement on this subject with different risk of infections in different trials . A new prospective randomized trial is necessary to clarify this topic.

Curr Opin Immunol, 2001 Feb, 13(1), 104 - 8
The role of Toll-like receptors in host defense against microbial infection; Krutzik SR et al.; The Toll family of proteins is central to Drosophila host defense against microbial infection . Maintained throughout evolution, mammalian Toll-like receptors (TLRs) are proteins that participate in innate immunity to bacteria in at least four ways . First, TLRs participate in the recognition of molecular patterns present on microorganisms . Second, TLRs are expressed at the interface with the environment, the site of microbial invasion . Third, activation of TLRs induces expression of co-stimulatory molecules and the release of cytokines that instruct the adaptive immune response . Fourth, activation of TLRs leads to direct antimicrobial effector pathways that can result in elimination of the foreign invader . The recent investigation of TLRs in these areas has provided new insights into mechanisms of innate immunity.

Curr Opin Immunol, 2001 Feb, 13(1), 89 - 95
Antimicrobial peptides and proteins in the innate defense of the airway surface; Travis SM et al.; Recent studies have advanced our understanding of innate immune mechanisms that protect the airways and maintain a sterile lung . Multiple antimicrobial peptides and proteins have been identified in airway secretions and their roles are beginning to be established in animal models . Moreover, evidence for coupling between the innate and adaptive immune systems is beginning to emerge . The understanding of the innate airway defense system offers the opportunity for the development of novel therapeutic approaches.

Periodontol 2000, 2001, 25, 77 - 88
Nonsurgical periodontal therapy; Drisko CH; Regular home care by the patient in addition to professional removal of subgingival plaque is generally very effective in controlling most inflammatory periodontal diseases . When disease does recur, despite frequent recall, it can usually be attributed to lack of sufficient supragingival and subgingival plaque control or to other risk factors that influence host response, such as diabetes or smoking . Causative factors contributing to recurrent disease include deep inaccessible pockets, overhangs, poor crown margins and plaque-retentive calculus . In most cases, simply performing a thorough periodontal debridement under local anesthesia will stop disease progression and result in improvement in the clinical signs and symptoms of active disease . If however, clinical signs of disease activity persist following thorough mechanical therapy, such as increased pocket depths, loss of attachment and bleeding on probing, other pharmacotherapeutic therapies should be considered . Augmenting scaling and root planing or maintenance visits with adjunctive chemotherapeutic agents for controlling plaque and gingivitis could be as simple as placing the patient on an antimicrobial mouthrinse and/or toothpaste with agents such as fluorides, chlorhexidine or triclosan, to name a few . Since supragingival plaque reappears within hours or days after its removal, it is important that patients have access to effective alternative chemotherapeutic products that could help them achieve adequate supragingival plaque control . Recent studies, for example, have documented the positive effect of triclosan toothpaste on the long-term maintenance of both gingivitis and periodontitis patients . Daily irrigation with a powered irrigation device, with or without an antimicrobial agent, is also useful for decreasing the inflammation associated with gingivitis and periodontitis . Clinically significant changes in probing depths and attachment levels are not usually expected with irrigation alone . Recent reports, however, would indicate that, when daily irrigation with water was added to a regular oral hygiene home regimen, a significant reduction in probing depth, bleeding on probing and Gingival Index was observed . A significant reduction in cytokine levels (interleukin-1beta and prostaglandin E2, which are associated with destructive changes in inflamed tissues and bone resorption also occurs . If patient-applied antimicrobial therapy is insufficient in preventing, arresting, or reversing the disease progression, then professionally applied antimicrobial agents should be considered including sustained local drug delivery products . Other, more broadly based pharmacotherapeutic agents may be indicated for multiple failing sites . Such agents would include systemic antibiotics or host modulating drugs used in conjunction with periodontal debridement . More aggressive types of juvenile periodontitis or severe rapidly advancing adult periodontitis usually require a combination of surgical intervention in conjunction with systemic antibiotics and generally are not controlled with nonsurgical anti-infective therapy alone . It should be noted, however, that, to date, no home care products or devices currently available can completely control or eliminate the pathogenic plaques associated with periodontal diseases for extended periods of time . Daily home care and frequent recall are still paramount for long-term success . Nonsurgical therapy remains the cornerstone of periodontal treatment . Attention to detail, patient compliance and proper selection of adjunctive antimicrobial agents for sustained plaque control are important elements in achieving successful long-term results . Frequent re-evaluation and careful monitoring allows the practitioner the opportunity to intervene early in the disease state, to reverse or arrest the progression of periodontal disease with meticulous nonsurgical anti-infective therapy.

Periodontol 2000, 2001, 25, 59 - 76
Preventive strategies and supportive treatment; Hancock EB et al.; There is a preponderance of evidence in the literature that periodontal and other oral diseases, such as caries, can be treated and controlled by thorough mechanical plaque removal by the patient, the use of antimicrobial agents and antibiotics when necessary, and participation with the therapist in a well monitored, long-range program of supportive periodontal therapy . Recent evidence suggests that the control and prevention of oral disease, especially periodontitis, is especially important for patients with various systemic conditions that can be impacted by oral infections . It is far better for patients and therapists to practice primary and even secondary prevention with effective plaque control and regular, consistent supportive periodontal therapy, than having to rely on tertiary prevention for disease that has progressed to a level that requires costly treatment, is time-consuming and carries a greater risk of morbidity.

J Antimicrob Chemother, 2001 Jan, 47(1), 93 - 6
Antimicrobial activities of dihydrofolate reductase inhibitors, used singly or in combination with dapsone, against Mycobacterium ulcerans; Dhople AM; Development of new treatments against Mycobacterium ulcerans infection has become crucial because of its wide-scale prevalence throughout the world . The effects of dihydrofolate reductase inhibitors, used either singly or in combination with dapsone against M . ulcerans were evaluated in vitro . When used singly, epiroprim was the most potent, with MICs between 0.5 and 1.0 mg/L, while trimethoprim was totally ineffective . The MICs of K-130 and brodimoprim ranged from 1.0-2.0 mg/L for the former to 2.0-16.0 mg/L for the latter . When combined with dapsone, synergic effects were observed with epiroprim . These results indicate the great potential of epiroprim in treating M . ulcerans infections.

J Antimicrob Chemother, 2001 Jan, 47(1), 1 - 13
Acridine-a neglected antibacterial chromophore; Wainwright M; The use of acridines as antimicrobial agents was first proposed by Ehrlich and Benda in 1912, and the first clinical use of these agents occurred in 1917 . Many compounds containing the acridine chromophore were synthesized and tested, and the aminoacridines found wide use, both as antibacterial agents and as antimalarials, during World War II . The emergence of the penicillins eclipsed the acridines in antisepsis due to the greater therapeutic efficacies of the former . However, with the current massive increases in drug-resistant bacterial infection, new acridine derivatives may be of use . In addition, the topical utilization of aminoacridines in conjunction with directed low-power light offers bactericidal action at much lower doses.

Pharmacoeconomics, 2000 Nov, 18(5), 451 - 7
Cost analysis of an adult outpatient parenteral antibiotic therapy (OPAT) programme . A Canadian teaching hospital and Ministry of Health perspective; Wai AO et al.; BACKGROUND: Outpatient parenteral antibiotic therapy (OPAT) programmes have become prevalent over the past 2 decades . From the US perspective, these programmes have been shown to reduce healthcare costs . No comprehensive analysis has been published from the Canadian perspective . OBJECTIVE: To describe a Canadian OPAT programme for the 3-year period since its inception and to conduct a treatment cost analysis . DESIGN AND METHODS: Demographics and resource utilisation data (health professional labour, laboratory and diagnostic tests, antimicrobials, delivery, home nursing care, catheters and catheter placement) were prospectively collected for enrollees in the OPAT programme over the evaluation period . Avoided hospital resource utilisation was estimated via retrospective chart review by the investigators . Costs were retrospectively assigned to each resource and total cost avoidance by the OPAT programme was determined from each perspective . PERSPECTIVE: A teaching hospital and a provincial Ministry of Health (MOH) . MAIN OUTCOME MEASURES AND RESULTS: 140 treatment courses were initiated for 117 adult patients (mean age 54 years) who were enrolled into the programme . Mean pre-OPAT length of hospital stay was 12 days, and mean OPAT duration was 22.5 days . Bone/joint (39%), skin and soft tissue (16%), cardiac (13%) and respiratory tract (12%) infections were the most common infections managed . The most commonly used antimicrobials were vancomycin (29%), cloxacillin +/- gentamicin (22%) and ceftriaxone +/- gentamicin (11%) 85% of enrollees successfully completed their planned antimicrobial treatment regimens . Premature discontinuation of antimicrobial therapy for various reasons occurred in the remaining 15% of courses . The mean cost per treatment course of OPAT was 1910 Canadian dollars ($Can) from the hospital perspective and $Can6326 from the MOH perspective . Assuming that patients would have otherwise completed their antimicrobial therapy in hospital, the mean cost per treatment course was estimated to be $Can14,271 . The overall cost avoidance of the OPAT programme was $Can1,730,520 (hospital perspective) and $Can1,009,450 (MOH perspective) over the 3-year assessment period . Sensitivity analyses revealed the results to be robust to plausible changes . CONCLUSIONS: This analysis supports the premise that an adult OPAT programme can substantially reduce healthcare costs in the Canadian healthcare setting.

Arch Soc Esp Oftalmol, 2000 Apr, 75(4), 215 - 59
Infectious uveitis: a review; Tabbara KF; Uveitis may be caused by infectious or non-infectious disorders . Although most cases of uveitis are considered to be immune-mediated disorders, certain forms of uveitis are caused by infectious agents . The disease may become latent, smoldering and chronic and may mimic other causes of auto-immune uveitis . While auto-immune or immune-mediated disorders causing uveitis respond to steroids or immunosuppressive therapy, such treatment may prove to be devastating in certain infectious diseases causing uveitis . It is, therefore, highly desirable to identify cases of chronic uveitis caused by infectious diseases in order to initiate specific and appropriate antimicrobial therapy . The diagnosis of infectious uveitis can be established in most cases based on age and sex of the individual, mode of onset the morphology of the lesion, the laterality, and the association with other systemic infectious diseases . Laboratory tests in these disorders and imaging techniques are used to refine the diagnosis . In this review, bacterial, fungal and parasitic infections leading to uveitis are discussed . Clinical findings, laboratory diagnosis and management are elucidated.

Curr Opin Ophthalmol, 2001 Feb, 12(1), 68 - 74
Use of antimicrobials to prevent postoperative infection in patients with cataracts; Liesegang TJ; Despite the high frequency of cataract surgery, there are still no definitive studies on antibiotic prophylaxis against endophthalmitis after cataract surgery . Most surgeons follow an empiric approach . The results of several recent studies shed additional light on this complex topic . There is better knowledge of the usual source of the infection and the specific organisms incriminated . This review presents some principles of prophylactic treatment and selected literature that addresses the effectiveness of antisepsis, topical preoperative antibiotics, intracameral antibiotics, subconjunctival antibiotics, systemic antibiotics, and postoperative antibiotics . The worldwide problem of antibiotic resistance should temper our approach . Some organizational statements are reviewed, and personal recommendations are offered . Controversy still abounds.

Z Kardiol, 2000 Nov, 89(11), 1046 - 52
{Acute myocarditis and cardiomyopathy in Lyme borreliosis}; Scheffold N et al.; Heart involvement of Lyme disease occurs in about 4-10% of patients with Lyme borreliosis . The most common manifestation is acute, self-limiting Lyme carditis, which manifests mostly as transient conduction disorders of the heart, pericarditis and myocarditis . Laboratory tests (ELISA, immunoblotting and PCR) usually have limited sensitivity and specificity, and criteria of performance and interpretation have not yet been fully evaluated . Therefore the laboratory evidence should only be interpreted in conjunction with other clinical and diagnostic features . Recently there has been convincing evidence published that long standing dilated cardiomyopathy in many cases is associated with a chronic Borrelia burgdorferi (BB) infection . Several studies showed a higher prevalence of BB antibodies in patients with severe heart failure in endemic areas (e.g., 26% versus 8% in healthy individuals) . The isolation of spirochetes from the myocardium gave further evidence that BB may cause chronic heart muscle disease . In several studies antimicrobial treatment showed an improvement of the left ventricular function in patients with dilated cardiomyopathy associated with BB . However the duration of dilated cardiomyopathy before treatment plays an important part in the clinical outcome of BB-associated chronic myocarditis.

Arzneimittelforschung, 2000 Nov, 50(11), 1023 - 7
Synthesis and antimicrobial activity of new 2-phenylethynylbenzothiazoles and related salts; Magdolen P et al.; New 2-phenylethynylbenzothiazoles were synthesized by coupling reaction between 2-iodobenzothiazole and substituted phenylacetylenes under palladium catalysis . The modified Wittig reaction was used to prepare the substituted phenylacetylenes from corresponding benzaldehydes . 2-Phenylethynylbenzothiazoles were next quarternized with trimethyloxonium tetrafluoroborate to 3-methylbenzothiazolium salts . Antimicrobial in vitro activities were determined for all new compounds.

J Pediatr, 2001 Jan, 138(1), 109 - 12
Abundant human beta-defensin-1 expression in milk and mammary gland epithelium; Jia HP et al.; Human beta-defensin-1 (HBD-1) was detected in breast milk in concentrations of approximately 1 to 10 microg/mL . Breast tissue during lactation showed HBD-1 expression in mammary gland epithelia and within luminal secretions . The peptide demonstrated antimicrobial activity against Escherichia coli . HBD-1 may augment neonatal host defenses through antimicrobial effects or prime the adaptive immune system at mucosal surfaces.

J Investig Dermatol Symp Proc, 2000 Dec, 5(1), 55 - 60
Proteoglycans and cutaneous vascular defense and repair; Gallo RL; Proteoglycans are hybrid molecules composed of a core protein and covalently attached glycosaminoglycan chain(s) . The structure, location, and processing of these molecules enables them to encode specific information that is used in multiple physiologic processes . Endothelial cells in the skin are influenced by proteoglycans through binding interactions between glycosaminoglycans and extracellular matrix, growth factors, cytokines, adhesion receptors, enzymes, and enzyme inhibitors . In wound repair, proteoglycans such as the syndecans are induced by antimicrobial peptides and can control growth factor responsiveness . The glycosaminoglycans further signal endothelial cells to increase expression of ICAM-1 and other molecules important for leukocyte adhesion . Thus, proteoglycans represent a powerful central regulatory element in skin that influences a wide variety of events and participates in host defense and tissue repair.

Dermatology, 2000, 201(4), 343 - 6
The effect of a new tissue-adhesive wound dressing on the healing of traumatic abrasions; Quinn J et al.; BACKGROUND: Octylcyanoacrylate is a new medical-grade adhesive with antimicrobial properties . It forms a thin, flexible, occlusive bandage . OBJECTIVE: To determine the gross and histological effects of the spray bandage when treating abrasions . METHODS: Abrasions were produced on the flanks of 18 albino guinea pigs and randomized to treatment with a control (Biobrane) or octylcyanoacrylate dressing . The wounds were assessed with digital photography using a previously validated method . Histopathological analysis was done on day 14 . RESULTS: There were no differences in the mean wound-healing ratios on days 1 (1.25 vs . 1.23, p = 0.61), 7 (1.15 vs . 1.13, p = 0 . 14) and 14 (1.03 vs . 1.02, p = 0.63) for tissue adhesive and Biobrane, respectively . There were no differences found on histopathological analysis either . CONCLUSIONS: This external spray bandage was well tolerated and did not show any signs of histotoxicity or adverse wound healing .

Semin Immunol, 2000 Dec, 12(6), 511 - 6
T lymphocyte recognition of human group 1 CD1 molecules: implications for innate and acquired immunity; Sugita M et al.; Recent evidence has established that non-MHC-encoded molecules of the CD1 family mediate MHC-independent pathways for antigen presentation and T cell activation . Human group 1 CD1 molecules (CD1a, CD1b, CD1c) are expressed mainly on professional antigen-presenting cells, and mediate presentation of microbial lipid and glycolipid antigens to T cells . These group 1 CD1 molecules differentially sample distinct endocytic compartments that may contain different sets of lipid antigens derived from intracellular microbes, and activate antigen-specific T cells . These T cells lyse infected antigen-presenting cells and secrete Th1 cytokines, such as interferon- gamma, and granulysin, a potent antimicrobial protein, and thus can control microbial infection . Reactivity to CD1a, b, and c molecules in the absence of foreign antigen has also been detected in T cells bearing alphabeta and gammadelta TCRs . These T cells may recognize self-lipid antigens and are considered to be autoreactive . In particular, the main tissue subset of gammadelta T cells (V delta 1(+)subset) show prominent reactivity to CD1c, and produce interferon- gamma and granulysin . These CD1c directly reactive T cells may mediate immunity against microbial infection even before antigen-specific T cells differentiate and expand . Together, human CD1a, b and c molecules elicit T cell-dependent immunity to the universe of foreign and self-lipid antigens in both innate and acquired immunity settings .

Crit Rev Immunol, 2000, 20(5), 407 - 31
Cationic antimicrobial peptides and their multifunctional role in the immune system; Scott MG et al.; Many species of life contain cationic antimicrobial peptides as components of their immune systems . The antimicrobial activity of these peptides has been studied extensively, and many peptides have a broad spectrum of activity not only against gram-negative and gram-positive bacteria but also against antibiotic-resistant bacteria, fungi, viruses, and parasites . Such cationic antimicrobial peptides can also act in synergy with host molecules, such as other cationic peptides and proteins, lysozyme, and also conventional antibiotics, to kill microbes . It has been found that certain peptides are produced in large quantities at sites of infection/inflammation, and their expression can be induced by bacterial products such as endotoxic lipopolysaccharide (LPS) and proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) . These peptides often have a high affinity for bacterial products, such as LPS, allowing them to modulate the host response and reduce the inflammatory response in sepsis . More recently, they have been found to interact directly with host cells to modulate the inflammatory process and innate defenses.

Pediatr Infect Dis J, 2000 Dec, 19(12 Suppl), S141 - 6
Pharmacodynamics and pharmacokinetics of cefdinir, an oral extended spectrum cephalosporin; Guay DR; BACKGROUND: Oral second and third generation cephalosporins are undergoing continuing research and development in the arena of pediatric infectious disease in an attempt to fill voids created by existing agents in the quest for the "ideal" antimicrobial . This paper reviews the in vitro antimicrobial activity (pharmacodynamics) and pharmacokinetics of cefdinir, an extended spectrum oral cephalosporin, with an emphasis on those aspects relevant to the pediatric patient population . METHODS: A MEDLINE literature search was conducted for the years 1985 through 2000, identifying all English language papers examining the in vitro antimicrobial activity and human pharmacokinetics of cefdinir . Bibliographies of these papers were reviewed, as were relevant data on file with the manufacturer . DATA SYNTHESIS: Cefdinir exhibits broad range in vitro activity against Gram-positive and Gram-negative aerobes . It exhibits superior activity against Gram-positive aerobes, compared with drugs like cefixime, ceftibuten, cefuroxime and cefpodoxime . In addition it is stable to hydrolysis by many of the common betalactamases . The pharmacokinetic parameters of cefdinir in children are similar to those obtained in adults using similar milligram per m2 doses (300, 600 mg in adults = 7, 14 mg/kg in children, respectively) . CONCLUSIONS: The pharmacodynamic and pharmacokinetic characteristics of cefdinir as described in this paper, as well as the results of the clinical trials program, support the use of this agent in the treatment of a wide variety of pediatric infectious diseases.

Pediatr Infect Dis J, 2000 Dec, 19(12), 1167 - 71
Helicobacter pylori culture and antimicrobial susceptibility from pediatric patients in Michigan; Tolia V et al.; BACKGROUND: We recently observed a high failure rate in the eradication of Helicobacter pylori infection in children with 2-week triple therapy using lansoprazole, amoxicillin and clarithromycin . We performed a prospective evaluation of antral biopsies of all children subsequently diagnosed with H . pylori gastritis for culture and antimicrobial susceptibility assessment . METHODS: All children with antral nodularity and/or an elevated anti-H . pylori IgG titer underwent antral biopsies for histology, urease test and culture while undergoing an upper endoscopy for routine indications . All positive cultures were tested for antimicrobial susceptibility by E-test for clarithromycin, amoxicillin, tetracycline and metronidazole . RESULTS: Thirty-one children (16 male, 15 female) between 2 and 19 years of age were diagnosed with H . pylori gastritis by histology . However, culture was positive in only 22 of 31 (71%) patients . The E-test in vitro antimicrobial susceptibility testing revealed that 95.6% of the isolates were susceptible to amoxicillin, 59% to clarithromycin and 54.6% to metronidazole . There was no resistance to tetracycline . CONCLUSION: Evaluation of antibiotic resistance profiles from pediatric patients from different geographic areas can help in optimizing therapeutic regimen to prevent treatment failures . Metronidazole and clarithromycin resistance is much higher in our pediatric population than reported in adults and could be a major contributor to failure of H . pylori eradication.

J Clin Periodontol, 2001 Jan, 28(1), 90 - 5
Local delivery of chlorhexidine gluconate (PerioChip) in periodontal maintenance patients; Heasman PA et al.; AIM: The aim of this randomised, split-mouth, single-blind study was to determine the efficacy of controlled-release delivery of chlorhexidine gluconate 2.5 mg (PerioChip) in patients with residual bleeding pockets (>5 mm) at least 3 months following oral hygiene and root debridement phase therapy . MATERIAL AND METHODS: 26 patients (non-smokers) were screened and potential study sites identified . Clinical parameters recorded at baseline and all subsequent visits were plaque index (PI), pocket probing depth (PPD), bleeding index (BI) and clinical attachment level (CAL) . All study sites were debrided using ultrasonic instrumentation . PerioChips (PC) were placed in the selected sites of two quadrants (left or right) whilst identified sites in the remaining quadrants were left without adjunctive antimicrobial treatment . Clinical measurements were made at follow-up visits after 1, 3 and 6 months . Mean changes from baseline in PPD, BI and CAL were calculated with the patient as the experimental unit and comparability between the treatments was determined using t-tests . RESULTS: At baseline there were no significant differences between PC and control sites for mean PI, PD, BI or CAL . The mean (SE) reductions in PPD for PC and control treatments were: 0.47 (0.1), 0.46 (0.1); 0.76 (0.1), 0.55 (0.1); 0.78 (0.1), 0.45 (0.1) for months 1, 3 and 6 respectively . Only at month 6 did the difference between treatments approach statistical significance (p=0.06) . Mean (SE) reductions in CAL over the same periods were: 0.17 (0.1), 0.04 (0.08); 0.38 (0.1), 0.21 (0.1); 0.43 (0.1), 0.15 (0.09) p=0.048 . Mean (SE) reduction in BI between PC and control treatments only reached statistical significance at 6 months: 1.08 (0.1), 0.59 (0.1) p=0.05 . CONCLUSION: These data suggest that PerioChip is beneficial for patients on maintenance therapy although the benefit is not apparent until 6 months after placement.

J Econ Entomol, 2000 Dec, 93(6), 1644 - 56
Mass rearing the weevil Hylobius transversovittatus (Coleoptera: Curculionidae), biological control agent of Lythrum salicaria, on semiartificial diet; Blossey B et al.; Lythrum salicaria L., purple loosestrife, an invasive Eurasian perennial, is degrading wetlands across temperate North America . Chemical, physical, and mechanical methods failed to provide long-term control . Therefore, four host-specific insect species (two leaf feeders, a root feeder, and a flower feeder) were introduced as biological control agents . To increase the availability of adults of the root feeding weevil Hylobius transversovittatus Goeze for field releases, we developed a semiartificial diet . Suitability of different diet formulations (varying vitamin mixes, salt mixes, antimicrobials, water content, root content) and temperatures for larval development were evaluated . We also monitored how rearing on artificial diet and the number of larvae per container affected larval development time, larval survival, adult weight, and incidences of deformities . Rearing larvae on artificial diet reduced development time from 1-2 yr to 2-3 mo . Larval development was fastest and survival rates highest under constant temperatures of 25 degrees C . Hatch rate and larval survival decreased if eggs were surface sterilized . Using FABCO antimicrobials could not prevent fungal contamination; use of methyl paraben and sorbic acid was successful in suppressing fungal and bacterial growth throughout larval development time to <10% . The moisture content of the diet did not significantly affect larval survival, development, or adult weight . Decreasing the proportion of purple loosestrife roots in the diet reduced adult weight and the proportion of larvae completing development, and increased development time; no larvae were able to complete development in root-free diet . With an increase in the number of larvae per cup, survival rates were reduced . The experiments revealed a female biased sex ratio: females consistently developed faster and were heavier than males . Incidence of adult deformities was consistently below 5% . Increased availability of adults for field release as a result of mass production using the semiartificial diet will accelerate the biocontrol program targeting purple loosestrife . We are able to produce several hundred weevils per week and have adapted the diet to rear other root-feeding weevils.

Sex Transm Infect, 2000 Oct, 76(5), 383 - 5
Knowledge, attitudes, and practices regarding sexually transmitted infections among general practitioners and medical specialists in Karachi, Pakistan; Khandwalla HE et al.; OBJECTIVES: To determine the knowledge, attitudes, and practices regarding diagnosis and treatment of sexually transmitted infections (STIs) among specialists--that is, dermatologists, gynaecologists and urologists, and general practitioners (GPs) in Karachi, Pakistan . METHODS: Interviewers administered structured questionnaires to doctors conducting outpatient clinics at tertiary hospitals and/or private clinics in Karachi . All private clinics within a 10 km radius of the Aga Khan University, and all tertiary hospitals having more than 100 inpatient beds were included in the study . RESULTS: 100 doctors (54 specialists and 46 GPs) responded . 80 doctors reported seeing at least one STI patient/month . The most commonly diagnosed STI the doctors reported was urethritis/cervicitis syndrome . 50% of the doctors knew the recommended antibiotics for gonorrhoea though only 46% of these knew the correct dosage . Specialists were three times more likely to recognise the clinical presentation of herpes and twice as likely to treat chlamydia, syphilis, and herpes with appropriate antimicrobials than GPs . 85% of the doctors advised their STI patients regarding condom usage; 36% thought that STI patients had loose sexual morals; 43% believed STI patients were drug addicts . Over 90% of the physicians were willing to attend educational sessions and follow a national STI treatment protocol . CONCLUSION: Doctors in Karachi, especially GPs, are deficient in appropriately managing and counselling STI patients . Among the specialists, urologists and dermatologists were more likely to manage STIs correctly than gynaecologists . Karachi doctors should be educated in the correct management and counselling of STIs to prevent further spread of STIs including AIDS.

An Esp Pediatr, 2000 Nov, 53(5), 488 - 91
{Sigmoid sinus thrombosis as a complication of otitis media}; Jimenez Moya AI et al.; Complications of otitis media are relatively infrequent, especially since the introduction of effective antimicrobial agents and specific surgical techniques . We present a case of cerebral pseudotumor due to left sigmoid sinus thrombosis as an intracranial complication of otitis media . We review the various clinical manifestations of sigmoid sinus thrombosis and its therapeutic options.

Ann Surg, 2001 Jan, 233(1), 26 - 33
Effect of single-dose prophylactic ampicillin and sulbactam on wound infection after tension-free inguinal hernia repair with polypropylene mesh: the randomized, double-blind, prospective trial; Yerdel MA et al.; OBJECTIVE: To assess the value of single-dose, intravenous, prophylactic ampicillin and sulbactam (AS) in the prevention of wound infections during open prosthetic inguinal hernia repair by a double-blind, prospective, randomized trial . SUMMARY BACKGROUND DATA: The use of antibiotic prophylaxis during open prosthetic inguinal hernia surgery is controversial, and no prospective trial has been conducted to examine this issue . METHODS: Patients undergoing unilateral, primary inguinal hernia repair electively with the Lichtenstein technique using polypropylene mesh were randomized to receive 1.5 g intravenous AS before the incision or an equal volume of placebo according to a predetermined code of which the surgeons were unaware . Patients with recurrent, femoral, bilateral, giant, or incarcerated hernias or any systemic diseases were excluded . Age, sex, body mass index, American Society of Anesthesiologists score, type of hernia, type of anesthesia, duration of surgery, and use of drains were recorded . Infection was defined according to the criteria of Centers for Disease Control . Patients were evaluated 1 week, 1 month, 6 months, and 1 year after surgery by an independent surgeon . All complications were recorded . Results were assessed using chi-square, Fisher's exact, and Student t tests as appropriate . RESULTS: Between September 1996 and July 1998, 280 patients (140 AS, 140 placebo group) entered the protocol . Four patients from the AS group and seven from the placebo group were excluded because of inadvertent antibiotic administration or follow-up problems . Groups were well matched for all the variables studied and postoperative complications, excluding wound infections, which occurred at a rate of 0.7% in the AS group and 9% in the placebo group (P =.00153) . Twelve patients in the placebo group developed wound infections, requiring five repeat hospital admissions in three patients . These three patients suffered deep infections reaching the graft, which resulted in graft loss in two . The single infected patient in the AS group had his graft removed as well because of deep persistent infection . CONCLUSIONS: This study documented a significant (10-fold) decrease in overall wound infections when single-dose, intravenous AS was used during Lichtenstein hernia repair . Deep infections and wound infection-related readmissions were also reduced by the use of AS . Proponents of mesh repairs may therefore be advised to use prophylactic single-dose intravenous antibiotic coverage in the light of the results of this trial . AS proved to be an effective antimicrobial agent.

Infect Control Hosp Epidemiol, 2000 Dec, 21(12), 792 - 5
Reality check: how should we control antimicrobial use? Current practices and controversies; Coignard B et al.; The infectious diseases community shares a wide consensus about the need for control of antimicrobial use . However, current practices toward this goal remain controversial . This "Reality Check" session assessed attendees of the 4th Decennial Conference regarding their knowledge and practices about control of antimicrobial use in hospitals.

J Enzyme Inhib, 2000, 15(6), 517 - 31
Antifungal activity of Ag(I) and Zn(II) complexes of aminobenzolamide (5-sulfanilylamido-1,3,4-thiadiazole-2-sulfonamide) derivatives; Mastrolorenzo A et al.; Aminobenzolamide (5-sulfanilylamido-1,3,4-thiadiazole-2-sulfonamide) is a potent inhibitor of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), being at the same time structurally similar to the antimicrobial sulfonamides . Here we report that the reaction of aminobenzolamide with arylsulfonyl isocyanates affords a series of new arylsulfonylureido derivatives which were subsequently used as ligands (in the form of conjugate bases, as sulfonamide anions) for the preparation of metal complexes containing Ag(I) and Zn(II) . All the new compounds proved to be very potent inhibitors of CA (isozymes I, II and IV) . The newly synthesized complexes, unlike the free ligands, also act as effective antifungal agents against several Aspergillus and Candida spp., some of them showing activities comparable to ketoconazole, with minimum inhibitory concentrations in the range of 1.8-5 microg/mL . The mechanism of antifungal action of these complexes seem to be unconnected with inhibition of lanosterol-14-alpha-demethylase, since the levels of sterols assessed in the fungi cultures were equal in the absence or in the presence of the tested compounds . Probably the new complexes act as inhibitors of phosphomannose isomerase, a key enzyme in the biosynthesis of yeast cell walls.

J Clin Periodontol, 2000 Dec, 27(12), 910 - 7
Comparison of clinical outcomes following treatment of chronic adult periodontitis with subgingival scaling or subgingival scaling plus metronidazole gel; Griffiths GS et al.; BACKGROUND, AIMS: Conventional treatment of chronic periodontitis involves mechanical debridement of periodontal pockets . Recently, subgingival antimicrobials have been used adjunctively following such debridement . This 2-centre study compared the clinical effects of subgingival scaling (SRP) with SRP plus subgingival application of 25% metronidazole gel, Elyzol (SRP+gel), in patients with chronic adult periodontitis . METHOD: Voluntary informed written consent was obtained from 45 subjects at the Eastman (mean age 46, range 34-63) and 43 subjects at RAF Halton (mean age 47, range 34-71) who participated in this blind, randomised split-mouth design study . All had at least 2 sites in each quadrant with probing pocket depth (PPD) > or = 5 mm . PPD, bleeding on probing (BOP), and clinical probing attachment levels (CAL) measured using a stent, were recorded at baseline and at 1, 3, 6 and 9 months post-therapy . After subgingival scaling of all quadrants, 2 quadrants were randomly selected to be treated with metronidazole gel . RESULTS: A paired t-test on baseline values showed no bias between groups . Both treatments effectively reduced the signs of periodontitis . At each follow-up visit, reduction in PPD, CAL and BOP after the combined treatment was greater than for SRP alone . Paired t-tests showed that the improvement in the SRP+gel group was statistically significantly better (p<0.001) than for SRP alone (mean 0.5 +/- 0.6 mm . 95% CI 0.4-0.6 mm.) Similarly, the % of sites which improved to a final pocket depth of < or = 3 mm and the % of sites which improved over the 9 months of the study by as much as > or = 2 mm were greater for SRP+gel than for SRP alone . CONCLUSIONS: At the end of the study, the mean reductions for PPD were 1.0 mm (SRP) compared to 1.5 mm (SRP+gel), and for CAL they were 0.4 mm (SRP) compared to 0.8 mm (SRP+gel), with mean difference for CAL between treatments of 0.4 +/- 0.6 mm (95% confidence intervals of 0.3-0.6 mm) . The combination therapy of SRP+gel was superior to the conventional treatment of SRP alone, and these differences were maintained for 9 months.

Kansenshogaku Zasshi, 2000 Nov, 74(11), 989 - 93
{A case of severe Legionnaires' disease complicated by rhabdomyolysis, acute renal failure, liver dysfunction and encephalopathy}; Matsumoto N et al.; A 67-year-old male was admitted to our hospital due to a high fever with abnormal shadows on chest X-ray films . On admission, his laboratory data showed hyponatremia, rhabdomyolysis and liver dysfunction . Encephalopathy, acute renal failure and respiratory failure developed, despite fluid management and antimicrobial therapy . His condition worsened rapidly in a few days enough to require mechanical ventilation . Legionnaires' disease was suspected, because pneumonia was found to be associated with multiple organ dysfunction . Intravenous erythromycin and methylprednisolone were administered . The patient's condition was rapidly improved, although he needed hemodialysis for 30 days . Later, indirect fluorescent antibody testing of the patient's serum against Legionella pneumophila was definitely positive (1:1024) . We reported the first case of severe Legionnaires' disease in Miyazaki Prefecture, Japan.

Ann Surg, 2001 Jan, 233(1), 79 - 87
Results of a clinical trial of clinafloxacin versus imipenem/cilastatin for intraabdominal infections; Solomkin JS et al.; OBJECTIVE: Clinafloxacin is a novel quinolone with wide activity against the plethora of microorganisms encountered in intraabdominal infections . This trial was performed to examine its clinical efficacy . SUMMARY BACKGROUND DATA: Clinafloxacin is representative of a new class of quinolones with considerable antimicrobial activity resulting from their mechanisms of action and pharmacodynamics . There is, however, concern about specific potential toxicities, including photosensitivity . METHODS: This prospective, randomized, double-blind trial was conducted to compare clinafloxacin with imipenem/cilastatin as adjuncts in the management of complicated intraabdominal infections . RESULTS: Five hundred twenty-nine patients were included in the intent-to-treat population, with 312 meeting all criteria for the valid population . Patients with a wide range of infections were enrolled; perforated or abscessed appendicitis was the most common (approximately 50%) . One hundred twenty-three of the 150 valid patients treated with clinafloxacin (82%) had successful outcomes, as did 130 of the 162 (80%) treated with imipenem . For the intent-to-treat groups, 219 of 259 patients treated with clinafloxacin (85%) had successful outcomes, as did 219 of 270 patients treated with imipenem/cilastatin (81%) . Treatment failure occurred in 39 patients who underwent drainage . There were substantially more gram-negative organisms recovered from the patients with treatment failure who were initially treated with imipenem/cilastatin . CONCLUSIONS: The results of this study clearly demonstrate the safety and efficacy of clinafloxacin in the treatment of a range of intraabdominal infections, and in patients with a broad range of physiologic disturbances.

Infection, 2000 Nov-Dec, 28(6), 375 - 8
Variation in antimicrobial utilization for febrile neutropenia in cancer patients . The CEMIC Study Group . Club d'Etudes des Maladies Infectieuses en Cancer; Harbarth S et al.; BACKGROUND: No previous study has compared hospitals with respect to the variation of antimicrobial utilization (AU) for cancer patients with febrile neutropenia (FNE) . PATIENTS AND METHODS: We conducted an observational cohort study, carried out in 18 tertiary care centers across nine countries, in order to describe AU patterns for cancer patients with FNE and to evaluate whether prescription was appropriate . RESULTS: A total of 148 patients was exposed to 483 antimicrobial agents and 318 therapeutic courses, corresponding to 1,766 antimicrobial exposure-days.The most frequently used initial treatment consisted of a combination of a broad-spectrum beta-lactam agent and an aminoglycoside (50%) . The extent of initial monotherapy varied between 5% in German and 30% in French centers . Glycopeptides, fluconazole and acyclovir were incorporated into initial empiric therapy in 21,13, and nine instances, respectively . The French centers prescribed the largest number of antimicrobial courses per FNE (mean 2.5 +/-1.5), whereas the center with the highest antimicrobial exposure density was observed in the USA (2.8 exposure-days per 1 FNE-day) . AU was judged to be inappropriate by at least one criterion in 59 patients (40%) . CONCLUSION: This pilot study revealed important variation in AU intensity and prescription preferences in FNE patients and may help to develop appropriate strategies to improve antimicrobial therapy for this patient population.

Immunol Rev, 2000 Oct, 177, 195 - 203
The neutrophil as a cellular source of chemokines; Scapini P et al.; Neutrophils are known to play an important role in inflammatory responses by virtue of their ability to perform a series of effector functions that collectively represent a major mechanism of innate immunity against injury and infection . In recent years, however, it has become obvious that the contribution of neutrophils to host defence and natural immunity extends well beyond their traditional role as professional phagocytes . Indeed, neutrophils can be induced to express a number of genes whose products lie at the core of inflammatory and immune responses . These include not only Fc receptors, complement components, cationic antimicrobial and NADPH oxidase proteins, but also a variety of cytokines (including tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-1R alpha, IL-12 and vascular endothelial growth factor), and chemokines such as IL-8, growth-related gene product, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, interferon-gamma-inducible protein of 10 kDa and monokine induced by interferon-gamma . Because these chemokines are primarily chemotactic for neutrophils, monocytes, immature dendritic cells and T-lymphocyte subsets, a potential role for neutrophils in orchestrating the sequential recruitment of distinct leukocyte types to the inflamed tissue is likely to occur . The purpose of this review is to summarize the essential features of the production of chemokines by polymorphonuclear neutrophil leukocytes and the contribution that we have made to characterize some aspects of this newly discovered crucial function of neutrophils.

Int J Antimicrob Agents, 2001 Jan, 17(1), 57 - 61
In vitro activity of KRM-1648, either singly or in combination with ofloxacin, against Mycobacterium ulcerans; Dhople AM; The antimicrobial effect of a benzoxazinorifamycin, KRM-1648, either alone or in combination with ofloxacin, was evaluated in vitro against two type strains and six clinical isolates of Mycobacterium ulcerans . Growth of M . ulcerans was measured by plate counts and the BACTEC radiometric method . The minimal inhibitory concentration as well as minimal bactericidal concentration of KRM-1648 against M . ulcerans was between 0.012 and 0.025 mg/l, while corresponding values for rifampicin and rifabutin were in the range of 0.1-0.8 mg/l and 0.1-0.4 mg/l respectively . When combined with ofloxacin, KRM-1648 exhibited strong synergistic activity while only additive effects were observed with the combination of rifampicin (or rifabutin) and ofloxacin . These results suggest that KRM-1648 has a great potential in the treatment of M . ulcerans infection.

Int J Antimicrob Agents, 2001 Jan, 17(1), 39 - 44
Comparison of the Etest and the NCCLS-approved agar dilution method to detect metronidazole and clarithromycin resistant Helicobacter pylori; Osato MS et al.; Although the NCCLS has approved the agar dilution method as the test of choice for antimicrobial susceptibility testing of Helicobacter pylori, a critical evaluation of this method in clinical trials to detect antibiotic resistance has not been performed . This study compares the Etest and agar dilution methods for detection of metronidazole and clarithromycin resistance in clinical isolates of H . pylori . MIC data were gathered from US-based clinical trials . The Etest was performed on Mueller-Hinton sheep blood agar plates following incubation for 4 days under 12% CO(2) . The agar dilution test was performed according to the recently approved NCCLS methodology using aged sheep blood in a Mueller-Hinton agar base . Metronidazole resistance as determined by Etest was significantly higher than that determined by agar dilution (39%; 690/1768 vs . 25 . 1%; 367/1465)(P<0.01) . Clarithromycin resistance as determined by Etest was higher than that determined by agar dilution, but was not significantly different (12.5%; 209/1671 vs . 10.6%; 150/1414)(P>0.5) . Inter-patient metronidazole resistance showed that the MIC values for identical isolates tested by both methods were equivalent in 58% (109/188) . Of the 42% with a >2log(2) difference in MIC values, 17 . 6% had a change in susceptibility pattern . For clarithromycin, 71.4% (237/332) of the MIC values for identical isolates tested by both methods had equivalent MIC values . Of the MIC values with a >2log(2) difference in MIC values, only 3% showed a change in susceptibility pattern . Intra-patient variability, i.e . paired isolates from the same patient, was assessed only for metronidazole . Of the 1393 paired isolates tested by Etest, 38.8% were shown to be resistant . Almost 69% of the Etest MIC determinations were deemed equivalent and 16.7% had a change in susceptibility pattern . Of the 639 paired isolates tested by agar dilution, 23.9% were resistant to metronidazole . Almost 72% of the agar dilution MIC values were equivalent and 11.3% of the determinations had a change in susceptibility pattern . Clarithromycin resistance rates are similar, when determined by either test method . The Etest yields a significantly higher prevalence of metronidazole resistance among H . pylori compared with the agar dilution method and both methods yield discordant results, when isolates from different parts of the same stomach are compared . Neither method is reliable in determining metronidazole resistance in H . pylori.

Int J Antimicrob Agents, 2001 Jan, 17(1), 9 - 19
Quality measures of antimicrobial drug use; Gyssens IC; Antimicrobial use is the major determinant in the development of resistance . Many parameters of importance for optimal quality of antimicrobial therapy have already been defined . Maximal efficacy of the treatment should be combined with minimal toxicity at the lowest cost . Quality of antimicrobial drug use is dependent on knowledge of many aspects of infectious diseases . Considering efficacy, many of our indications for antimicrobial use need critical evaluation . Irrational use should be discouraged . Avoidance of the development of resistance is a quality parameter that will need increasing attention . This paper reviews the well-established factors that may influence the appropriateness of pharmacotherapy with antimicrobial drugs . It cites recent evidence supporting principles of prudent prescribing and gives an overview of audits that have addressed these parameters . Measures relating to resistance are discussed.

Int J Antimicrob Agents, 2001 Jan, 17(1), 1 - 8
Pharmacodynamic effects of subinhibitory antibiotic concentrations; Odenholt I; The pharmacodynamics of antibiotics have become increasingly important for the determination of optimal dosing regimens . Studies over the past decade have demonstrated marked differences in the time course of antimicrobial activity for different classes of antibiotics both in vitro, in animals and in human trials . One of the explanations for the success of intermittent dosing regimens has been the delay in regrowth after the concentration has fallen under the MIC, the so called postantibiotic effect (PAE) . In addition to the PAE, the success of discontinuous dosing regimens may be attributed to both the function of a normal host defence and to the effects of subinhibitory antibiotic concentrations (sub-MICs) . It has been shown that there is a difference between the effects of sub-MICs following a suprainhibitory dose (postantibiotic sub-MIC effect; PA SME) and the effects of sub-MICs (SME) alone . It seems that the PA SME is more clinically relevant compared with the PAE, since exposure to suprainhibitory concentrations will always be followed by sub-MICs in vivo . A long PA SME could indicate that longer dosing intervals may be used for that antibiotic /bacterial combination and together with the known effects of sub-MICs on bacterial virulence and the influence of the immune system, it may explain the efficacy of antibiotics with short half-lives even of they are given infrequently.

Int J Immunopharmacol, 2000 Dec, 22(12), 1083 - 91
Immunomodulators in infectious diseases: panoply of possibilites; Masihi KN; Infections which caused ravages in the past centuries are again resurgent and newly emerging pathogens capable of human diseases continue to surface . Multidrug antibiotic resistance has turned into a major medical problem . Judicious concepts for combating infections in the 21st century have acquired a new poignancy . Immunomodulators of natural, synthetic, and recombinant origin can stimulate host defense mechanisms for the prophylaxis and treatment of diverse viral, bacterial, parasitic and fungal diseases . Some immunomodulator preparations are already licensed for use in patients and numerous others are being extensively investigated in preclinical and clinical studies . Immunomodulators offer a novel adjunct to established antimicrobial therapies.

J Ethnopharmacol, 2001 Jan, 74(1), 45 - 51
Clinical effect of a Mexican sanguinaria extract (Polygonum aviculare L.) on gingivitis; Gonzalez Begne M et al.; It is well known that gingivitis is a bacterially-elicited inflammation of the marginal gingiva . A number of chemical agents have been evaluated over the years with regard to their antimicrobial effects in the oral cavity; however, all are associated with side effects that prohibit regular long-term use . Therefore, the effectiveness of a natural Mexican Sanguinaria extract (Polygonum aviculare L.) against gingivitis, was assessed in 60 male dentistry students between the ages of 18 and 25 years . Over a period of 2 weeks, these students used the Sanguinaria extract (1 mg/ml) in oral rinse twice daily as a unique oral health measurement (no tooth-brushing was allowed) . The O'Leary Plaque Index and the Loe and Silness Gingivitis Index were recorded at baseline (day 0) in all the subjects . Also, a complete prophylaxis was performed after both indices were obtained . The antibacterial and antiinflammatory effects of the extract were evaluated on days 7, 11 and 14 . The results showed that the Mexican Sanguinaria extract in oral rinse significantly decreased gingivitis from day 0 (-x=1 . 056) to day 14 (-x=1.011) (P</=0.05) . In contrast, a significant increase in dental plaque was observed from day 0 (-x=91.38) to day 14 (-x=98.69) (P</=0.05); however, the consistency of this plaque permitted its mechanical flushing easily . From this study, it is concluded that the Mexican Sanguinaria extract in oral rinse can be employed supportively in the therapy of gingivitis.

J Clin Microbiol, 2001 Jan, 39(1), 404 - 5
Bursitis due to Mycobacterium goodii, a recently described, rapidly growing mycobacterium; Friedman ND et al.; We report a case of olecranon bursitis due to Mycobacterium goodii in a 60-year-old man . Prior to recognition of his infection, he received intrabursal steroids and underwent olecranon bursectomy . His infection was cured with antimicrobial therapy consisting of doxycycline and ciprofloxacin . This case illustrates that previously unrecognized members of the Mycobacterium smegmatis group of mycobacteria have pathogenic potential.

J Clin Microbiol, 2001 Jan, 39(1), 394 - 7
High levels of resistance to metronidazole and clarithromycin in Helicobacter pylori strains in children; Kalach N et al.; The aim of the study was to evaluate the prevalence of resistance to amoxicillin, metronidazole, and clarithromycin before treatment of Helicobacter pylori infection in children and to assess the evolution of resistance with time . The study was carried out between 1994 and 1999 with 150 H . pylori-positive children through gastric culture (antimicrobial susceptibility) and histology . All cultured H . pylori strains were sensitive to amoxicillin, 64 (43%) were resistant to metronidazole, 32 (21%) were resistant to clarithromycin, and 14 (9%) were resistant to both metronidazole and clarithromycin . The overall prevalence of resistance to metronidazole and clarithromycin did not change significantly with time . The study highlights the generalized high-level and stable metronidazole and clarithromycin resistance of H . pylori strains from children.

J Clin Microbiol, 2001 Jan, 39(1), 304 - 8
Comparison of fluorescent in situ hybridization and conventional culturing for detection of Helicobacter pylori in gastric biopsy specimens; Russmann H et al.; In this study, we have investigated 201 gastric biopsy specimens obtained from dyspeptic patients for the presence of Helicobacter pylori . By means of fluorescent in situ hybridization (FISH) with rRNA-targeted fluorescence-labeled oligonucleotide probes specific for H . pylori, this pathogen was detected in 63 biopsy specimens . By using conventional culturing, H . pylori was isolated from 49 of these 63 gastric biopsy specimens . In contrast, FISH failed to identify H . pylori in four samples from which the pathogen was cultured . The lowest sensitivity was obtained by using the urease test . H . pylori was detected indirectly by this method in 43 of 67 biopsy specimens, which were positive for the pathogen as determined by FISH and/or culturing . All 49 H . pylori isolates that were detected by FISH and culturing underwent antimicrobial susceptibility testing for clarithromycin, a macrolide drug that is a key component in the therapy of peptic ulcer disease caused by this pathogen . Clarithromycin susceptibility testing of cultured isolates was carried out by the E-test, whereas FISH was used on biopsy specimens to detect clarithromycin-resistant mutant strains . No discrepancies were found between these two methods . Thirty-seven strains were clarithromycin sensitive, and eight H . pylori isolates were resistant to the macrolide . From another four biopsy specimens, a mixture of clarithromycin-sensitive and -resistant strains was identified by both methods . Thus, FISH is a reliable technique for determining the clarithromycin susceptibility of this pathogen . Taken together, FISH is a more sensitive and rapid technique than culturing for detection of H . pylori in gastric biopsy specimens . However, in the microbiology routine diagnostic laboratory, the combination of both FISH and conventional culturing significantly increases the sensitivity in detection of H . pylori.

J Clin Microbiol, 2001 Jan, 39(1), 66 - 8
Validity of cultures of fluid collected through drainage catheters versus those obtained by direct aspiration; Everts RJ et al.; To examine the validity of cultures of fluid collected through drainage catheters, we reviewed retrospectively fluid specimens that had been collected through catheters in place for at least 2 days . These specimens were taken from patients at a large tertiary-care hospital . A total of 974 specimens representing 620 patient episodes were received . For 554 (89%) episodes there was no reliable imaging evidence for localized infection, rendering the results uninterpretable . The remaining 66 (11%) episodes were followed within 2 days by radiologically guided or open aspiration of one or more fluid collections (predominantly in the abdomen or pelvis) near the drainage catheter, allowing comparison of culture results of 59 direct aspirates with those of prior catheter drainage . In 33 (56%) of these 59 cases, matched culture results were equivalent for therapeutic decision making . However, relying on results of catheter drainage cultures would have led to inadequate antimicrobial therapy in 13 (22%) cases, to excessive therapy in 11 (19%) cases, and to both in 2 cases (3%) . We conclude that radiological imaging should be standard practice in the assessment of deep-tissue infections in patients with drainage catheters, and that direct aspiration of potentially infected fluid collections is the most reliable method of obtaining specimens for culture that should be used to guide therapy.

Br J Surg, 2001 Jan, 88(1), 4 - 21
Systematic review of antimicrobial agents used for chronic wounds; O'Meara SM et al.; BACKGROUND: This paper is one of a series of eight systematic reviews that aim to identify effective interventions for chronic wounds . Here, antimicrobial agents are evaluated . METHODS: Electronic databases and other relevant sources were accessed to identify published and unpublished material . Studies were eligible for inclusion if they used concurrent controls, recruited participants with chronic wounds, evaluated an intervention designed to prevent or treat chronic wounds, and incorporated an objective assessment of wound healing . All included studies were assessed against a comprehensive checklist for methodological quality . A narrative overview was conducted . RESULTS: Thirty trials were included, 25 of randomized design . Small sample size and other methodological problems meant that findings were often difficult to interpret . Results do not support the routine use of systemic antibiotics for leg ulcers or diabetic foot ulcers without acute infection, but they may be useful as an adjunct to surgery for pilonidal sinuses . Several topical preparations may be helpful, including dimethyl sulphoxide, silver sulphadiazine, benzoyl peroxide, oxyquinoline and gentamicin . CONCLUSION: Most of this research requires replication in larger, well designed studies to establish both clinical and cost effectiveness.

Med Res Rev, 2001 Jan, 21(1), 61 - 72
Benzo{c}phenanthridine bases and their antituberculosis activity; Ishikawa T; The antituberculosis activity of fully-aromatized quaternary benzo{c}phenanthridine bases prepared in our laboratory was tested under the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) program . This review summarizes our syntheses of these bases and discusses their structure-activity relationships against primary tuberculosis.

Appl Environ Microbiol, 2001 Jan, 67(1), 484 - 9
Prevalence and characteristics of shiga toxin-producing Escherichia coli from healthy cattle in Japan; Kobayashi H et al.; The prevalence of Shiga toxin-producing Escherichia coli (STEC) in Japan was examined by using stool samples from 87 calves, 88 heifers, and 183 cows on 78 farms . As determined by screening with stx-PCR, the prevalence was 46% in calves, 66% in heifers, and 69% in cows; as determined by nested stx-PCR, the prevalence was 100% in all animal groups . Of the 962 isolates picked by colony stx hybridization, 92 isolates from 54 farms were characterized to determine their O serogroups, virulence factor genes, and antimicrobial resistance . Of these 92 isolates, 74 (80%) could be classified into O serogroups; 50% of these 74 isolates belonged to O serogroups O8, O26, O84, O113, and O116 and 1 isolate belonged to O serogroup O157 . Locus of enterocyte effacement genes were detected in 24% of the isolates, and enterohemorrhagic E . coli (EHEC) hlyA genes were detected in 72% of the isolates . Neither the bundle-forming pilus gene nor the enteropathogenic E . coli adherence factor plasmid was found . STEC strains with characteristics typical of isolates from human EHEC infections, which were regarded as potential EHEC strains, were present on 11.5% of the farms.

J Antibiot (Tokyo), 2000 Oct, 53(10), 1154 - 7
Microbial and chemical conversion of antibiotic K41 . II . Preparation of K41-DA1, -DA2 and -DA3 deamicetosyl derivatives of antibiotic K41; Hoshi M et al.; Antibiotic derivative K41-DA1, -DA2 and -DA3 (2 approximately 4), deamicetosyl derivatives of antibiotic K41 (1), were prepared by acidic degradation of K41 and following hydrogenation reaction . K41-DA2 (3) showed comparable antimicrobial activities to K41 in vitro but not in vivo.

Ann N Y Acad Sci, 2000 Nov, 918, 84 - 98
Genital tract infections and perinatal transmission of HIV; Taha TE et al.; In areas of the world where genital tract infections (GTIs) are common, the prevalence of HIV and the rate of mother-to-child transmission (MTCT) of HIV are also high . Although observational studies suggested that GTIs are associated with MTCT of HIV, no controlled clinical trial has confirmed this finding . It is likely that GTIs that cause either discharges or ulcers during pregnancy increase perinatal transmission of HIV . Several potential biological mechanisms might facilitate perinatal transmission . For example, chorioamnionitis, increased viral shedding in cervicovaginal secretions, increased HIV acquisition during pregnancy, inflammatory cytokine production, preterm labor, prolonged rupture of membranes, ascending infection, and increased intrapartum infectious secretions are factors that can be associated with GTIs . Several studies have shown that treating clinical conditions associated with inflammation might alter HIV shedding . It is conceivable that preventing ascending infection or reducing exposure of the infant to infectious material during birth could reduce MTCT . This can possibly be achieved by antimicrobial therapy during pregnancy and intrapartum . Such an approach is practical, is less expensive, and has secondary benefits related to prevention of adverse pregnancy outcomes associated with GTIs . Antibiotics might also complement reductions in MTCT of HIV obtained by antiretrovirals given to the mother around the time of delivery . In addition, antibiotics could reduce infectious causes of morbidity and mortality in infant and mother.

Eur J Pediatr, 2000 Dec, 159(12), 878 - 84
Narrow- versus broad-spectrum parenteral anatimicrobials against common infections of childhood: a prospective and randomised comparison between penicillin and cefuroxime; Vuori-Holopainen E et al.; Overuse of broad-spectrum antimicrobials has resulted in increasing bacterial resistance in many countries . We hypothesised that common childhood infections requiring parenteral medication are still curable with narrow-spectrum and inexpensive penicillin . A prospective and randomised study was performed in two referral hospitals in Helsinki . A total of 154 children aged 3 months to 15 years with pneumonia or other lower respiratory infections, sepsis-like infections, or other common acute infections warranting hospitalisation and parenteral antimicrobials were included . At random, 50% of children received procaine penicillin intramuscularly, the other 50% cefuroxime intravenously for 4-7 days . The course of illness was monitored with predetermined laboratory and radiological indices, by filling in a special form daily and a follow-up for 30 days after discharge . The infectious agent was searched for with a large laboratory set-up covering 23 bacterial, viral or protozoan species . The two groups were very similar at presentation . Probable aetiology was disclosed in 56% of the penicillin and in 68% of the cefuroxime recipients, the leading agent in both groups being Pneumococcus . In 8% only a viral aetiology was found . The children recovered with the same speed, regardless of which antimicrobial used, there being one possible failure in each group but no difference in the frequency of needing a physician again within 1 month of discharge . No adverse event was attributable to either drug . CONCLUSION: Procaine penicillin is as effective and safe as cefuroxime for common community-acquired infections in immunocompetent children.

Bioorg Med Chem, 2000 Dec, 8(12), 2719 - 28
Synthesis and antimicrobial activity of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles; Aiello E et al.; A number of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles 6a-g (7b-f) were synthesized and tested for antibacterial and antifungal activity . Some of these compounds displayed antifungal activity at non-cytotoxic concentrations . Derivative 6c was 9 times more potent in vitro than miconazole and 20 times more selective against C . neoformans . 6c was also 8- and 125-fold more potent than amphotericin B and fluconazole, respectively . None of the compounds was active against bacteria . Preliminary structure-activity relationship (SAR) studies showed that the NO group at position 4 of the pyrazole ring is essential for the activity . Lipophilicity of the pyrazole moiety, N-alkyl chain length and planarity of the two heterocyclic rings appear to play a decisive role in modulating cytotoxicity and antifungal activity.

J Leukoc Biol, 2000 Dec, 68(6), 785 - 92
Leukocyte antimicrobial peptides: multifunctional effector molecules of innate immunity; Risso A; Antimicrobial peptides are effector molecules of innate immunity that provide a first line of defense against pathogens . In mammals, they are stored in granules of leukocytes and are present in those sites that are exposed to microbial invasion, such as mucosal surfaces and skin . In the last decade, biochemical investigations and recombinant DNA technology have allowed the identification and characterization of several antimicrobial peptides from various animal and vegetal species . Most of the mammalian peptides have been grouped in two broad families: defensins and cathelicidin-derived peptides . Functional studies have shown that the toxicity mechanisms for many peptides consist of a rapid permeabilization of the target cell membrane . In addition to their microbicidal activity, some members of both families are multifunctional molecules, playing a modulating role in the inflammation and the antigen-driven immune response.

J Leukoc Biol, 2000 Dec, 68(6), 779 - 84
Expression of mammalian defensin genes; Kaiser V et al.; Antimicrobial peptides are a prevalent mechanism of host defense found throughout nature . In mammals, defensins are among the most abundant of these broad-spectrum antibiotics, and are expressed in epithelial and hematopoietic cells . The defensin peptides are especially abundant in neutrophils; however, gene expression is limited to the promyelocyte stage . In epithelial cells, defensin genes are found as both constitutively expressed and inducible . Induction has been observed in vitro by stimulation with bacterial lipopolysaccharide as well as inflammatory mediators . In vivo, up-regulation of several defensin genes occurs in both infectious and inflammatory states . Gene regulation occurs via signal transduction pathways common to other innate immune responses, utilizing transcription factors such as nuclear factor (NF)-kappaB and NF interleukin-6 . Together, the data suggest a broad-based innate host defense whereby potent antimicrobial peptides are present to prevent initial colonization by pathogenic microorganisms . In addition, the recognition of bacteria coupled with a nascent inflammatory response can bolster this defense by a coordinated up-regulation of the peptides.

Pharmacol Toxicol, 2000 Nov, 87(5), 218 - 22
Relaxant effects of Hydrastis canadensis L . and its major alkaloids on guinea pig isolated trachea; Abdel-Haq H et al.; Hydrastis or goldenseal, one of the most popular medicinal herbs in the U.S.A., is used in mild pathological conditions like cold and flu, based on the pharmacological properties of its active components, berberine (anticholinergic, antisecretory, and antimicrobial) and beta-hydrastine (astringent) . We previously reported the relaxant effect of a total ethanolic extract of hydrastis on carbachol precontracted isolated guinea pig trachea, and with the present study, using the same experimental model, we aimed at evaluating the contribution of its major alkaloids, berberine, beta-hydrastine, canadine and canadaline to the total effect . Furthermore, using specific pharmacological tools, like timolol and xanthine amine congener, we attempted to elucidate its mechanism of action . The EC50 of berberine, beta-hydrastine, canadine and canadaline, were 34.2+/-0.6, 72.8+/-0.6, 11.9+/-1.2 and 2.4+/-0.8 microg/ml, respectively . Timolol effectively antagonized the effect of canadine (EC50 = 19.7+/-3.0 microg/ml) and canadaline (EC50 = 17.1+/-1.2 microg/ml) but not that of berberine and beta-hydrastine, while xanthine amine congener antagonized the effect of beta-hydrastine (EC50 = 149.9+/-35.3 microg/ml) and canadaline (EC50 = 26.1+/-3.0 microg/ml) but not that of berberine and canadine . Besides, the hydrastis extract, at concentrations between 0.01 and 0.1 microg/ml, potentiated the relaxant effect of isoprenaline on carbachol-precontracted isolated guinea pig trachea . These data, which are insufficient to draw definite mechanistic conclusions, indicate that the aforementioned alkaloids may act by interacting with adrenergic and adenosinic receptors.

J Periodontol, 2000 Nov, 71(11), 1792 - 801
Position paper: sonic and ultrasonic scalers in periodontics . Research, Science and Therapy Committee of the American Academy of Periodontology; Drisko CL et al.; Ultrasonic and sonic scalers appear to attain similar results as hand instruments for removing plaque, calculus, and endotoxin . Ultrasonic scalers used at medium power seem to produce less root surface damage than hand or sonic scalers . Due to instrument width, furcations may be more accessible using ultrasonic or sonic scalers than manual scalers . It is not clear whether root surface roughness is more or less pronounced following power-driven scalers or manual scalers . It is also unclear if root surface roughness affects long-term wound healing . Periodontal scaling and root planing includes thorough calculus removal, but complete cementum removal should not be a goal of periodontal therapy . Studies have established that endotoxin is weakly adsorbed to the root surface, and can be easily removed with light, overlapping strokes with an ultrasonic scaler . A significant disadvantage of power-driven scalers is the production of contaminated aerosols . Because ultrasonics and sonics produce aerosols, additional care is required to achieve and maintain good infection control when incorporating these instrumentation techniques into dental practice . Preliminary evidence suggests that the addition of certain antimicrobials to the lavage during ultrasonic instrumentation may be of minimal clinical benefit . However, more randomized controlled clinical trials need to be conducted over longer periods of time to better understand the long-term benefits of ultrasonic and sonic debridement.

Ophthalmic Physiol Opt, 2000 Nov, 20(6), 429 - 41
The microbiology of the eye; Armstrong RA; Infection of the external structures of the eye is one of the commonest types of eye disease worldwide . In addition, although relatively impermeable to microorganisms, infection within the eye can result from trauma, surgery or systemic disease . This article reviews the general biology of viruses, bacteria, fungi and protozoa and the major ocular infections that they cause . In addition, the effectiveness of the various antimicrobial agents in controlling ocular disease is discussed . Because of changes in the normal ocular flora, continuous monitoring of the microbiology of the eye will continue to be important in predicting future types of eye infection . Basic research is also needed into the interactions of microbes at the ocular surface . There is increasing microbial resistance to the antimicrobial agents used to treat ocular infections and hence, new antimicrobial agents will continue to be needed together with new methods of drug delivery to increase the effectiveness of existing antimicrobial agents.

Chemistry, 2000 Nov 3, 6(21), 3991 - 6
The first synthesis of (-)-asperpentyn and efficient syntheses of (+)-harveynone, (+)-epiepoformin and (-)-theobroxide; Barros MT et al.; A generally applicable strategy for the synthesis of a range of polyoxygenated cyclohexane natural products has been developed . The enantioselective syntheses of (-)-theobroxide, a polyoxygenated cyclohexane natural compound with potent growth inducing properties in potato microtubers has been achieved via a 1,2 O-silyl migration between trans-hydroxyl groups and a remote hydroxyl directed epoxidation of an enone derived from quinic acid . A thus derived alpha-iodoenone was subjected to Stille coupling with tetramethylstannane to afford the first title compound . A similar strategy enabled a route to the complete asymmetric synthesis of the acetylenic phytotoxin (+)-harveynone . By selective reduction of (-)-theobroxide, (+)-epiepoformin was also prepared in enantiopure form and similarly, stereoselective reduction of (+)-harveynone completed the first enantioselective synthesis of (-)-asperpentyn, another natural compound with antimicrobial activity.

Mayo Clin Proc, 2000 Dec, 75(12), 1321 - 6
Fulminant autoimmune cortical encephalitis associated with thymoma treated with plasma exchange; Rickman OB et al.; A 55-year-old man presented with fever, malaise, dysarthria, and intermittent twitching of his right hand . He progressed rapidly to aphasia, intractable myoclonic seizures, and unresponsiveness . Magnetic resonance imaging (MRI) of the head demonstrated multiple nonenhancing areas of signal abnormality involving the cortex of both cerebral hemispheres . Extensive evaluation revealed no infectious cause for his symptoms . Muscle acetylcholine receptor binding and modulating antibodies, striational antibodies, and a neuronal autoantibody specific for collapsin response-mediator protein were detected . An invasive thymoma was discovered and resected . Brain biopsy revealed microglial activation, gliosis, and scant perivascular lymphocytic inflammation . His condition worsened despite treatment with anticonvulsants, intravenous corticosteroids, and antimicrobials . Plasma exchange was performed . The myoclonus stopped; he regained consciousness and gradually improved to the point that he could talk and ambulate with assistance . An MRI revealed regression of the lesions with residual cortical atrophy . This case demonstrates that paraneoplastic encephalitis may occur with thymoma and may extend to cortical regions outside the limbic system.

Pharmazie, 2000 Nov, 55(11), 803 - 10
Synthesis, antimicrobial testing and QSAR study of new 2-phenylethenylbenzothiazolium salts substituted by cyclic amines; Magdolen P et al.; A series of new 2-phenylethenylbenzothiazolium salts substituted by cyclic amines has been prepared by the condensation of 2-methyl benzothiazolium bromide with substituted benzaldehydes . The nucleophilic substitution of 4-fluorobenzaldehyde with appropriate cyclic amines has been used to obtain the starting benzaldehydes . The compounds with saturated cycloamino substituents have shown enhanced activity against Euglena and some derivatives with piperazine substituent were active against Gram positive bacteria.

APMIS Suppl, 2000, 101, 1 - 48
Occurrence, selection and spread of resistance to antimicrobial agents used for growth promotion for food animals in Denmark; Aarestrup FM; 14.1 INTRODUCTION: This thesis is based on a number of monitoring and research programmes initiated at the Danish Veterinary Laboratory with the aim to determine the occurrence, selection and spread of resistance to antimicrobial agents used for growth promotion . The thesis gives a brief overview of the use, consumption, function and benefit of antimicrobial growth promoters and a more thorough description of the potential resistance problems arising by the use of these agents . 14.2 THE USE OF ANTIMICROBIAL AGENTS IN A HISTORICAL PERSPECTIVE: Soon after the introduction of antimicrobial agents for therapy of bacterial infections in humans and animals, the growth promoting effect of antimicrobial agents was observed, and since the beginning of the 1950'ties antimicrobial agents have been included in feed for food animals as a way to improve growth and reduce production costs . 14.3 CONSUMPTION OF ANTIMICROBIAL GROWTH PROMOTERS: Exact figures on the consumption of antimicrobial agents for clinical and growth promoting purposes are very difficult to get, and estimates are only available for a few countries . In Denmark, the total annual consumption of antimicrobial agents for growth promotion increased from 67 tonnes to 116 tonnes from 1989 to 1995 . After the ban on avoparcin in 1995 the total consumption of growth promoters decreased to 94 tonnes . An increase up to 107 tonnes took place during 1996 and 1997, but during 1998, the consumption decreased to approximately 49 tonnes . The data that are available for different countries show that the use of antimicrobial agents for growth promotion normally equals or exceeds the usage of antimicrobial agents for therapy for food animals . Based on the information available, it can be estimated that the financial sale of antimicrobial agents for animals amounts to approximately 25% to 35% of the world-wide sale, of which the use of antimicrobial agents as feed additives is at least 50% . 14.4 MODE OF ACTION OF ANTIMICROBIAL GROWTH PROMOTERS: The mode of action of antimicrobial growth promoters is not fully understood . However, the main effects are believed to be a reduction of the growth of bacteria in the intestinal tract and thereby less microbial degradation of useful nutritients, and the prevention of infections with pathogenic bacteria . 14.5 BENEFIT FROM THE USE OF ANTIMICROBIAL GROWTH PROMOTERS: Numerous studies on the economic benefit of the use of antimicrobial growth promoters have been performed . The growth response is normally larger in young animals than in older animals . Large variations in the estimates have been observed, but in general a improvement in growth rate and feed utilisation has been observed . 14.6 SUSCEPTIBILITY AND RESISTANCE TO ANTIMICROBIAL GROWTH PROMOTERS: The definition of a bacterium as susceptible or resistant to an antimicrobial agent ultimately depends on clinical outcome . Since the exact mode of action of antimicrobial growth promoters are not known, the only way to define break points is based on the population distributions of susceptibilities to different agents . For antimicrobial agents used both for therapy and growth promotion the break points for therapy have been used . For avilamycin, avoparcin, flavomycin, monensin and salinomycin, that are used for growth promotion only, tentative break points based on population distributions have to be defined . The tentative break points for avoparcin and avilamycin have been confirmed by cross-resistance to other antimicrobial agents belonging to the same class and the presence of resistance mechanisms . 14.7 OCCURRENCE OF AND SELECTION FOR RESISTANCE TO ANTIMICROBIAL AGENTS USED FOR GROWTH PROMOTION: Information on the occurrence of resistance is needed to guide policy and detect changes that require intervention strategies . In 1995, a continuous monitoring of antimicrobial resistance in bacteria isolated from food animals was established in Denmark . Among food animals three categories of bacteria (indicator bacteria, zoonotic bacteria and animal pathogens) are continuously isolated from broilers, cattle and pigs and tested for susceptibility to antimicrobial agents used for therapy and growth promotion by disc diffusion or MIC-determinations . In all known cases antimicrobial resistance has emerged following the introduction of new antimicrobial compounds for therapy . The occurrence of resistance to antimicrobial agents used for growth promotion indicates that resistance will also emerge following the introduction of antimicrobials for growth promotion . Comparison of the occurrence of resistance among reservoirs with different usage of antimicrobial agents for growth promotion also shows that the occurrence of resistance will follow the usage . Epidemiological studies have shown that the use of both avilamycin and avoparcin for growth promotion will select for resistance among E . (ABSTRACT TRUNCATED)

Biochemistry, 2000 Dec 26, 39(51), 15765 - 74
Structure of the bovine antimicrobial peptide indolicidin bound to dodecylphosphocholine and sodium dodecyl sulfate micelles; Rozek A et al.; Indolicidin is a cationic, 13-residue antimicrobial peptide (ILPWKWPWWPWRR-NH(2)) which is unusually rich in tryptophan and proline . Its antimicrobial action involves the bacterial cytoplasmic membrane . Fluorescence and circular dichroism spectra demonstrated the structural similarity of indolicidin in complexes with large unilamellar phospolipid vesicles and with detergent micelles . The structure of indolicidin bound to zwitterionic dodecylphosphocholine (DPC) and anionic sodium dodecyl sulfate (SDS) micelles was determined using NMR methods and shown to represent a unique membrane-associated peptide structure . The backbone structure in DPC, well defined between residues 3 and 11, was extended, with two half-turns at residues Lys-5 and Trp-8 . The backbone structure in SDS, well defined between residues 5 and 11, was also extended, but lacked the bend in the C-terminal half . Indolicidin in complexes with DPC had a central hydrophobic core composed of proline and tryptophan, which was bracketed by positively charged regions near the peptide termini . The tryptophan side chains, with one exception, folded flat against the peptide backbone, thus giving the molecule a wedge shape . Indolicidin in complexes with SDS had an arrangement of hydrophobic and cationic regions similar to that found in the presence of DPC . The tryptophan side chains were less well defined than for indolicidin in DPC and extended away from the peptide backbone . The preferred location of indolicidin in DPC micelles and lipid bilayers, analyzed using spin-label probes, was at the membrane interface.

Biochemistry, 2000 Dec 26, 39(51), 15757 - 64
Three-dimensional structure of RK-1: a novel alpha-defensin peptide; McManus AM et al.; NMR spectroscopy and simulated annealing calculations have been used to determine the three-dimensional structure of RK-1, an antimicrobial peptide from rabbit kidney recently discovered from homology screening based on the distinctive physicochemical properties of the corticostatins/defensins . RK-1 consists of 32 residues, including six cysteines arranged into three disulfide bonds . It exhibits antimicrobial activity against Escherichia coli and activates Ca(2+) channels in vitro . Through its physicochemical similarity, identical cysteine spacing, and linkage to the corticostatins/defensins, it was presumed to be a member of this family . However, RK-1 lacks both a large number of arginines in the primary sequence and a high overall positive charge, which are characteristic of this family of peptides . The three-dimensional solution structure, determined by NMR, consists of a triple-stranded antiparallel beta-sheet and a series of turns and is similar to the known structures of other alpha-defensins . This has enabled the definitive classification of RK-1 as a member of this family of antimicrobial peptides . Ultracentrifuge measurements confirmed that like rabbit neutrophil defensins, RK-1 is monomeric in solution, in contrast to human neutrophil defensins, which are dimeric.

Crit Care, 2000, 4(6), 327 - 32 Epub 2000 Oct 02.
Opinion: the clinical use of selective digestive decontamination; Kollef MH; Several recent meta-analyses have shown that the use of SDD can reduce the occurrence of nosocomial pneumonia among ventilated patients in the intensive care unit (ICU) setting . However, the use of SDD has also been demonstrated to increase subsequent patient colonization and infection with antibiotic-resistant bacteria, particularly Gram-positive cocci . Therefore, the routine use of SDD cannot be advocated at the present time . The mortality benefit of SDD appears to occur in surgical/trauma patients, and to be associated primarily with the administration of parenteral antibiotics . This is already an accepted practice in most patients during the perioperative period (eg prophylactic parenteral antibiotics for 24 h) . Prolonged decontamination of the aerodigestive tract with topical antimicrobials does not appear to influence outcome, and should not be routinely employed.

Int J Dermatol, 2000 Nov, 39(11), 844 - 5
Cornifying Darier's disease; Katta R et al.; A 48-year-old Caucasian man recounted the onset of keratotic papules on the trunk at the age of 8 years, with subsequent spread to the forearms, scalp, and forehead . His most severe disease was present on the legs . He complained of pain, itching, and noted exacerbations in the summer and with sweating . The family history was negative . On physical examination, the most striking finding was that of extensive, markedly hyperkeratotic plaques on the lower legs >(Fig . 1) . His scalp, forehead, chest, and back exhibited mild involvement, with scattered brown keratotic papules, while his forearms showed mildly hyperkeratotic plaques . Flat-topped brown papules were present on the dorsum of the hands, with a few keratotic papules on the palms, and a few nails with distal notching and red longitudinal streaks . There were no palmar pits or oral mucosal lesions . A shave biopsy was performed of a plaque on the leg, and showed a papillomatous and markedly hyperkeratotic lesion >(Fig . 2) . Suprabasal acantholysis in the elongated rete produced characteristic lacunae . The acantholysis was associated with dyskeratosis including corps ronds and grains >(Fig . 3) . Together, these features were characteristic of Darier's disease . Treatment years earlier with topical retinoids, topical steroids, topical keratolytics, and multiple oral antimicrobials had been unsuccessful, and isotretinoin had been discontinued due to elevated triglycerides . Treatment was initiated with acitretin and, after 3 months, mild improvement was noted

Insect Mol Biol, 2000 Dec, 9(6), 635 - 9
Wolbachia neither induces nor suppresses transcripts encoding antimicrobial peptides; Bourtzis K et al.; Wolbachia are intracellular maternally inherited microorganisms that are associated with reproductive abnormalities such as cytoplasmic incompatibility (CI), feminization and parthenogenesis in the various arthropod species they infect . Surveys indicate that these bacteria infect more than 16% of all insect species as well as isopods, mites and nematodes, making Wolbachia one of the most ubiquitous parasites yet described . However, nothing is known about the interactions of this bacterium with the host's immune system . We studied the expression of inducible antimicrobial markers in the adults of two Wolbachia infected insect species, Drosophila simulans and Aedes albopictus . The lack of available immune markers in the mosquito species led us to clone part of the defensin gene from this species, which was found to be very similar to the other mosquito defensins cloned from Anopheles gambiae and Aedes aegypti . Comparisons of the expression pattern of the antibacterial markers between Wolbachia-infected and cured lines, and also between bacteria-challenged and unchallenged adults indicated that Wolbachia does not either constitutively induce or suppress the transcription of these antibacterial genes . In addition, no difference in the transcription of these genes was found between double and single Wolbachia-infected strains or between strains in which Wolbachia has different tissue tropisms.

Aliment Pharmacol Ther, 2000 Dec, 14(12), 1639 - 43
Role of antimicrobial susceptibility testing on efficacy of triple therapy in Helicobacter pylori eradication; Toracchio S et al.; BACKGROUND: Helicobacter pylori treatment failure may be due to resistance to macrolides and 5-nitroimidazoles . AIM: To test whether a preliminary in vitro susceptibility test of H . pylori to tinidazole and clarithromycin and a consequent specific regimen could improve the eradication rate . METHODS: A total of 109 consecutive H . pylori-positive patients with dyspeptic symptoms were included . At endoscopy, biopsy from the antrum was obtained for H . pylori culture and antimicrobial susceptibility testing . Fifty-six patients were treated with omeprazole, tinidazole and clarithromycin for 10 days (group OTC) and 53 patients received therapy on the basis of the susceptibility test (group SUSC) . Treatment success was evaluated by the 13C-urea breath test 1 month after the end of therapy . RESULTS: Eight patients dropped out . Overall primary resistance to clarithromycin, tinidazole and both antibiotics was 13%, 33% and 4%, respectively . In group OTC, H . pylori was eradicated in 81% and 75% of patients by per protocol and intention-to-treat analysis, respectively . Per protocol and intention-to-treat eradication rates for group SUSC were 98% and 91% (P < 0.05 vs . group OTC) . CONCLUSIONS: These data show that in H . pylori infection, antibiotic therapy based on the results of culture and susceptibility testing gives, in comparison to standard therapy, a significant improvement in eradication rate.

Cardiovasc Res, 2001 Jan, 49(1), 69 - 77
PR-39, a proline/arginine-rich antimicrobial peptide, exerts cardioprotective effects in myocardial ischemia-reperfusion; Ikeda Y et al.; OBJECTIVE: PR-39, a proline/arginine-rich antimicrobial peptide, has been shown to inhibit the NADPH oxidase activity of polymorphonuclear leukocytes (PMNs) by blocking assembly of this enzyme . We hypothesized that PR-39 could attenuate PMN-induced cardiac dysfunction by suppression of superoxide production . METHODS: We examined the effects of PR-39 in isolated ischemic (20 min) and reperfused (45 min) rat hearts administered PMNs at the onset of reperfusion . RESULTS: PR-39 (4 or 10 microg/ml) given i.v . 30 min prior to ischemia-reperfusion (I-R) significantly improved left ventricular developed pressure (LVDP, P<0.01) and the maximal rate of development of LVDP (i.e . +dP/dt max, P<0.01) compared to I-R hearts obtained from rats given 0.9% NaCl . PR-39-treated PMNs (10 microg/ml) also significantly attenuated cardiac contractile dysfunction after I-R (P<0.01) . Superoxide release was significantly reduced (P<0.01) in N-formylmethionyl-leucylphenylalanine stimulated PMNs pretreated with 4 or 10 microg/ml PR-39 . PR-39 also significantly attenuated P-selectin expression on the rat coronary microvascular endothelium and CD18 upregulation in rat PMNs . In addition, PR-39 significantly reduced PMN vascular adherence and infiltration into the post-ischemic myocardium . CONCLUSION: These results provide evidence that PR-39 significantly attenuates PMN-induced cardiac contractile dysfunction in the I-R rat heart at least in part via suppression of superoxide release . This cardioprotection occurred both by inhibition of PMN and endothelial NADPH oxidase.

Antimicrob Agents Chemother, 2001 Jan, 45(1), 356 - 8
Use of a recombinant strain of Mycobacterium avium expressing beta-galactosidase to evaluate the activities of antimycobacterial agents inside macrophages; Maisetta G et al.; A reliable and low-cost method that enables rapid screening of the activity exerted by new antimicrobial agents on intracellularly growing Mycobacterium avium has been developed . To this aim, a recombinant (lacZ) strain of M . avium expressing the Escherichia coli beta-galactosidase gene was used to evaluate, in murine macrophages, the susceptibility of M . avium to common antimycobacterial agents . beta-Galactosidase levels, measured in the presence of each of the antibiotics tested, were closely correlated with the number of CFU recovered from the M . avium lacZ strain-infected macrophages.

Antimicrob Agents Chemother, 2001 Jan, 45(1), 331 - 4
The ovine cathelicidin SMAP29 kills ovine respiratory pathogens in vitro and in an ovine model of pulmonary infection; Brogden KA et al.; Cathelicidins are antimicrobial peptides from sheep (SMAP29 and SMAP34), rabbits (CAP11 and CAP18), rodents (CRAMP), and humans (FALL39, LL37, and h/CAP18) . In a broth microdilution assay against nine ovine pathogens, SMAP29, SMAP34, mouse CRAMP, CAP18, CAP18(31), CAP18(28), CAP18(22), and CAP18(21a) were the most active, with MICs as low as 0.6 microg/ml . Other cathelicidins were less active . In lambs with pneumonia, 0.5 mg of SMAP29 reduced the concentration of bacteria in both bronchoalveolar lavage fluid and consolidated pulmonary tissues . Hence, the antimicrobial activity of SMAP29 suggests that it has applications in the treatment of respiratory tract infections.

Antimicrob Agents Chemother, 2001 Jan, 45(1), 212 - 6
In vitro antimicrobial susceptibility testing of bacterial enteropathogens causing traveler's diarrhea in four geographic regions; Gomi H et al.; The emergence of resistant enteropathogens has been reported worldwide . Few data are available on the contemporary in vitro activities of commonly used antimicrobial agents against enteropathogens causing traveler's diarrhea (TD) . The susceptibility patterns of antimicrobial agents currently available or under evaluation against pathogens causing TD in four different areas of the world were evaluated . Pathogens were identified in stool samples from U.S., Canadian, or European adults (18 years of age or older) with TD during 1997, visiting India, Mexico, Jamaica, or Kenya . MICs of 11different antimicrobials were determined against 284 bacterial enteropathogens by the agar dilution method . Ciprofloxacin, levofloxacin, ceftriaxone, and azithromycin were highly active in vitro against the enteropathogens, while traditional antimicrobials such as ampicillin, trimethoprim, and trimethoprim/sulfamethoxazole showed high levels and high frequencies of resistance . Rifaximin, a promising and poorly absorbable drug, had an MIC at which 90% of the strains tested were inhibited of 32 microg/ml, 250 times lower than the concentration of this drug in the stools . Amdinocillin, nalidixic acid, and doxycycline showed moderate activity . Fluoroquinolones are still the drugs of choice for TD in most regions of the world, although our study has a limitation due to the lack of Escherichia coli samples from Kenya and possible bias in selection of the patients for evaluation . Azithromycin and rifaximin should be considered as promising new agents . The widespread in vitro resistance of the traditional antimicrobial agents reported since the 1980s and the new finding of resistance to fluoroquinolones in Southeast Asia are the main reasons for monitoring carefully the antimicrobial susceptibility patterns worldwide and for developing and evaluating new antimicrobial agents for the treatment of TD.

Antimicrob Agents Chemother, 2001 Jan, 45(1), 129 - 37
Validation of a noninvasive, real-time imaging technology using bioluminescent Escherichia coli in the neutropenic mouse thigh model of infection; Rocchetta HL et al.; A noninvasive, real-time detection technology was validated for qualitative and quantitative antimicrobial treatment applications . The lux gene cluster of Photorhabdus luminescens was introduced into an Escherichia coli clinical isolate, EC14, on a multicopy plasmid . This bioluminescent reporter bacterium was used to study antimicrobial effects in vitro and in vivo, using the neutropenic-mouse thigh model of infection . Bioluminescence was monitored and measured in vitro and in vivo with an intensified charge-coupled device (ICCD) camera system, and these results were compared to viable-cell determinations made using conventional plate counting methods . Statistical analysis demonstrated that in the presence or absence of antimicrobial agents (ceftazidime, tetracycline, or ciprofloxacin), a strong correlation existed between bioluminescence levels and viable cell counts in vitro and in vivo . Evaluation of antimicrobial agents in vivo could be reliably performed with either method, as each was a sound indicator of therapeutic success . Dose-dependent responses could also be detected in the neutropenic-mouse thigh model by using either bioluminescence or viable-cell counts as a marker . In addition, the ICCD technology was examined for the benefits of repeatedly monitoring the same animal during treatment studies . The ability to repeatedly measure the same animals reduced variability within the treatment experiments and allowed equal or greater confidence in determining treatment efficacy . This technology could reduce the number of animals used during such studies and has applications for the evaluation of test compounds during drug discovery.

J Immunol, 2000 Dec 15, 165(12), 7102 - 8
Granulysin, a T cell product, kills bacteria by altering membrane permeability; Ernst WA et al.; Granulysin, a protein located in the acidic granules of human NK cells and cytotoxic T cells, has antimicrobial activity against a broad spectrum of microbial pathogens . A predicted model generated from the nuclear magnetic resonance structure of a related protein, NK lysin, suggested that granulysin contains a four alpha helical bundle motif, with the alpha helices enriched for positively charged amino acids, including arginine and lysine residues . Denaturation of the polypeptide reduced the alpha helical content from 49 to 18% resulted in complete inhibition of antimicrobial activity . Chemical modification of the arginine, but not the lysine, residues also blocked the antimicrobial activity and interfered with the ability of granulysin to adhere to Escherichia coli and Mycobacterium tuberculosis . Granulysin increased the permeability of bacterial membranes, as judged by its ability to allow access of cytosolic ss-galactosidase to its impermeant substrate . By electron microscopy, granulysin triggered fluid accumulation in the periplasm of M . tuberculosis, consistent with osmotic perturbation . These data suggest that the ability of granulysin to kill microbial pathogens is dependent on direct interaction with the microbial cell wall and/or membrane, leading to increased permeability and lysis.

FEBS Lett, 2000 Dec 15, 486(3), 185 - 90
Original involvement of antimicrobial peptides in mussel innate immunity; Mitta G et al.; Recently, the existence and extended diversity of antimicrobial peptides has been revealed in two mussel species . These molecules are classified into four groups according to common features of their primary structure: defensins, mytilins, myticins and mytimycin . In Mytilus galloprovincialis, gene structure reveals synthesis as precursors in circulating hemocytes . Synthesised even in absence of challenge, the precursors mature and the peptides are stored in granules as active forms . The different peptides are engaged in the destruction of bacteria inside phagocytes, before being released into hemolymph to participate in systemic responses . Such involvement in anti-infectious responses is unique, and apparently more related to those of mammalian phagocytes than to those of insects.

Int J Antimicrob Agents, 2000 Dec, 16(4), 381 - 94
Methylene blue derivatives--suitable photoantimicrobials for blood product disinfection?
Wainwright M.
Photodynamic antimicrobial agents based on the well-established phenothiazinium biological stain methylene blue offer a simple method for the inactivation or destruction of pathogens contained in donated blood and blood products . The technique is currently concentrated on viruses and the disinfective procedure can be carried out in blood bags using basic low-power light sources . Pathogens of the bacterial, yeast and protozoal classes are also susceptible to phenothiaziniums . The photoantimicrobial mode of action is usually via oxidative damage to cellular components, either due to redox reactions between the agent and a biomolecular target or by the action of reactive oxygen species generated in situ by photodynamic action . The targeting of various microbial species is discussed in relation to the physicochemical make-up of the photosensitizers, and future directions are suggested.

Clin Infect Dis, 2001 Jan, 32(1), 116 - 23 Epub 2000 Dec 15.
Determinants of antimicrobial prophylaxis use and treatment for wasting among patients with advanced human immunodeficiency virus disease in the United States, 1995-1998; Murphy EL et al.; Despite US Public Health Service (USPHS) recommendations for antimicrobial prophylaxis for patients with advanced human immunodeficiency virus (HIV) disease, the proportion of patients who receive prophylaxis is not known . We measured the prevalence of antimicrobial prophylaxis use, and treatment for HIV wasting at baseline among 531 patients with advanced HIV disease enrolled in a multicenter randomized trial of red blood cell transfusion . Use of antimicrobial prophylaxis and treatment for wasting in the 30 days before enrollment was ascertained in patients eligible for primary prophylaxis, secondary prophylaxis, or both, according to USPHS guidelines . There was high utilization of primary and secondary Pneumocystis carinii pneumonia prophylaxis, variability in primary Mycobacterium avium complex prophylaxis by center, and low use of primary cytomegalovirus prophylaxis . Treatment of wasting was more common in white than nonwhite patients and in patients with HIV disease who lived in the region west of the Mississippi River of the United States versus those whose lived in the eastern region.

Clin Infect Dis, 2001 Jan, 32(1), 76 - 102 Epub 2000 Dec 15.
Type 1/Type 2 immunity in infectious diseases; Spellberg B et al.; T helper type 1 (Th1) lymphocytes secrete secrete interleukin (IL)-2, interferon-gamma, and lymphotoxin-alpha and stimulate type 1 immunity, which is characterized by intense phagocytic activity . Conversely, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and stimulate type 2 immunity, which is characterized by high antibody titers . Type 1 and type 2 immunity are not strictly synonymous with cell-mediated and humoral immunity, because Th1 cells also stimulate moderate levels of antibody production, whereas Th2 cells actively suppress phagocytosis . For most infections, save those caused by large eukaryotic pathogens, type 1 immunity is protective, whereas type 2 responses assist with the resolution of cell-mediated inflammation . Severe systemic stress, immunosuppression, or overwhelming microbial inoculation causes the immune system to mount a type 2 response to an infection normally controlled by type 1 immunity . In such cases, administration of antimicrobial chemotherapy and exogenous cytokines restores systemic balance, which allows successful immune responses to clear the infection.

Plant Mol Biol, 2000 Sep, 44(2), 187 - 97
Characterization and cDNA cloning of two glycine- and histidine-rich antimicrobial peptides from the roots of shepherd's purse, Capsella bursa-pastoris; Park CJ et al.; Two novel antimicrobial peptides were isolated and characterized from the roots of shepherd's purse, Capsella bursa-pastoris . These antimicrobial peptides, named shepherin I and shepherin II, consist of 28 and 38 amino acids, respectively, and are glycine- and histidine-rich peptides . Shepherin I and shepherin II have 67.9% and 65.8% (mol/mol) glycine, respectively, and 28.6% and 21.1% (mol/mol) histidine, respectively . Both shepherins have a Gly-Gly-His motif . These antimicrobial peptides exhibit antimicrobial activity against Gram-negative bacteria and fungi . Circular dichroism spectra of shepherin I and shepherin II showed that shepherin I and shepherin II in 50% trifluoroethanol have 66.7% and 75% random coils, respectively, without any alpha-helices . cDNA sequence analysis revealed that shepherin I and shepherin II are produced from a single polypeptide, designated shep-GRP, consisting of 120 amino acids; shep-GRP has five distinct domains, an amino-terminal putative signal peptide, a shepherin I, a linker dipeptide, a shepherin II and a carboxy-terminal peptide . Southern blot analysis indicates that the gene encoding shepherins belongs to a low-complexity gene family . Northern blot analysis revealed that transcripts of shep-GRP are present in roots but not in leaves and stems.

Med Arh, 2000, 54(3), 147 - 51
{Use of antimicrobial drug prescriptions in children with a common cold or diarrhea}; Mulic S et al.; There are justified reasons to assume that antibicrobial drugs are too frequently prescribed in routine pediatric practice . The main aim of the study was to prove the frequency of antimicrobial administration to children . A total of 209 children of either sex and under 18 years of age with common colds and 95 children with diarrhea who were examined at the Primary Health Care Department of Hospital Konjic, Bosnia and Herzegovina for the period of Jan 1999-Apr 2000 were investigated for antimicrobial therapy . Antimicrobials were prescribed to 175 (83.73 per cent) patients with common cold and 78 (82.11 per cent) patients with diarrhea . Taking into consideration that the aetiology of these conditions was predominantly viral, the outcome of this study provides the evidence of irrational administration of antimicrobials and states the possible ones: diagnostic difficulties in routine pediatric practice, low educational level of physicians, lack of consulting skills, overworked primary health care physicians, influence of inpatient parents about prescribing antibiotics and influence of pharmaceutical industry . It is widely known that the negative effects of such superflous administration could leave numerous consequences to the patients health condition . Besides that, irrational use of the above mentioned drugs financially charges health system funds . It is therefore necessary to enhance consulting skills, to improve research and evidence based guidelines and monitoring strategies as well in order to support rational antimicrobial administration to children . The observation that irrational use of antibiotics was detected frequently with both common cold and diarrea suggests the need for continous monitoring and analyses of antibiotic administration to children from our region.

Chest, 2000 Dec, 118(6), 1826 - 7
Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma; Garey KW et al.; Prolonged use of prednisone is associated with serious side effects, such as osteoporosis, particularly among elderly individuals . Macrolide antibiotics exhibit anti-inflammatory effects that are distinct from their antimicrobial properties . Thus, the purpose of this case report is to describe the effects of prolonged treatment with clarithromycin, 500 mg bid, in reducing prednisone requirements in three elderly patients with prednisone-dependent asthma . Three patients (one woman and two men) aged 63 to 69 years, who had been treated with 5 to 10 mg prednisone daily for at least the last 12 months, were given clarithromycin, 500 mg bid . They were followed regularly for changes in daily prednisone dose, spirometry, quality of life, and adverse events . The prednisone dose was tapered in a stepwise fashion at each clinic visit . Within 3 to 6 months of initiation of treatment with clarithromycin, and throughout the 12-month follow-up, two of three patients discontinued prednisone therapy, while the third patient displayed increased spirometry readings and noted an increasingly better quality of life . Pulmonary function tests were stable or improved over this time period, with no reported adverse events, including increased rate of infections . One patient relapsed upon discontinuation of clarithromycin therapy but has since responded to re-initiation of treatment . Long-term oral clarithromycin may have a role in reducing prednisone requirements in elderly patients with prednisone-dependent asthma.

Am J Infect Control, 2000 Dec, 28(6), 415 - 20
Antibiotic use and cost indicators at a rural hospital: a pilot project; Mylotte JM et al.; BACKGROUND: Recently, simple antibiotic use and cost indicators were developed for use in long-term care facilities . It was hypothesized that these indicators also may be applicable to the acute hospital setting . METHODS: For a 24-month period, data were collected quarterly on antibiotic use and cost indicators for 11 primary care physicians in a 40-bed rural hospital . Indicators included antimicrobial use ratio (AUR, ratio of the number of antibiotic days to the number of patient care days), cost per antibiotic day, and cost of antibiotics per patient care day . One-way analysis of variance and simple linear regression were used to analyze data . RESULTS: Quinolones (oral plus parenteral) accounted for 26% of the total antibiotic days (N = 6020) followed by ceftriaxone (19%) and cefuroxime (11.8%; oral plus parenteral) . Overall trends in antibiotic use and cost included a significant increase in quarterly AUR (R(2) = 0.78, P =.004) and cost per patient care day (R(2) = 0 . 82, P =.002) but no significant change in quarterly total antibiotic costs or cost per antibiotic day . Among physicians there was a significant difference in mean quarterly AUR (P <.001) and mean quarterly cost per patient care day (P <.001) but no significant difference in mean quarterly cost per antibiotic day . Variation in physician-specific cost per patient care day was best explained by variation in AUR (R(2) = 0.75, P <.001) . CONCLUSIONS: Significant variation in simple antibiotic use and cost indicators was identified at a rural hospital from both the facility and physician perspective . Standardized methods for antibiotic use and cost monitoring, like the one described in this article, are required before the relationship between antibiotic use and resistance can be fully understood.

Immunity, 2000 Nov, 13(5), 737 - 48
Tissue-specific inducible expression of antimicrobial peptide genes in Drosophila surface epithelia; Tzou P et al.; The production of antimicrobial peptides is an important aspect of host defense in multicellular organisms . In Drosophila, seven antimicrobial peptides with different spectra of activities are synthesized by the fat body during the immune response and secreted into the hemolymph . Using GFP reporter transgenes, we show here that all seven Drosophila antimicrobial peptides can be induced in surface epithelia in a tissue-specific manner . The imd gene plays a critical role in the activation of this local response to infection . In particular, drosomycin expression, which is regulated by the Toll pathway during the systemic response, is regulated by imd in the respiratory tract, thus demonstrating the existence of distinct regulatory mechanisms for local and systemic induction of antimicrobial peptide genes in Drosophila.

Phytother Res, 2000 Dec, 14(8), 641 - 3
Biologically active steroid from the green alga Ulva lactuca; Awad NE; The marine green alga, Ulva lactuca, was shown to contain 3-O-beta-D glucopyranosyl-stigmasta-5,25-dien . The structure of the compound was established on the basis of its spectroscopic data and it was extracted for the first time from this alga . The topical antiinflammatory activity of this compound was examined using the mouse ear oedema assay as an experimental model of topical inflammation . Also, the antimicrobial activity of the isolated compound was tested against 10 various microorganisms (G+, G-, fungi and yeast strains).

Phytother Res, 2000 Dec, 14(8), 623 - 9
Pharmacological and antimicrobial studies on different tea-tree oils (Melaleuca alternifolia, Leptospermum scoparium or Manuka and Kunzea ericoides or Kanuka), originating in Australia and New Zealand; Lis-Balchin M et al.; Three different species of Myrtaceae growing in Australia and New Zealand are known as 'Tea-tree': the Australian Tea tree (Melaleuca alternifolia), the New Zealand Manuka (Leptospermum scoparium) and Kanuka (Kunzea ericoides) . All three essential oils are used by aromatherapists, although only Melaleuca has been tested for toxicity, and its antimicrobial effects studied . The pharmacology and antimicrobial activity of the three 'tea-tree' oils was determined using guinea-pig ileum, skeletal muscle (chick biventer muscle and the rat phrenic nerve diaphragm) and also rat uterus in vitro . Differences were shown between the three essential oils in their action on smooth muscle: Manuka had a spasmolytic action, while Kanuka and Melaleuca had an initial spasmogenic action . Using the diaphragm, Manuka and Melaleuca decreased the tension and caused a delayed contracture; Kanuka had no activity at the same concentration . The action on chick biventer muscle was, however, similar for all three oils, as was the action on the uterus, where they caused a decrease in the force of the spontaneous contractions . The latter action suggests caution in the use of these essential oils during childbirth, as cessation of contractions could put the baby, and mother, at risk . The comparative antimicrobial activity showed greater differences between different samples of Manuka and Kanuka than Melaleuca samples . The antifungal activity of Kanuka was inversely proportional to its strong antibacterial activity, whilst Manuka displayed a stronger antifungal effect, though not as potent as Melaleuca . The antioxidant activity of Manuka samples was more consistent than that of Kanuka, while Melaleuca showed no activity . The variability in the Manuka and Kanuka essential oils suggests caution in their usage, as does the fact that the oils have not been tested for toxicity.

Phytother Res, 2000 Dec, 14(8), 617 - 22
Immunoenhancing properties of Plantago major leaf extract; Gomez-Flores R et al.; Plantago major (PM), also known as plantain, is a weed found in temperate zones worldwide . PM leaves have been associated with various biological properties ranging from antiinflammatory, antimicrobial and antitumour to wound healing . However, its mechanism of action associated with boosting of the immune function remains to be elucidated . We found that endotoxin-free methanol extracts from PM leaves, at doses of 50, 100, 250, and 500 microg/mL, were associated with 4.4 +/- 1, 6 +/- 1, 12 +/- 0.4, and 18 +/- 0.4-fold increases of nitric oxide (NO) production, and increased TNF-alpha production (621 +/- 31, 721 +/- 36, 727 +/- 36, and 1056 +/- 52 U/mL, respectively) by rat peritoneal macrophages, in the absence of IFN-gamma or LPS . NO and TNF-alpha production by untreated macrophages was negligible . In addition, PM extracts potentiated Con A-induced lymphoproliferation (3- to 12-fold increases) in a dose-dependent fashion, compared with the effect of Con A alone . The regulation of immune parameters induced by plant extracts may be clinically relevant in numerous diseases including chronic viral infections, tuberculosis, AIDS and cancer.

Dev Comp Immunol, 2001 Mar, 25(2), 137 - 47
Cloning and developmental expression of a family of pleurocidin-like antimicrobial peptides from winter flounder, Pleuronectes americanus (Walbaum); Douglas SE et al.; Low molecular weight antimicrobial peptides are an important component of the innate immune system in animals, yet they have not been examined widely in fish . Of particular interest is their expression during development and in response to environmental conditions and disease . Here, we report the isolation of four genomic sequences encoding putative antimicrobial peptides from the winter flounder, Pleuronectes americanus (Walbaum), as well as reverse transcription-PCR products from two tissues that form the first defensive barrier to microbes - skin and intestine . Alignment of the predicted polypeptide sequences shows a conserved hydrophobic signal peptide of 22 amino acids followed by 25 amino acids that are identical (WF2) or homologous to the amino acid sequence of pleurocidin, followed by a conserved acidic portion . Southern hybridisation analysis indicates that related peptides are encoded in the genomes of other flatfish species . Northern and RT-PCR analyses of RNA from multiple tissues show that two of the pleurocidin genes are expressed predominantly in the skin whereas two other genes are expressed mainly in the intestine . RT-PCR assays of total RNA from larvae of different ages provide the first evidence of developmental expression of antimicrobial peptides in fish and indicate that the pleurocidin gene is first expressed at 13 days post-hatch in winter flounder.

Dev Comp Immunol, 2001 Mar, 25(2), 101 - 15
Products of proteolytic cleavage of transferrin induce nitric oxide response of goldfish macrophages; Stafford JL et al.; Enzymatic cleavage product of transferrin induced the production of nitric oxide (NO) by LPS-stimulated goldfish macrophages . A NO-inducing factor was purified from the supernatants of mitogen-stimulated goldfish kidney leukocytes using fast performance liquid chromatography (FPLC) and the purified proteins analyzed by microcapillary reverse-phase HPLC nano-electrospray tandem mass spectrometry . The proteins were identified as truncated forms of transferrin, having approximate molecular weights (MW) of 33, 35, and 37kDa (kilodaltons) . The precursor form (i.e . full-length) of transferrin did not enhance NO production by LPS-stimulated goldfish macrophages, but enzymatic cleavage of this precursor form correlated with enhanced production of NO by goldfish macrophages . Enzymatic cleavage of transferrin was dependent on the presence of stimulated kidney leukocytes and was shown to occur in response to both mixed lymphocyte reactions (MLR) and the mitogenic stimulation of goldfish kidney leukocytes . Time course analysis revealed that 24h after kidney leukocyte MLR or mitogen stimulation, cleaved transferrin products appeared in the supernatants of cultured cells, which was related to the on-set of NO-inducing activity of these preparations . To confirm these findings, bovine transferrin was digested in vitro using protease XXVII . The resulting cleavage products had approximate MW of 33, 35, and 37kDa . When these peptides were subjected to the purification protocols used to purify a NO-inducing factor from goldfish leukocyte supernatants, they were shown to elute to identical fractions . To examine the potential role of fish transferrin in mediating goldfish NO production, carp transferrin was purified from serum and following protease-digestion and purification by FPLC, the truncated proteins were found to elute to similar fractions as bovine transferrin . Furthermore, mitogen-stimulated leukocyte supernatants prepared in the absence of bovine serum (carp serum only) retained NO-inducing activity, indicating that this response was not an artifact of bovine serum components (i.e . bovine transferrin) . Anti-bovine and anti-carp transferrin polyclonal antibodies identified the presence of truncated forms of transferrin in the active fractions of FPLC-separated mitogen-stimulated leukocyte supernatants prepared in the presence of bovine or carp serum, respectively . Thus, our results suggest a novel role for fish transferrin as one of the factors that mediates teleost macrophage antimicrobial functions.

Phytother Res . 2000 Dec;14(8):661.
S . K . Adesina, O . Idowu, A . O . Ogundaini, H . Oladimeji, T . A . Olugbade, G . O . Onawunmi and M . Pais, 'Antimicrobial constituents of the leaves of EAcalypha wilkesiana and acalypha hispida' . Phytotherapy research14(5) 2000, 371-374
Adesina SK, Idowu O, Ogundaini AO, Oladimeji H, Olugbade TA, Onawunmi GO, Pais M.
The original article to which this Erratum refers was published in Phytotherapy Research 14(5) 2000, 371-374 . Following publication of this paper in the August 2000 issue of Phytotherapy Research (14(5):371-374), it has come to our attention that the dates of receipt and acceptance were printed incorrectly . The corrected dates appear below . The publishers would like to apologise for any confusion caused . Received 28 August 1996 Accepted 15 June 1997

J Biol Chem, 2001 Mar 16, 276(11), 7811 - 9 Epub 2000 Dec 11.
A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload; Pigeon C et al.; Considering that the development of hepatic lesions related to iron overload diseases might be a result of abnormally expressed hepatic genes, we searched for new genes up-regulated under the condition of iron excess . By suppressive subtractive hybridization performed between livers from carbonyl iron-overloaded and control mice, we isolated a 225-base pair cDNA . By Northern blot analysis, the corresponding mRNA was confirmed to be overexpressed in livers of experimentally (carbonyl iron and iron-dextran-treated mice) and spontaneously (beta(2)-microglobulin knockout mice) iron-overloaded mice . In addition, beta(2)-microglobulin knockout mice fed with a low iron content diet exhibited a decrease of hepatic mRNA expression . The murine full-length cDNA was isolated and was found to encode an 83-amino acid protein presenting a strong homology in its C-terminal region to the human antimicrobial peptide hepcidin . In addition, we cloned the corresponding rat and human orthologue cDNAs . Both mouse and human genes named HEPC are constituted of 3 exons and 2 introns and are located on chromosome 7 and 19, respectively, in close proximity to USF2 gene . In mouse and human, HEPC mRNA was predominantly expressed in the liver . During both in vivo and in vitro studies, HEPC mRNA expression was enhanced in mouse hepatocytes under the effect of lipopolysaccharide . Finally, to analyze the intracellular localization of the predicted protein, we used the green fluorescent protein chimera expression vectors . The murine green fluorescent protein-prohepcidin protein was exclusively localized in the nucleus . When the putative nuclear localization signal was deleted, the resulting protein was addressed to the cytoplasm . Taken together, our data strongly suggest that the product of the new liver-specific gene HEPC might play a specific role during iron overload and exhibit additional functions distinct from its antimicrobial activity.

Clin Ther, 2000 Oct, 22(10), 1239 - 50
Retrospective analysis of the safety profile of oral and intravenous ciprofloxacin in a geriatric population; Heyd A et al.; BACKGROUND: Ciprofloxacin is a broad-spectrum fluoroquinolone antibiotic used in the treatment of a wide range of mild to moderate gram-positive and gram-negative infections . Although extensive information is available on the safety profile of ciprofloxacin in adults, few published data exist regarding the tolerability and toxicity of this drug in patients aged > or = 65 years . OBJECTIVES: The objectives of this retrospective analysis were to compare the safety profile of ciprofloxacin in patients aged > or = 65 years versus patients aged <65 years and to compare the adverse-event profile of ciprofloxacin with that of other comparator antimicrobial agents used in clinical trials . METHODS: We retrospectively reviewed 23 prospective, controlled anti-infective clinical trials in the US Bayer ciprofloxacin database that included patients aged > or = 65 years . These trials comprised the submission file of the original and supplemental New Drug Application for ciprofloxacin . The incidence of treatment-emergent and drug-related adverse events was assessed . RESULTS: Of the 6863 patients in these 23 clinical trials, 3579 received ciprofloxacin therapy and 3284 received comparator antimicrobial agents . Of the ciprofloxacin-treated patients, 898 (25.1%) were aged > or = 65 years; 887 (27.0%) of the patients who received comparator antimicrobial agents were aged > or = 65 years . Among ciprofloxacin-treated patients, drug-related adverse events were reported more often in those aged <65 years (24.0%) compared with those aged > or = 65 years (17.9%) . The incidence of drug-related adverse events in the comparator group was also higher in those aged <65 years (25.1%) than in those aged > or = 65 years (16.8%) . Premature discontinuation due to any adverse event was reported in 3.9% (105 of 2681) and 3.7% (33 of 898) of ciprofloxacin-treated patients aged <65 years and > or = 65 years, respectively . Corresponding rates for the comparator antimicrobial group were 3.9% (93 of 2397) and 3.8% (34 of 887), respectively, for patients aged <65 years and > or = 65 years . The most common drug-related adverse events reported for ciprofloxacin-treated patients aged <65 years and > or = 65 years were digestive system-related (18.1% and 11.4%, respectively) and central nervous system-related events (6.6% and 4.9%, respectively) . CONCLUSIONS: This retrospective analysis suggests that there is no clinically important difference in the safety profile of ciprofloxacin in patients aged > or = 65 years versus patients aged <65 years.

J Vet Pharmacol Ther, 2000 Jun, 23(3), 169 - 74
Single-dose pharmacokinetics of flumequine in the eel (Anguilla anguilla) after intravascular, oral and bath administration; Hansen MK et al.; Knowledge of the pharmacokinetic properties of drugs to combat bacterial infections in the European eel (Anguilla anguilla) is limited . One antimicrobial agent likely to be effective is flumequine . The aim of this study was to investigate the pharmacokinetic properties of flumequine in European eels in fresh water . Flumequine was administered to eels (Anguilla anguilla) intravenously (i.v.) and orally (p.o.) at a dose of 10 mg/kg body weight, and as a bath treatment at a dose of 10 mg/L water for 2 h . The study was performed in fresh water with a temperature of 23 + 0.3 degrees C, pH 7.15 . Identical experimental designs were used . Two additional bath treatments were also performed, one in which the pH in the water was lowered by approximately 1 unit to 6.07 (dose: 10 mg/L) and one at a dose of 40 mg/L for 2 h in a full-scale treatment . Following i.v . administration, the volume of distribution at steady state was 3.4 L/kg . Total body clearance was 0.012 L/h per kg and the elimination half-life (t1/2lambda z) was calculated to be 314 h . Mean residence time was 283 h . Following oral administration, the t1/2lambda z was 208 h . Maximal plasma concentration (Cmax) was 9.3 mg/L, at 7 h after administration (Cmax) . The oral bioavailability (F) was calculated to be 85% . Following bath administration in 10 mg/L for 2 h, maximal plasma concentration was 2.1 mg/L, observed immediately after the end of the bath . The 'bioavailability' in eel following a 2-h bath treatment was 19.8% . Reducing the pH in the bath to 6.07 produced a maximal plasma concentration of 5.5 mg/L, observed immediately after the end of the bath . The 'bioavailability' was increased to 41% by the lowering of the pH . A similar effect was observed in a full-scale treatment (1 kg eels/L water) . The CO2 produced by the eel lowered the pH and increased 'bioavailability' to 35%.

J Vet Pharmacol Ther, 2000 Jun, 23(3), 163 - 8
Single-dose pharmacokinetics of flumequine in cod (Gadus morhua) and goldsinny wrasse (Ctenolabrus rupestris); Hansen MK et al.; Knowledge of the pharmacokinetic properties of drugs to combat bacterial infections in cod (Gadus morhua) and wrasse (Ctenolabrus rupestris) is limited . One antimicrobial agent likely to be effective is flumequine . The aim of this study was to investigate the pharmacokinetic properties of flumequine in these two species . Flumequine was administered intravenously to cod (G . morhua) at a dose of 5 mg/kg bodyweight and wrasse (C . rupestris) at a dose of 10 mg/kg . Flumequine was also administered orally to both species at a dose of 10 mg/kg body weight, and as a bath treatment at a dose of 10 mg/L water for 2 h . Identical experimental designs were used otherwise . The study was performed in seawater with a salinity of 3.2% and a temperature of 8.0 +/- 0.2 degrees C (cod) and 14.5 +/- 0.4 degrees C (wrasse) . Pharmacokinetic modelling of the data showed that flumequine had quite different pharmacokinetic properties in cod and wrasse . Following intravenous administration, the volumes of distribution at steady-state (Vss) were 2.41 L/kg (cod) and 2.15 L/kg (wrasse) . Total body clearances (Cl) were 0.024 L/hxkg (cod) and 0.14 L/hxkg (wrasse) and the elimination half-lives (t1/2lambda z) were calculated to be 75 h (cod) and 31 h (wrasse) . Mean residence times (MRT) were 99 h (cod) and 16 h (wrasse) . Following oral administration, the t1/2 lambda z were 74 h (cod) and 41 h (wrasse) . Maximal plasma concentrations (tmax) were 3.5 mg/L (cod) and 1.7 mg/L (wrasse), and were observed 24 h post-administration in cod and 1 h post-administration in wrasse . The oral bioavailabilities (F) were calculated to be 65% (cod) and 41% (wrasse) . Following bath administration, maximal plasma concentrations were 0.13 mg/L (cod) and 0.09 mg/L (wrasse), and were observed immediately after the end of the bath.

Nihon Kokyuki Gakkai Zasshi, 2000 Sep, 38(9), 702 - 5
{A case report of pulmonary nocardiosis successfully treated with a combination of sulfamethoxazole-trimethoprim (ST) and sparfloxacin}; Kimura K et al.; We encountered a case of pulmonary nocardiosis that responded dramatically to combined ST and sparfloxacin treatment . A 55-year-old woman presented with fever, cough and yellowish sputum . She had been under treatment with oral prednisolone (15 mg per day) since July 1997 after a diagnosis of Evans syndrome . A high fever of 39.8 degrees C was noted on January 30, 1998 . The patient was hospitalized for bloody sputum, bilateral hypochondriac pain and evidence of infiltrative opacities in the left lower lobe on chest radiography . Bacterial pneumonia was suspected, and she was treated with piperacillin, but her clinical symptoms did not improve . Sputum culture and serologic examination failed to lead to a definitive diagnosis . Nocardia farcinica was isolated by culturing tissue obtained by CT-guided transcutaneous pulmonary biopsy, leading to a diagnosis of pulmonary nocardiosis . The results of an MIC test for antimicrobial agents led to treatment with a combination of ST and sparfloxacin, and the clinical symptoms improved . These clinical observations suggest that, when pneumonia is diagnosed in patients who have been receiving oral steroids for a prolonged period, pulmonary nocardiosis should be considered in the differential diagnosis to enable selection of appropriate antimicrobial agents.

Adv Drug Deliv Rev, 2000 Dec 15, 45(2-3), 255 - 69
Microdialysis in clinical drug delivery studies; Muller M; The introduction of in vivo microdialysis (MD) to clinical pharmacological studies has opened the opportunity to obtain previously inaccessible information about the drug distribution process to the clinically relevant target site . The aim of this review is to provide a comprehensive overview of the current literature about MD in drug delivery studies from a clinical perspective . In particular the application of MD in clinical--antimicrobial, oncological and transdermal--and neurological research will be described and the scope of MD in pharmacokinetic-pharmacodynamic (PK-PD) studies will be discussed . It is concluded that MD has a great potential for both academic and industrial research, and may become the method of choice for drug distribution studies in humans.

Tidsskr Nor Laegeforen, 2000 Sep 30, 120(23), 2761 - 3
{Postoperative wound infections in elective colorectal surgery}; Flatmark K et al.; BACKGROUND: Surgical wound infections still represent a significant problem in colorectal surgery . We wanted to investigate the frequency of postoperative wound infections in patients who had elective colorectal surgery at Lillehammer County Hospital . By reviewing relevant literature we also wanted to assess the evidence base for using antimicrobial prophylaxis in colorectal surgery, which regimens are to be preferred, and the probable reduction in wound infections . MATERIAL AND METHODS: 99 patients were followed up at 14 days after surgery; presence or absence of wound infection was noted . Samples for culture were obtained in all patients with suspected wound infection . Literature on the subject was studied focusing on systematic reviews . RESULTS: Eight out of 99 patients (8%) had wound infections . In a systematic review of 147 studies comparing different antibiotic regimens, the overall infection rate for patients receiving antibiotic prophylaxis was 11% . INTERPRETATION: The surgical wound infection rate was comparable with the results from relevant systematic reviews . The effect of antimicrobial prophylaxis is well documented . A combination of an anaerobic and an aerobic drug should be used, but no gold standard can be identified . Two adequate regimens have been investigated in controlled studies carried out in Norway.

Immunology, 2000 Nov, 101(3), 300 - 8
Nitric oxide and virus infection; Akaike T et al.; Nitric oxide (NO) has complex and diverse functions in physiological and pathophysiological phenomena . The mechanisms of many events induced by NO are now well defined, so that a fundamental understanding of NO biology is almost established . Accumulated evidence suggests that NO and oxygen radicals such as superoxide are key molecules in the pathogenesis of various infectious diseases . NO biosynthesis, particularly through expression of an inducible NO synthase (iNOS), occurs in a variety of microbial infections . Although antimicrobial activity of NO is appreciated for bacteria and protozoa, NO has opposing effects in virus infections such as influenza virus pneumonia and certain other neurotropic virus infections . iNOS produces an excessive amount of NO for long periods, which allows generation of a highly reactive nitrogen oxide species, peroxynitrite, via a radical coupling reaction of NO with superoxide . Thus, peroxynitrite causes oxidative tissue injury through potent oxidation and nitration reactions of various biomolecules . NO also appears to affect a host's immune response, with immunopathological consequences . For example, overproduction of NO in virus infections in mice is reported to suppress type 1 helper T-cell-dependent immune responses, leading to type 2 helper T-cell-biased immunological host responses . Thus, NO may be a host response modulator rather than a simple antiviral agent . The unique biological properties of NO are further illustrated by our recent data suggesting that viral mutation and evolution may be accelerated by NO-induced oxidative stress . Here, we discuss these multiple roles of NO in pathogenesis of virus infections as related to both non-specific inflammatory responses and immunological host reactions modulated by NO during infections in vivo.

Planta Med, 2000 Oct, 66(7), 672 - 4
Composition and antimicrobial activity of the essential oil of Scutellaria albida ssp . albida from Greece; Skaltsa HD et al.; Steam distilled essential oil from aerial parts of Scutellaria albida ssp . albida was analyzed by GC and GC/MS . Fifteen compounds were identified of which linalool (52.63%) and trans-nerolidol (9.03%) were the major constituents . Furthermore, the oil was tested against four bacteria and two yeasts and was found to be moderately active against all microorganisms tested.

Planta Med, 2000 Oct, 66(7), 670 - 2
Essential oil of Phlomis lanata growing in Greece: chemical composition and antimicrobial activity; Couladis M et al.; The essential oil obtained from the aerial parts of Phlomis lanata has been analyzed by GC/MS . 48 compounds representing 96.85% of the oil were identified; alpha-pinene, limonene and trans-caryophyllene were found as its main components . The essential all showed a moderate in vitro activity against six Gram (+/-) bacteria and a stronger one against the three tested pathogenic fungi.

Planta Med, 2000 Oct, 66(7), 647 - 50
Antimicrobial activity and chemical composition of the bark oil of Croton stellulifer, an endemic species from S . Tomé e Príncipe; Martins AP et al.; The composition and the antimicrobial activity of the bark oil of Croton stellulifer, an endemic and rare species of these islands (S . Tome and Principe) are reported . Analysis was carried out by GC, GC/MS and 13C-NMR . The major constituents were alpha-phellandrene (15.4-18.6%), p-cymene (14.4-17.7%), linalool (12.0-12.6%) and alpha-pinene (8.1-9.1%) . Kessane, a sesquiterpenoid oxide, not yet reported in the genus Croton, was identified by NMR . The essential oil of C . stellulifer was active against both bacterial and fungal strains, except Aspergillus niger.

Mycoses, 2000 Oct, 43(9-10), 367 - 72
Case report . Pathohistological findings in a clinical case of disseminated infection with Fusarium oxysporum; Peltroche-Llacsahuanga H et al.; Despite appropriate antimicrobial and antifungal therapy (amphotericin B), a disseminated infection with Fusarium oxysporum in a 75-year-old immunocompromised patient (acute myeloid leukaemia, minimal leucocyte count of 0.5 giga l-1) led rapidly to death . A similarly fatal course of an F . oxysporum infection has been reported in several cases . Fusarium oxysporum could be isolated shortly before death from blood cultures and from a swab taken from skin efflorescences . An autopsy revealed histopathologically typical fungal infiltrates in the mucosa of the pharynx, epiglottis, trachea, and oesophagus and in the parenchyma of the spleen, the lung and both kidneys . Because of the high risk of a fatal outcome of this infection, the clinician should aim at maximum diagnostic enforcement . We propose both analysis of blood cultures and immediate skin biopsy--with PAS-staining--of suspicious dermal efflorescences for microscopic examination . The treatment of choice is discussed controversially but a beneficial effect has been reported from granulocyte transfusion, subcutaneous administration of GM-CSF and concomitant treatment with amphotericin B.

J Am Osteopath Assoc, 2000 Oct, 100(10), 635 - 9
Galbreath technique: a manipulative treatment for otitis media revisited; Pratt-Harrington D; Otitis media is a common disorder that results in numerous visits to the physician each year . Antimicrobials, antihistamines, steroids, and surgery have all been used to treat otitis media; however, the literature makes little mention of osteopathic manipulative treatment in this regard . This article describes a technique that was first described in 1929 by William Otis Galbreath, DO . By simple mandibular manipulation, the eustachian tube is made to open and close in a "pumping action" that allows the ear to drain accumulated fluid more effectively . Physicians can easily teach this procedure to parents for use at home.

Microbiol Mol Biol Rev, 2000 Dec, 64(4), 655 - 71
Probiotic bacteria as biological control agents in aquaculture; Verschuere L et al.; There is an urgent need in aquaculture to develop microbial control strategies, since disease outbreaks are recognized as important constraints to aquaculture production and trade and since the development of antibiotic resistance has become a matter of growing concern . One of the alternatives to antimicrobials in disease control could be the use of probiotic bacteria as microbial control agents . This review describes the state of the art of probiotic research in the culture of fish, crustaceans, mollusks, and live food, with an evaluation of the results obtained so far . A new definition of probiotics, also applicable to aquatic environments, is proposed, and a detailed description is given of their possible modes of action, i.e., production of compounds that are inhibitory toward pathogens, competition with harmful microorganisms for nutrients and energy, competition with deleterious species for adhesion sites, enhancement of the immune response of the animal, improvement of water quality, and interaction with phytoplankton . A rationale is proposed for the multistep and multidisciplinary process required for the development of effective and safe probiotics for commercial application in aquaculture . Finally, directions for further research are discussed.

Arzneimittelforschung, 2000 Oct, 50(10), 941 - 5
{In Process Citation}; Jaeger K et al.; Early post-operative infections remain the most important cause of morbidity and mortality in patients following orthotopic liver transplantation (OLTx) . Since polymorphonuclear neutrophils (PMNs) are one of the major determinants of antimicrobial defence, the alteration of their functions may influence the outcome of infection in these patients . Ciclosporin predominantly used as immunosuppressive drug following organ transplantation inhibits superoxide anion production during respiratory burst (RB) of PMNs . Growth factors have been shown to modulate the RB of PMNs in healthy volunteers . It has been examined whether PMNs from patients under immunosuppression following OLTx can be primed by in vitro administration of interleukin-3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF) . For flow-cytometric evaluation, leukocytes were obtained as supernatant following sedimentation and were incubated with IL-3 (500 U ml-1), IL-3 and GM-CSF (500 U ml-1), or IL-3 and G-CSF (500 U ml-1) . The RB was measured by intracellular oxidation of non-fluorescent dihydrorhodamine to green fluorescent rhodamine after induction of phorbol 12-myristate 13-acetate (PMA) or a combination of tumour necrosis factor alpha (TNF-alpha) and N-formyl-methionyl-leucyl-phenylalanine (FMLP) . Following stimulation with PMA, the RB of patients following OLTx could be increased significantly after priming with the combination of IL-3/G-CSF (p < 0.03); following stimulation with TNF-alpha/FMLP the RB could be increased significantly by IL-3 (p < 0.01), IL-3/G-CSF (p < 0.002), and IL-3/GM-CSF (p < 0.002) . Regarding the clinical administration of IL-3, GM-CSF and G-CSF following OLTx, the role of these cytokines for prophylaxis or treatment of early postoperative infections should be further investigated.

Arzneimittelforschung, 2000 Oct, 50(10), 915 - 24
Syntheses and cytotoxic, antimicrobial, antifungal and cardiovascular activity of new quinoline derivatives
Khan KM, Saify ZS, Khan ZA, Ahmed M, Saeed M, Schick M, Kohlbau HJ, Voelter W.
New derivatives of quinoline (CAS 91-22-5, Z-1) were synthesized and their potential therapeutical significance and structure-activity relationship were tested . The brine shrimp bioassay was carried out to study their in vitro cytotoxicity, and besides, also their antimicrobial, antifungal and cardiovascular activities were investigated . Some structures showed a high degree of activity on the isolated rabbit jejunum . Extensive spectroscopic techniques such as EIMS, FABMS, peak matching MS, UV, IR and 1H NMR were employed to confirm the structure of the synthetic products.

J Am Dent Assoc, 2000 Nov, 131(11), 1600 - 9
A survey of antibiotic use in dentistry; Epstein JB et al.; BACKGROUND: Antibiotics are important in the management and prophylaxis of infection in patients at risk of experiencing microbial disease . As a result of the increase in antimicrobial resistance, the authors conducted a survey to assess current antibiotic use in dental practice . METHODS: The authors mailed a two-page, pretested survey to all licensed dental practitioners in British Columbia, Canada . A total of 2,542 surveys were mailed; 19.9 percent were returned by fax or mail . The authors examined an association between factors analyzed using a chi 2 test . RESULTS: Respondents were demographically consistent with all registered dentists in British Columbia . They reported writing an average of 4.45 prescriptions per week . Antibiotics prescribed after treatment primarily were penicillin and its derivatives . Recommended adult doses of penicillin were prescribed by 59.2 percent of respondents; recommended daily doses of amoxicillin were prescribed by 72.2 percent of respondents . The average prescription duration was 6.92 days . Respondents prescribed prophylactic antibiotics an average of 1.15 times per week for prophylaxis of bacterial endocarditis; 17.5 percent reported postoperative dosing for prophylaxis, ranging from a one- to seven-day prescription with an average of 6.91 postoperative doses . Preoperative antibiotics were prescribed for patients with a history of rheumatic fever or any heart murmur or prosthetic hip . Antibiotics were prescribed more frequently for surgical procedures and patients with acquired immunodeficiency syndrome than for other circumstances . CONCLUSIONS: More than 80 percent of respondents reported that they followed current American Heart Association prophylaxis guidelines . The authors, however, noted discrepancies in prophylactic use of antibiotics for bacterial endocarditis and for patients with large joint prostheses, as well as in prescribing antibiotics in the presence of clinical infection . In therapeutic use, approximately 85 percent of respondents followed appropriate prescription guidelines for dosing and duration of therapy . CLINICAL IMPLICATIONS: Appropriate and correct use of antibiotics is essential to ensure that effective and safe treatment is available and that practices that may enhance microbial resistance are avoided . To improve standards of care, dentists need up-to-date pharmacology in dental education, as well as continuing education, further outcome studies and continuous assessment of dental practices.

J Am Dent Assoc, 2000 Nov, 131(11), 1580 - 92
Nonsurgical periodontal therapy in 2000: a literature review; Greenstein G; BACKGROUND: This article addresses the advantages and limitations of nonsurgical periodontal therapies to treat patients with mild-to-moderate chronic periodontitis . TYPES OF STUDIES REVIEWED: Controlled clinical trials were selected that assessed the efficacy of the following treatment methods: mechanical instrumentation, ultrasonic debridement, supragingival irrigation, subgingival irrigation, local drug delivery, administration of systemic antibiotics and host-response modulation . Evidently, data with regard to alterations of probing depth, clinical attachment levels and inflammatory status were evaluated . RESULTS: Comparison of the data from test and control groups revealed the following results . Manual and ultrasonic debridement can be used to treat most patients with mild-to-moderate chronic periodontitis . Patients who do not practice optimal plaque control can enhance their personal hygiene procedures by using supragingival irrigation . Subgingival irrigation usually does not provide any benefit beyond that achieved with root planing . Systemic and locally delivered antimicrobial agents appear to be most beneficial among patients who do not respond to conventional treatment . Host modulation may enhance root planing modestly . CLINICAL IMPLICATIONS: The data indicate that most patients with mild-to-moderate periodontitis can be treated with nonsurgical therapies . However, clinicians need to be aware of the limitations of each technique with regard to the magnitude of improvement that it can induce at specific sites.

Curr Opin Biotechnol, 2000 Dec, 11(6), 625 - 36
Bacterial virulence as a target for antimicrobial chemotherapy; Alksne LE et al.; As bacterial resistance to currently used antibiotics increases, so too must efforts to identify novel agents and strategies for the prevention and treatment of bacterial infection . In the past, antimicrobial drug discovery efforts have focused on eradicating infection by either cidal or static agents, resulting in clearance of the bacterium from the infected host . To this end, drug discovery targets have been those proteins or processes essential for bacterial cell viability . However, inhibition of the interaction between the bacterium and its host may also be a target . During establishment of an infection, pathogenic bacteria use carefully regulated pathways of conditional gene expression to transition from a free-living form to one that must adapt to the host milieu . This transition requires the regulated production of both extracellular and cell-surface molecules, often termed virulence factors . As the biological imperatives of the invading organism change during the course of an infection, the expression of these factors is altered in response to environmental cues . These may be changes in the host environment, for example, pH, metabolites, metal ions, osmolarity, and temperature . Alternatively, effector molecules produced by the bacterium to sense changing cell density can also lead to changes in virulence gene expression . Although the mechanisms of pathogenesis among different bacteria vary, the principles of virulence are generally conserved . Bacterial virulence may therefore offer unique opportunities to inhibit the establishment of infection or alter its course as a method of antimicrobial chemotherapy.

Contraception, 2000 Aug, 62(2), 99 - 103
Cyclodextrin enhances spermicidal effects of magainin-2-amide; Wojcik C et al.; Magainins are antimicrobial peptides with known spermicidal activity . Their activity is inhibited by cholesterol present in eukaryotic cell membranes . Pretreatment of spermatozoa with methyl-beta-cyclodextrin, which extracts cholesterol from cell membranes and induces capacitation, sensitizes them to magainin-2-amide as shown by a decrease in human sperm motility determined by computer-assisted sperm analysis and a concomitant decrease in sperm viability, as measured by MitoTracker(R) Red CMXRos labeling . Magainin-2-amide affects mainly the fast progressive spermatozoa inducing them directly into an immotile state, without an increase in motile non-progressive and slow progressive spermatozoa . We conclude that methyl-beta-cyclodextrin highly potentiates the deleterious effect of magainin-2-amide on human spermatozoa . Most probably, this effect can be explained by cholesterol extraction from sperm cell membranes.

Contraception, 2000 Aug, 62(2), 91 - 7
A new vaginal antimicrobial contraceptive formulation: phase I clinical pilot studies; Ladipo OA et al.; Pilot clinical trials were performed with a new vaginal suppository called "Long Acting, Sustained Release of Spermicide" ("LASRS") . No visual or colposcopic lesions or patient complaints occurred as a result of using LASRS with increasing doses of nonoxynol-9 (up to 20%) for 5 days or of applying the highest dose of nonoxynol-9 (20%; total 400 mg) for 8 h . Colposcopic or visual lesions were also not induced when LASRS with 20% nonoxynol-9 was used for 7 consecutive days by the study participants except for those who developed symptomatic monilia vaginitis . Symptoms were reported although these were mostly minor . A long-lasting, bioadhesive, translucent layer (film) of formulation formed over the vaginal and cervical surfaces . Postcoital spermicidal studies showed LASRS to be highly effective for prolonged periods of time . Although intercourse was delayed for 5 to 8.5 h after insertion of the formulation, an average of only 0 . 2 motile sperm/HPF could be found in cervical mucus . These studies suggest LASRS to possess advantages over presently marketed formulations by having long-term efficacy and by forming a bioadhesive, presumably protective layer over the genital tract epithelium . The results also suggest the formulation to decrease the vaginal irritation caused by nonoxynol-9 as noted by colposcopy . These pilot data support a more extensive study with the LASRS suppository.

J Antimicrob Chemother, 2000 Dec, 46(6), 873 - 7
Infection in the twenty-first century: predictions and postulates; Geddes A; The late Paul Garrod, in whose honour this lecture is named, was 'the right man at the right time' . He seized the opportunities offered by the dawning of the chemotherapeutic era with vigour and enthusiasm and was a formidable link between the traditional laboratory-based bacteriologist and the more clinically orientated 'modern' medical microbiologist . Professor Garrod was a founder member of the British Society for Antimicrobial Chemotherapy and I had the privilege of meeting him on many occasions . He would have relished the many challenges facing today's microbiologists, infectious disease physicians and public health experts . These will have major implications for antimicrobial chemotherapy in the twenty-first century . The emergence and prevalence of infectious diseases, and the necessity for discovering therapies to treat them, are influenced by many factors . In this lecture I will discuss four which could have a major influence on infectious diseases in the twenty-first century-global warming, biological warfare/terrorism, the dissemination of infections, including those caused by resistant pathogens, by travellers and certain untreatable zoonotic diseases.

Nat Biotechnol, 2000 Dec, 18(12), 1307 - 10
Fungal pathogen protection in potato by expression of a plant defensin peptide; Gao AG et al.; Defensins are small cysteine-rich peptides with antimicrobial activity . We demonstrate that the alfalfa antifungal peptide (alfAFP) defensin isolated from seeds of Medicago sativa displays strong activity against the agronomically important fungal pathogen Verticillium dahliae . Expression of the alfAFP peptide in transgenic potato plants provides robust resistance in the greenhouse . Importantly, this resistance is maintained under field conditions . There have been no previous demonstrations of a single transgene imparting a disease resistance phenotype that is at least equivalent to those achieved through current practices using fumigants.

J Org Chem, 2000 Dec 1, 65(24), 8197 - 203
Synthesis and surface and antimicrobial properties of novel cationic surfactants; Viscardi G et al.; A series of surfactants with tuned polarity were prepared, including a new class of compounds: gluco-pyridinium surfactants . Pure anomers were obtained by chromatographic separation . The conductivity and surface tension of surfactant solutions in water were measured, and provided interesting information regarding their aggregation behavior . Peculiarities were observed in the premicellar range . Tensidic parameters correlated with antimicrobial activity . A few parameters, mainly the hydrophobicity of the headgroup, may play a role in finding more efficient antimicrobial structures.

J Biomol NMR, 2000 Oct, 18(2), 145 - 51
Production of stable isotope enriched antimicrobial peptides in Escherichia coli: an application to the production of a 15N-enriched fragment of lactoferrin; Majerle A et al.; A method is described for the production of recombinant isotopically enriched peptides in E . coli . Peptides are produced in high yield as fusion proteins with ketosteroid isomerase which form insoluble inclusion bodies . This insoluble form allows easy purification, stabilizes the peptide against degradation and prevents bactericidal activity of the peptide . Cyanogen bromide cleavage released peptide which was conjugated with alkylamines to form lipopeptide . An important advantage of this system is that it allows production of peptides that are toxic to bacteria, which we have demonstrated on a dodecapeptide based on residues 21-31 of human bactericidal protein lactoferrin.

Biomaterials, 2001 Jan, 22(2), 165 - 73
Fabrication and characterization of a sponge-like asymmetric chitosan membrane as a wound dressing; Mi FL et al.; A novel asymmetric chitosan membrane has been prepared by immersion-precipitation phase-inversion method and evaluated as wound covering . This new type of chitosan wound dressing which consists of skin surface on top-layer supported by a macroporous sponge-like sublayer was designed . The thickness of the dense skin surface and porosity of sponge-like sublayer could be controlled by the modification of phase-separation process using per-evaporation method . The asymmetric chitosan membrane showed controlled evaporative water loss, excellent oxygen permeability and promoted fluid drainage ability but could inhibit exogenous microorganisms invasion due to the dense skin layer and inherent antimicrobial property of chitosan . Wound covered with the asymmetric chitosan membrane was hemostatic and healed quickly . Histological examination confirmed that epithelialization rate was increased and the deposition of collagen in the dermis was well organized by covering the wound with this asymmetric chitosan membrane . The results in this study indicate that the asymmetric chitosan membrane thus prepared could be adequately employed in the future as a wound dressing.

J Gastroenterol Hepatol, 2000 Oct, 15 Suppl, G30 - 3
Helicobacter pylori: past, present and future; Tytgat G; Much has been achieved in Helicobacter pylori research, to the point that the growth of new knowledge is bound to slow down . However, expectations for further developments remain high . Knowledge about the characteristic organism and behaviour is already extensive . Particularly intriguing are the differences in genetic make-up in the various geographical regions . Sadly, detailed knowledge on how the organism spreads is still lacking . The spectrum of clinical presentation in humans is largely known . Helicobacter pylori is disappearing worldwide, allowing the relative frequency of H . pylori-negative ulcer disease to increase . The extent to which H . pylori disappearance and eradication is responsible for decreasing prevalence of gastric cancer remains speculative . Antimicrobial therapy is dominated by proton pump inhibitor triple therapy as first line therapy, with quadruple therapy as second rescue line therapy . The long-term consequences of the rising resistance to the 'key' antimicrobials are so far unknown, because few data are available on therapeutic outcomes in routine practice outside pharmaceutical trials.

Nat Med, 2000 Dec, 6(12), 1330 - 3
In vivo veritas: the search for TB drug targets goes live; McKinney JD; The term 'microbial persistence' describes a phenomenon whereby microorganisms which are drug-susceptible when tested outside the body are nevertheless capable of surviving within the body despite intensive therapy with the appropriate antimicrobial drug . In clinical practice this phenomenon obviously has to do with the post-treatment 'carrier state' and with post-treatment relapse . In short, it is this phenomenon which is responsible for our inability to eradicate an infection from a person or a community by the use of drugs . - Walsh McDermott, The Yale Journal of Biology and Medicine 30, 257 (1958).

Nat Med, 2000 Dec, 6(12), 1327 - 9
Latent Mycobacterium tuberculosis-persistence, patience, and winning by waiting; Manabe YC et al.; Mycobacterium tuberculosis is a globally successful pathogen due to its ability to persist for long periods of time unrecognized by the human immune system . The panoply of genes that allows the organism to enter latency and then re-emerge later during endogenous reinfection are now being elucidated . Novel antimicrobials and vaccines will need to target these mycobacterial pathogenic mechanisms to suceed against tuberculosis.

Mol Med Today, 2000 Dec, 6(12), 470 - 4
Mining bacterial genomes for antimicrobial targets; Loferer H; The elucidation of whole-genome sequences is expected to have a revolutionary impact on the discovery of novel medicines . With the availability of complete genome sequences of more than 30 different species, the field of antimicrobial drug discovery has the opportunity to access a remarkable diversity of genomic information . In this review, I summarize how microbial genomics has changed strategies of drug discovery by applying bioinformatics, novel genetic approaches and genomics-based technologies, including analysis of gene expression using DNA microarrays.

FASEB J, 2000 Dec, 14(15), 2519 - 24
Mechanism of the antimicrobial drug trimethoprim revisited; Quinlivan EP et al.; We tested the hypothesis that the mechanism of action of the antifolate drug trimethoprim is through accumulation of bacterial dihydrofolate resulting in depletion of tetrahydrofolate coenzymes required for purine and pyrimidine biosynthesis . The folate pool of a strain of Escherichia coli (NCIMB 8879) was prelabeled with the folate biosynthetic precursor {(3)H}-p-aminobenzoic acid before treatment with trimethoprim . Folates in untreated E . coli were present as tetrahydrofolate coenzymes . In trimethoprim-treated cells, however, a rapid transient accumulation of dihydrofolate occurred, followed by complete conversion of all forms of folate to cleaved catabolites (pteridines and para-aminobenzoylglutamate) and the stable nonreduced form of the vitamin, folic acid . Both para-aminobenzoylglutamate and folic acid were present in the cell in the form of polyglutamates . Removal of trimethoprim resulted in the reconversion of the accumulated folic acid to tetrahydrofolate cofactors for subsequent participation in the one-carbon cycle . Whereas irreversible catabolism is probably bactericidal, conversion to folic acid may constitute a bacteriostatic mechanism since, as we show, folic acid can be used by the bacteria and proliferation is resumed once trimethoprim is removed . Thus, the clinical effectiveness of this important drug may depend on the extent to which the processes of either catabolism or folic acid production occur in different bacteria or during different therapeutic regimes.

Curr Opin Pulm Med, 2000 Nov, 6(6), 533 - 9
Phagocyte oxidants and nitric oxide in cystic fibrosis: new therapeutic targets?
van der Vliet A, Cross CE.
Chronic persistent respiratory tract (RT) infection and overly exuberant activation of host inflammatory-immune processes represent the paramount pathobiologic consequences of cystic fibrosis (CF) . The host inflammatory-immune system activation includes the production of reactive oxygen species (ROS) and nitric oxide (NO*), which are helpful in RT antimicrobial defenses but under conditions of excess are believed to be harmful to host tissues . However, the genetic defect underlying CF is recognized to uniquely affect inflammatory-immune (oxidative) processes, including alterations in cytokine release, phagocyte activation, antioxidant mechanisms, and NO* synthesis and metabolism, and these appear to contribute importantly to the persistent inflammation and infection in patients with CF . The dysregulation of inflammatory-immune responses has also been observed in CF epithelial cells and in some mouse models of CF, and marked advances in our understanding of these processes can be expected from future studies in such model systems . The emerging ideas of how ROS may influence molecular events that control inflammatory protease/antiprotease homeostasis and RT epithelial cell signaling and gene expression, and the role that augmentation of local antioxidant micronutrients (aerosolized and/or systemically administrated) might play in these effects, still remain to be further established and clarified . Further understanding of these processes can be expected to play an important role in future treatment directed toward the devastating effects of CF on the RT of patients with this disorder.

Z Naturforsch {C}, 2000 Sep-Oct, 55(9-10), 790 - 3
Propolis from the Mediterranean region: chemical composition and antimicrobial activity; Velikova M et al.; The chemical composition of propolis from Bulgaria, Turkey, Greece and Algeria was investigated by GC-MS . All of them contained mainly flavonoids and esters of caffeic and ferulic acids, which indicated that their main source are buds of poplars of the taxonomic section Aegieros . Some Turkish samples contained a low percent of diterpenic acids, while in Algerian samples significant amounts of a hydroxyditerpenic acid (M=322, its structure not determined by its MS) were found . All samples showed significant antibacterial and weak to moderate antifungal activity.

Z Naturforsch {C}, 2000 Sep-Oct, 55(9-10), 718 - 30
Elicitor-induced defence reactions in cell suspension cultures of soybean cultivars; Groten K et al.; Suspension cultured soybean (Glycine max {L.} Merr.) cells of four cultivars (Wilis, Lumut, Kalmit, Doko RC) were compared for their response to different fungal and bacterial elicitors . Cells were treated either with crude cell wall extracts of the fungal pathogens Phytophthora sojae (Pmg-elicitor) and Rhizoctonia solani (Riso-elicitor) or with two isolates of the bacterial pathogen Pseudomonas syringae pv . glycinea (Psg01/02) and a broad spectrum of antimicrobial defence reactions was measured . Cells of all four cultivars showed the same elicitor-induced rapid (H2O2 accumulation, alkalinization of the culture medium, peroxidative cross-linking of cell wall proteins) and slow (activation of phenylpropanoid metabolism, accumulation of phenolic compounds, induction of PR-proteins) defence responses . However, the reactivity of the cultivars was not identical in terms of time courses and intensities . Furthermore, the ability of the various elicitors to induce defence responses varied markedly . These differences indicate that (1) cells of the same species but of different cultivars are equipped with the same array of perception systems to recognise various stimuli but (2) the sensitivity of these perception systems or later steps in the signal transduction seem to be stimulated to a different extent in the analysed cultivars.

Am J Health Syst Pharm, 2000 Nov 15, 57 Suppl 3, S17 - 21
Approaches to drug therapy, formulary, and pathway management in a large community hospital; Halley HJ; Use of a clinical pathway for the management of community-acquired pneumonia (CAP) at a large community hospital is described . The pathway was developed and implemented by a multidisciplinary team . Fluoroquinolone therapeutic interchange and intravenous (i.v.) to oral (p.o.) conversion were part of the pathway; through literature review, levofloxacin was chosen as the preferred quinolone . Outcomes (length of stay {LOS} and readmission rates for pathway and nonpathway patients with CAP, economic impact of the fluoroquinolone interchange protocol, and resistance patterns) were evaluated . For pathway patients in 1998, LOS was 1.2 days shorter and the readmission rate was lower . Projected drug cost savings as a result of the fluoroquinolone interchange protocol were more than $22,000 annually . Pharmacists' interventions in antimicrobial prescribing for CAP patients can lead to cost efficiency and positively affect patient outcomes.

Am J Health Syst Pharm, 2000 Nov 15, 57 Suppl 3, S10 - 3
Experiences at a large teaching hospital with levofloxacin for the treatment of community-acquired pneumonia; Clark LC et al.; Costs, patient outcomes, and susceptibility patterns of selected organisms after the implementation of guidelines for the treatment of community-acquired pneumonia (CAP) at a large community teaching hospital were analyzed to assess the benefit of the guidelines . The guidelines, implemented in September 1998, included recommendations for the use of levofloxacin as the preferred antimicrobial, with rapid intravenous (i.v.) to oral (p.o.) conversion . Purchase data for levofloxacin, ceftriaxone, and azithromycin were analyzed, as well as susceptibilities and demographic and outcome data for patients admitted in 1999 in diagnosis-related groups (DRGs) 89 and 90 (simple pneumonia with and without comorbidities, respectively) . Patients in each DRG were divided into a levofloxacin use only (LUO) group and an all other therapies (AOT) group . Average length of stay (LOS), hospital costs, death rate, age, and ratio of oral to intravenous dosage administration were analyzed . A total of 571 patients in DRG 89 and 110 patients in DRG 90 were included . The average LOS for DRG 89 was not significantly different between LUO patients and AOT patients (3.56 +/- 2.23 days and 3.88 +/- 2.65 days, respectively) . Average total costs were significantly higher for AOT patients ($3385 +/- $2937 versus $2892 +/- $2397 for LUO patients); similar trends but no significant differences were found in the DRG 90 group . In the LUO groups in both DRGs, patients were more than five times as likely to receive an oral dosage form than patients in the AOT group . For DRG 89, the death rate was significantly lower for the LUO group (1.29%) than the AOT group (7.1%) . Susceptibility data for all organisms remained stable from 1998 to 1999 . The average costs in the AOT groups suggest that total hospital costs for 1999 in the LUO group were $241,516 less than costs would have been before guideline implementation . Combined drug acquisition cost savings in 1999 for levofloxacin, ceftriaxone, and azithromycin were $21,115 . The use of CAP treatment guidelines was associated with reductions in antimicrobial costs, total hospitalization costs, LOS, and death rate, without a detrimental effect on organism susceptibility.

Am J Health Syst Pharm, 2000 Nov 15, 57 Suppl 3, S6 - 9
Development of a best-practice model at a university hospital to increase efficiency in the management of patients with community-acquired pneumonia; Gora-Harper ML et al.; An economic evaluation of drug acquisition, nursing care, pharmacy time, laboratory costs, supplies, and ancillary care was conducted as a first step toward developing a pneumonia management plan at the University of Kentucky Medical Center (UKMC) . UKMC costs were compared with costs at other hospitals treating pneumonia patients on Medicare . Overall costs for pneumonia at the 25% of hospitals nationwide with the lowest costs for Medicare patients with this condition were determined and compared with costs at UKMC . Against nationwide benchmarks, efficiencies at UKMC for treating simple pneumonia ranged from 45% for pharmacy expenses to 81% for nursing costs . Efficiencies for complicated pneumonia ranged from 47% for laboratory costs to 67% for nursing costs . The most cost-efficient antimicrobial treatment options were promoted and integrated into a pneumonia management plan based on Infectious Diseases Society of America treatment guidelines . A comparison of pneumonia treatment costs at UKMC with those at the 25% of hospitals nationwide with the lowest treatment costs for Medicare patients with pneumonia revealed that UKMC pharmacy costs could be optimized . Strategies for standardizing the care of patients with community-acquired pneumonia (CAP) are being implemented.

Cancer Lett, 2000 Nov 10, 160(1), 29 - 35
Garlic and onion oils inhibit proliferation and induce differentiation of HL-60 cells; Seki T et al.; Phytochemicals present in the genus Allium have potential pharmacological effects, such as antimicrobial, antithrombotic, antitumor, hypolipidaemic and hypoglycemic activities . In this present study, we examined the effects of garlic and onion oils on human promyelocytic leukemia cells, HL-60 . Incubation of HL-60 with garlic or onion oil (20 microg/ml) caused a marked suppression of HL-60 proliferation; the suppression was almost identical with those obtained by all-trans-retinoic acid (ATRA) or dimethyl sulfoxide (DMSO) used as positive controls . These oils induced the generation of nitroblue tetrazolium (NBT)-reducing activity, and about 20% of the HL-60 cells became NBT positive . CD11b, another marker of the differentiation of these cells, was also significantly induced by garlic oil or onion oil . The combination of garlic or onion oil with ATRA was more effective than either alone . These data suggest that garlic and onion oils have the ability to induce differentiation of HL-60 cells into those of the granulocytic lineage.

Hum Reprod, 2000 Dec, 15(12), 2536 - 44
Effectiveness and limits of antimicrobial treatment on seminal leukocyte concentration and related reactive oxygen species production in patients with male accessory gland infection; Vicari E; To evaluate whether bacteriological cure, sperm outcome, spontaneous pregnancy rate and white blood cell (WBC)-related reactive oxygen species (ROS) production were related to the extent of the infection and to an intermittent and repetitive antimicrobial treatment, 122 patients with bacterial {>10(5) colony-forming units (CFU)/ml} male accessory gland infections (MAGI) were studied . According to ultrasound criteria, patients had prostatitis (PR, n = 52), prostatovesiculitis (PV, n = 32) or prostatovesiculoepididymitis (PVE, n = 38) . Each group was further subdivided into two subsets: one subset (PR, n = 40; PV, n = 20; PVE, n = 25) was given ofloxacin or doxycycline for 14 consecutive days per month for 3 months; the other subset (PR, n = 12; PV, n = 12; PVE, n = 13) received no treatment . The female partners were also treated . All patients were evaluated before, during (1 and 3 months) and after (3 months) treatment . The bacteriological cure rate was the highest (92.5%) after the third antibiotic course in PR, followed by PV (70.4%), and the lowest in PVE (52.0%) . At 3 months after therapy discontinuation, some sperm parameters, seminal WBC concentration and ROS generation (assessed in the 45% Percoll fraction) were ameliorated in PR and PV, whereas no improvement occurred in patients with PVE, except for the percentage of coiled tails . Antibiotic treatment in PR and PV patients led to positive effects on sperm output and spontaneous pregnancy rate (40%) by removing pro-oxidant noxae (microbial and/or WBC-related ROS production) . The persistent infertility, dyspermia and sperm-derived ROS overproduction in PVE may relate to a significant percentage of antibiotic-independent re-infection and/or to low antioxidative epididymal properties, which persisted following antimicrobial treatment.

Drug Metab Dispos, 2000 Dec, 28(12), 1417 - 24
In vitro characterization of the oxidative cleavage of the octyl side chain of olanexidine, a novel antimicrobial agent, in dog liver microsomes; Umehara K et al.; The metabolism of olanexidine {1-(3,4-dichlorobenzyl)-5-octylbiguanide}, a new potent biguanide antiseptic, was investigated in dog liver microsomes to characterize the enzyme(s) catalyzing the biotransformation of olanexidine to C-C bond cleavage metabolites . Olanexidine was initially biotransformed to monohydroxylated metabolite 2-octanol (DM-215), and DM-215 was subsequently oxidized to diol derivatives threo-2,3-octandiol (DM-221) and erythro-2,3-octandiol (DM-222) . Diols were further biotransformed to a ketol derivative and C-C bond cleavage metabolite (DM-210, hexanoic acid derivative), an in vivo end product, in the incubation with dog liver microsomes . The formations of DM-215, DM-221, DM-222, and DM-210 followed Michaelis-Menten kinetics, and Eadie-Hofstee analysis of the metabolite formation activity confirmed single-enzyme Michaelis-Menten kinetics . The K(m) and V(max) values for the formation of DM-210 appeared to be 2.42 microM and 26.6 pmol/min/mg in the oxidation of DM-221 and 2.48 microM and 30.2 pmol/min/mg in the oxidation of DM-222 . The intrinsic clearance (V(max)/K(m)) of the C-C bond cleavage reactions was essentially the same with either DM-221 or DM-222 as substrate . These oxidative reactions were significantly inhibited by quinidine, a selective inhibitor of CYP2D subfamilies, indicating the metabolic C-C bond cleavage of the octyl side chain of olanexidine to likely be mediated via the CYP2D subfamily in dog liver microsomes . This aliphatic C-C bond cleavage by cytochrome P450s may play an important role in the metabolism of other drugs or endogenous compounds possessing aliphatic chains.

South Med J, 2000 Nov, 93(11), 1108 - 11
Chronic granulomatous meningitis with multiple cranial nerve lesions hydrocephalus, stroke, sinus thrombosis, and epilepsy; Finsterer J et al.; Most frequently, chronic granulomatous meningitis (CGM) is caused by infectious agents . However, in some cases the cause of CGM remains undetermined . It is unclear whether antimicrobial agents, including antituberculous drugs, are helpful in such cases . We describe a 61-year-old man who had multiple cranial nerve lesions, epilepsy, sinus thrombosis, stroke, and hydrocephalus attributable to CGM . Repeated extensive search for a causative agent in the cerebrospinal fluid (CSF) and the meninges remained negative . Only a single culture of the sputum revealed growth of Mycobacterium tuberculosis, which prompted antituberculous therapy with isoniazid, rifampicin, and ethambutol . After 6 months of therapy, neurologic abnormalities were slightly improved . We conclude that antimicrobial/ antituberculous agents have only a minor short-term effect in long-lasting CGM of undetermined cause.

J Pharm Biomed Anal, 2000 Nov, 23(6), 939 - 46
Immunochemical-based assays in the bioanalysis of immunoglobulins; Lamari F et al.; Intravenous immunoglobulin (IVIG) preparations consist of IgG derived from a pool of human plasma of healthy individuals and have been used as routine treatment of patients with primary and secondary immunodeficiencies, autoimmune, and/or inflammatory diseases . Emergence of new infectious agents and development of antibiotic resistance in many bacteria have posed serious problems in the treatment of infections . Since IVIGs contain natural antibodies that occur in the healthy population, their administration to immunocompromised hosts either as a prophylactic agent or as complementary treatment to the usual antimicrobial treatment have been studied . Contradictory results obtained by several clinical studies in respect to the clinical efficacy of IVIGs have in part been ascribed to the poor characterization of IVIG preparations in terms of their specific antibody content against the various pathogenic microorganisms . Immunoassays constitute a promising tool for bioanalysis of IVIGs thanks to the high sensitivity, repeatability and ease of implementation . Ensuring high selectivity, enzyme immunoassays have been used for determination of the levels of pathogen-specific antibodies in IVIG preparations . In this review, the application of immunoassays monitoring such specific antibodies in IVIGs and the relationship of estimated titers with their in vitro opsonic activity are summarized . The relationship of the content of specific antibodies in IVIGs and their functional efficacy with the outcome of clinical studies including patients with primary immunodeficiencies and premature neonates treated with IVIGs is also discussed.

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