mic

Biochemistry, 1995 Sep 19, 34(37), 11800 - 6
Second-site suppressor mutations for the Asp-66-->Cys mutant of the transposon Tn10-encoded metal-tetracycline/H+ antiporter of Escherichia coli; Yamaguchi A et al.; Asp66 is the only essential acidic residue in the putative hydrophilic loop2-3 region of the transposon Tn10-encoded metal-tetracycline/H+ antiporter {TetA(B)} {Yamaguchi, A., Nakatani, M., & Sawai, T . (1992a) Biochemistry 31, 8344-8348} . Escherichia coli cells producing a D66C mutant of TetA(B) showed no tetracycline resistance . A spontaneous second-site revertant was isolated from the cells carrying the D66C mutant gene, which showed moderate resistance to tetracycline {minimum inhibitory concentration (MIC), 50 micrograms/mL} . The entire sequencing of the revertant genes revealed two secondary mutations, i.e., the codon 40 of GCT (Ala)-->GAT (Asp) and T-->G at 17 bases upstream from the initiation codon of the tetA gene . There was a T-->G mutation at position -17, which was a mutation in the tet promoter/operator region, which caused a decrease in TetA(B) production . The full expression of the A40D/D66C double and the A40D single mutants, which were constructed by site-directed mutagenesis, was deleterious for cell growth . The -17T-->G mutation mitigated the deleterious effect of these mutants through reduction of expression . The -17T-->G single mutation introduced into the wild-type tet gene did not affect the level of resistance, although the expression was significantly reduced . Intact cells carrying the A40D/D66C and -17T-->G/A40D/D66C mutant plasmids showed a reduced level of tetracycline accumulation due to active efflux, whereas no significant tetracycline uptake was observed in inverted membrane vesicles prepared from these mutant-producing cells . The A40D mutation is located at opposite side of the membrane to the D66C mutation in the putative secondary structure of TetA(B) . The second-site mutation might mediate its effects through a structural perturbation propagated along the polypeptide backbone.

Mol Microbiol, 1995 Sep, 17(5), 889 - 900
Mycobacterium tuberculosis is a natural mutant with an inactivated oxidative-stress regulatory gene: implications for sensitivity to isoniazid; Deretic V et al.; The systems participating in detoxification of reactive oxygen intermediates in Mycobacterium tuberculosis are believed to play a dual role in the biology of this highly adapted human pathogen: (i) they may contribute to the survival of this bacterium in the host; and (ii) alterations in the gene encoding catalase/peroxidase have been linked to this organism's resistance to the front-line antituberculosis drug isoniazid . These relationships prompted us to extend investigations of the oxidative-stress-response systems in M . tuberculosis by analysing the alkyl hydroperoxide reductase gene ahpC and its putative regulator oxyR . Surprisingly, the oxyR gene was found to be inactivated by multiple lesions in M . tuberculosis H37Rv . These alterations were observed in all M . tuberculosis strains tested, and in members of the M . tuberculosis complex: Mycobacterium bovis BCG, Mycobacterium africanum, and Mycobacterium microti . The corresponding region carrying these genes in Mycobacterium leprae, an organism not sensitive to isoniazid, has a complete oxyR gene divergently transcribed from ahpC . An increase in minimal inhibitory concentration for isoniazid was observed upon transformation of M . tuberculosis H37Rv with cosmids carrying the oxyR-ahpC region of M . leprae . In keeping with the observed inactivation of oxyR, transcriptional activity of the corresponding region in M . tuberculosis was an order of magnitude lower than that of the oxyR gene from M . leprae . While the loss of this putative regulator of oxidative-stress response in M . tuberculosis is paradoxical considering the fact that survival in host macrophages is regarded as a critical feature of this pathogen, it offers a partial explanation for the exquisite sensitivity of M . tuberculosis to isoniazid.

Clin Exp Dermatol, 1995 Sep, 20(5), 377 - 83
Nail incorporation kinetics of terbinafine in onychomycosis patients; Schatz F et al.; Patients with toe-nail onychomycosis were treated with terbinafine (250 mg daily, n = 20) for either 6 or 12 weeks in a randomized double-blind study . Plasma and distal nail clippings were taken before initiation of therapy and 1, 6, 12, 18, 24, 36 and 48 weeks thereafter . Analytical data of terbinafine extracted from nail clippings or plasma were obtained by high-performance liquid chromatography (HPLC) . Nail extracts and isolated HPLC terbinafine peaks were analysed using a combined gas chromatography-mass spectroscopy system (GC-MS) for unequivocal identification of the drug . Terbinafine could be detected in the distal nail in the majority of the patients within 1 week of starting therapy . Maximum terbinafine levels of 0.52 and 1.01 micrograms/g were measured after 18 weeks in the 6- and 12-week treatment groups, respectively . While plasma levels decreased rapidly after termination of therapy terbinafine was detected in the nails as long as 30 weeks (6 weeks treatment) and 36 weeks (12 weeks treatment) after termination of therapy at a range of 0.28-0.19 microgram/g . The drug concentrations measured at all time points are well above the minimum inhibitory concentration (MIC) for dermatophytes and other fungi . These data suggest that the drug reaches the nail plate rapidly and persists there for several months after cessation of active treatment.

Mycoses, 1995 Sep-Oct, 38(9-10), 389 - 93
The anti-Malassezia furfur activity in vitro and in experimental dermatitis of six imidazole antifungal agents: bifonazole, clotrimazole, flutrimazole, ketoconazole, miconazole and sertaconazole; Van Gerven F et al.; Bifonazole, clotrimazole, flutrimazole, ketoconazole, miconazole and sertaconazole were tested for their activity against 23 isolates of Malassezia furfur by agar dilution in vitro . Topical formulations of the same agents were evaluated for efficacy against M . furfur skin infections in guinea pigs in vivo . The most potent inhibitor in vitro was ketoconazole (geometric mean minimum inhibitory concentration 0.51 microgram ml-1), followed by bifonazole (8.1 micrograms ml-1), then miconazole (14 micrograms ml-1), clotrimazole (15 micrograms ml-1) and flutrimazole (16 micrograms ml-1), with sertaconazole the least active (52 micrograms ml-1) . In animal experiments involving three consecutive days of topical treatments, bifonazole 1% cream, clotrimazole 1% cream, flutrimazole 1% and 2% creams, ketoconazole 2% cream and shampoo and miconazole 2% cream all reduced M . furfur dermatitis lesion severity below that of untreated control animals; however, sertaconazole 2% gel and cream showed no reduction in lesion severity below control . The results confirm that ketoconazole is a more potent inhibitor of M . furfur in vitro than other topical antifungal agents of its class and suggest that sertaconazole is the least effective of such agents among those tested.

Antimicrob Agents Chemother, 1995 Sep, 39(9), 2116 - 9
In vitro activity of levofloxacin, singly and in combination with rifamycin analogs, against Mycobacterium leprae; Dhople AM et al.; The in vitro susceptibility of Mycobacterium leprae to levofloxacin was studied by using two biochemical parameters to measure the metabolic activity of the organism . Levofloxacin consistently exhibited twofold greater bactericidal activity than ofloxacin, with the MIC being 0.75 microgram/ml . When combined with one of the three rifamycin analogs, synergism was obtained with KRM-1648 and rifabutin but not with rifampin.

Antimicrob Agents Chemother, 1995 Sep, 39(9), 2048 - 50
Once-daily versus twice-daily administration of ceftazidime in the preterm infant; van den Anker JN et al.; Ceftazidime pharmacokinetics in 28 preterm infants (gestational ages, 25.6 to 31.9 weeks) were studied on day 3 of life . Patients with suspected septicemia were randomized on day 1 of life in two groups . One group (n = 13) was administered 25 mg of ceftazidime per kg of body weight once daily, and the other (n = 15) was given 25 mg of ceftazidime per kg twice daily . Both groups also received 25 mg of amoxicillin per kg twice daily . Blood samples were collected on day 3 of life with an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an intravenous bolus injection . An additional blood sample was taken at 24 h from the group dosed once a day . High-performance liquid chromatography was used to determine serum ceftazidime concentrations . The pharmacokinetics of ceftazidime were best described by using a one-compartment model . The half-life for the elimination of the drug from serum, apparent volume of distribution, total body clearance of ceftazidime, and inulin clearance were not significantly different for both groups . The ceftazidime/inulin clearance ratio was 0.72 for both groups . However, trough concentrations in serum for the twice-daily group were significantly (P < 0.001) higher (42.0 +/- 13.4 mg/liter) than those for the once-daily group (13.1 +/- 4.7 mg/liter) . The latter concentrations were all still substantially higher than the MIC of ceftazidime for major neonatal pathogens . We conclude that the currently recommended dosage of 25 mg of ceftazidime per kg twice daily for preterm infants with gestational ages below 32 weeks may be adjusted during the first days of life to one daily dose at 25 mg/kg, provided that for the empirical treatment of septicemia, amoxicillin at 25 mg/kg is also given twice daily.

Arch Phys Med Rehabil, 1995 Sep, 76(9), 828 - 32
Amyotrophic lateral sclerosis: predictors for prolongation of life by noninvasive respiratory aids; Bach JR; The purpose of this study was to determine which pulmonary function variables best predicted the potential for prolonging survival of individuals with amyotrophic lateral sclerosis (ALS) by the use of physical medicine respiratory muscle aid alternatives to tracheostomy for ventilatory support and airway suctioning . The records of 27 such ALS ventilator users with less than 15 minutes of ventilator-free breathing time for a mean +/- standard deviation of 23.7 +/- 20.3 months (range, 1 to 65) were reviewed . All patients underwent measurements of vital capacity (VC), maximum insufflation capacity (MIC), MIC VC difference, forced expiratory volumes, and peak cough expiratory flows (PCEF) every 1 to 6 months, depending on rate of disease progression, until requiring 24-hour ventilatory support . The ability to generate assisted PCEF in excess of 3L/sec and the ability to hold an insufflation deeper than the VC were associated with the capacity to prolong survival by methods other than tracheostomy, whereas the extent of decrease in VC and autonomous breathing ability were not . Because the PCEF and MIC VC difference correlate with bulbar muscle function, it can be concluded that the ability to use 24-hour ventilatory support by noninvasive means is a function of residual bulbar muscle strength and is independent of VC or the extent of need for ventilatory support . Properly equipped and trained, some ALS patients can use noninvasive respiratory muscle aids to delay or eliminate the need for tracheostomy.

Acta Ophthalmol Scand, 1995 Aug, 73(4), 325 - 8
An in vitro study of fusidic acid susceptibility amongst isolates from conjunctival swabs; Hovenden JL et al.; The aim of this study was to examine the in vitro activity of fusidic acid against bacterial isolates from conjunctival swabs . Conjunctival swabs from 213 patients with conjunctivitis were examined . One or more pathogens were grown from 73 patients . Forty per cent of isolates were resistant to fusidic acid on disc sensitivity testing . Reduced sensitivity was detected by minimum inhibitory concentration testing in many isolates of H . influenzae and an isolate of S . pneumoniae . In addition, the in vitro activity of fusidic acid was determined against upper respiratory tract isolates of H . influenzae, S . pneumoniae and M . catarrhalis; this showed that many isolates had a reduced sensitivity to fusidic acid . Topical fusidic acid may not be optimal empiric therapy of bacterial conjunctivitis.

Kansenshogaku Zasshi, 1995 Aug, 69(8), 878 - 83
{Prevalence of pertussis in Fukuoka: incidence and MICs of antibiotics for Bordetella pertussis isolate}; Horikawa K et al.; For bacteriological examinations of whooping cough patients, nasopharyngeal specimens were directly inoculated on the cyclodextrin solid medium (CSM) supplemented with 5 micrograms of cephalexin (CEX) per ml . The inoculated plates were cultured in an incubator at 35 degrees C for 3 to 7 days . During the period from 1990 to 1993, B . pertussis (43 strains) and B . parapertussis (1 strain) were isolated from 145 whooping cough patients and 34 relatives . B . pertussis were isolated sufficiently in June to December during the year . It was suggested that during this period epidemics of whooping cough occurred . All isolates of B . pertussis had K antigen consisting of 1, 3, and 6 . The determination of minimal inhibitory concentrations (MIC) of antibiotics to B . pertussis was carried out by the micro dilution technique modified from the standard methods . The Stainer-Scholte broth, supplemented with heptakis (2,6-O-dimethyl) beta-cyclodextrin, was used for dilution of the drug, and also for cultivation of bacteria . For determining susceptibility of bacteria to antibiotics, twenty seven isolates of B . pertussis and one of B . parapertussis were precultured on CSM at 35 degrees C for 2 days . The turbidity of broth cultures was adjusted to that of McFarland no . 0.5, and diluted to the concentration of 10(6) CFU/ml . One hundred microliters of these suspensions were added to 25 microliters of each antibiotic solution . After incubation for 3 days at 35 degrees C, the turbidity of the bacteria was read macroscopically for determining the MICs . On the other hand, we compared the agar dilution MICs of 23 antibiotics to the broth microdilution MICs for 27 B . pertussis isolates.(ABSTRACT TRUNCATED AT 250 WORDS)

Genitourin Med, 1995 Aug, 71(4), 244 - 6
Azithromycin levels in cervical mucus and plasma after a single 1.0g oral dose for chlamydial cervicitis; Worm AM et al.; OBJECTIVE--To determine the kinetics of azithromycin in cervical mucus and plasma . SUBJECTS AND METHODS--Azithromycin concentrations were determined in plasma and mucus samples from 20 women with cervical chlamydial infection one, seven and fourteen days after a single oral 1.0 g dose . RESULTS--In mucus, all measurable azithromycin concentrations were above the minimal inhibitory concentration against Chlamydia trachomatis on day 7 as well as on day 14 . CONCLUSION--The high cervical mucus concentrations of azithromycin can explain the high clinical and microbiological efficacy.

Antimicrob Agents Chemother, 1995 Aug, 39(8), 1859 - 61
Bactericidal and morphological effects of amoxicillin on Helicobacter pylori; Berry V et al.; The growth kinetics of Helicobacter pylori after it has been exposed to amoxicillin have been investigated in conjunction with studies of cell morphology . A potent bactericidal effect was observed at concentrations 10-fold higher than the MIC, but this was accompanied by an increase in the residual numbers of coccoid forms observed . In the presence of 10 micrograms of amoxicillin per ml, these forms could be detected as rapidly as 6 h after exposure to the antibiotic . Although the clinical relevance of coccoid forms remains unknown, such forms should be considered when potential anti-Helicobacter agents are tested in vitro.

Antimicrob Agents Chemother, 1995 Aug, 39(8), 1667 - 70
Detection of gyrA and gyrB mutations in quinolone-resistant clinical isolates of Escherichia coli by single-strand conformational polymorphism analysis and determination of levels of resistance conferred by two different single gyrA mutations; Ouabdesselam S et al.; Twelve quinolone-resistant clinical isolates of Escherichia coli (nalidixic acid MICs, 64 to 512 micrograms/ml; norfloxacin MICs, 0.25 to 8 micrograms/ml) were transformed with plasmid pJSW101 carrying the gyrA+ gene and with plasmid pJB11 carrying the gyrB+ gene to examine the proportion of gyrA and gyrB mutations . Transformation with pJSW101 resulted in complementation (nalidixic acid MICs, 4 to 32 micrograms/ml; norfloxacin MICs, 0.06 to 0.25 micrograms/ml) . In contrast, no change in MICs were observed after transformation with pJB11 . A 418-bp fragment of gyrA from the 12 strains was amplified by PCR . Direct DNA sequencing of that fragment identified the causes of quinolone resistance in eight strains as a single point mutation leading to a substitution of the serine at position 83 (Ser-83) to Leu and in four strains as a single point mutation leading to a substitution of Asp-87 to Gly . Exchange of the fragment from one of these strains with that of gyrA+ and transformation of resistance with the hybrid gyrA plasmid indicated the contribution of Gly-87 to resistance and the stabilities of mutants containing GyrA (Gly-87) . Thus, gyrA gene mutations are probably encountered more often than gyrB gene mutations in clinical isolates of E . coli . In addition, the substitution of Asp-87 to Gly can be encountered in such strains . On the basis of the level of resistance found in the fragment exchange experiment, the quinolone resistance attributable to Gly-87 appears to be comparable to that attributable to Leu-83 . The levels of resistance found in the clinical isolates shown to have a Gly-87 mutation (nalidixic acid MICs, 64 to 512 micrograms/ml; norfloxacin MICs, 0.5 to 4 micrograms/ml) suggest that the Gly-87 mutation causes resistance at the level of the nalidixic acid MIC (64 micrograms/ml) or the norfloxacin MIC (0.5 micrograms/ml or less) and that the additional increments in resistance seen in the other strains with higher levels of resistance may be attributable to additional mutations . The single-strand conformational polymorphism analysis with PCR products readily detected te Leu-83 and Gly-87 mutations.

Antimicrob Agents Chemother, 1995 Aug, 39(8), 1661 - 6
Inhibitory and bactericidal activities of levofloxacin, ofloxacin, erythromycin, and rifampin used singly and in combination against Legionella pneumophila; Baltch AL et al.; The susceptibilities of 56 Legionella pneumophila isolates (43 clinical and 15 environmental isolates) to levofloxacin, ofloxacin, erythromycin, and rifampin were studied with buffered charcoal yeast extract (BCYE) agar (inoculum, 10(4) CFU per spot), and the susceptibilities of five isolates were studied with buffered yeast extract (BYE) broth (inoculum, 10(5) CFU/ml) . The MICs inhibiting 90% of strains tested on BCYE agar were 0.125, 0.25, 1.0, and < or = 0.004 micrograms/ml for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively . The MICs by the BYE broth dilution method were 1 to 3, 2, 1 to 2, and 1 tube lower than those by the agar dilution method for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively . The MBCs were 1 to 2 tubes higher than the broth dilution MICs for levofloxacin, 1 to 3 tubes higher than the broth dilution MICs for ofloxacin, 1 to 3 tubes higher than the broth dilution MICs for erythromycin, and the same as the broth dilution MICs for rifampin . In kinetic time-kill curve studies, at drug concentrations of 1.0 and 2.0 times the MIC, the most active drugs were levofloxacin and rifampin . At 72 h, concentrations of levofloxacin and rifampin of 2.0 times the MIC demonstrated a bactericidal effect against L . pneumophila . In contrast, at concentrations of 1.0 and 2.0 times the MICs regrowth was observed with ofloxacin and only a gradual decrease in the numbers of CFU per milliliter was observed with erythromycin . Only a minor inhibitory effect was observed with 0.25 or 0.5 time the MICs of all drugs at 24 to 48 h, with regrowth occurring at 72 h . In contrast to erythromycin or ofloxacin plus rifampin at 0.25 time the MICs, only levofloxacin plus rifampin demonstrated synergy . Thus, levofloxacin demonstrated the best inhibitory and bactericidal effects against L . pneumophila when it was studied alone or in a combination with rifampin.

Planta Med, 1995 Aug, 61(4), 313 - 6
Biological activities of pyrrolidinoindoline alkaloids from Calycodendron milnei; Saad HE et al.; Certain genera of the tribe Psychotrieae, specifically Calycodendron and Psychotria, found on Pacific Islands, synthesize a series of Nb-methyltryptamine-derived alkaloids made by linking together 2 to 8 pyrrolidinoindoline units . Nine alkaloids of this class have been isolated from the aerial parts and stem bark of Calycodendron milnei, a species endemic to the Vate Islands (New Hebrides), and examined for potential application as anti-cancer and anti-infective agents . All members of the series exhibited readily detected cytotoxic activity against proliferating and non-proliferating Vero African green monkey kidney cells in culture, with the most potent activity being exhibited by vatamine and quadrigemine C . Only hodgkinsine A exhibited substantial antiviral activity against a DNA virus, herpes simplex type 1, and an RNA virus, vesicular stomatitis virus . All members of the series showed readily detected anti-bacterial, anti-fungal, and anti-candidal activities using both tube dilution and disc diffusion assay methods . The most potent anti-microbial alkaloids were hodgkinsine A and quadrigemine C, which exhibited minimum inhibitory concentration (MIC) values as low as 5 micrograms/ml.

Jpn J Antibiot, 1995 Aug, 48(8), 1003 - 8
{Lytic action of cefminox against slowly growing bacteria}; Tsuruoka T et al.; Lytic action of cefminox (CMNX) against slowly growing Escherichia coli (E . coli) K-12 JE1011 was compared with that of the related cephamycin cefmetazole (CMZ) or ampicillin (ABPC) . The growth rate in doubling time was 30 min . at 37 degrees C . Minimal concentrations of CMNX, CMZ and ABPC showing clear lysis were 0.39, 3.13 and 12.5 micrograms/ml, respectively, under these conditions . When E . coli was cultured at 12 degrees C, the doubling time was 720 and 816 min . which were 24 and 27.2 fold as slow as those at 37 degrees C, respectively . In 12 degrees C culture, the minimal concentrations showing clear lysis were 0.78 (2 fold at 37 degrees C), 25 (8 fold) and 100 micrograms/ml and higher (8 fold or more) with CMNX, CMZ and ABPC, respectively . Therefore, it appeared that the lytic activity of CMNX was not significantly affected by bacterial growth rate and was demonstrated effectively against slowly growing bacteria at a low concentration . We determined release activity of cell wall peptidoglycan fragments by 5 beta-lactam antibiotics in addition to the above-mentioned 3 antibiotics . The results showed that the release activity was not proportional to the MIC and that of CMNX was the strongest among those antibiotics . The rapid and strong bactericidal action of CMNX against bacteria at the early stationary phase was suggested to result from the characteristic lytic action against slowly growing bacteria.

J Med Chem, 1995 Jul 7, 38(14), 2541 - 5
Cyclic variations of 3-quinolinecarboxamides and effects on antiherpetic activity; Wentland MP et al.; Supported by the antiherpetic properties of 3-quinolinecarboxamides and the importance of the planar intramolecular H-bonded beta-keto amide pharmacophore, a series of novel conformationally rigid analogues that contain a heterocyclic bridge between the 3- and 4-positions of the quinoline ring have been evaluated . Two isoxazolo-fused derivatives 17 and 23 displayed good in vitro antiherpetic potency that was similar to that of 1, the 3-quinolinecarboxamide that served as the comparison structure for this study . The pyrazolo, pyrrolo, and pyrimido derivatives showed considerably less or no activity . In vitro activity did not translate to in vivo efficacy . For 17, the lack of in vivo activity is likely a consequence of insufficient plasma drug levels (both Cmax and duration) in mice relative to the MIC versus HSV-2.

Mycoses, 1995 Jul-Aug, 38(7-8), 311 - 5
Preliminary screening of some squalenoid derivatives for toxicity towards dermatophytes; Airaudi D et al.; We report a preliminary study of the in vitro anti-dermatophyte activity of six squalenoid derivatives that inhibit 2,3-oxidosqualene cyclase and squalene epoxidase: 2-aza-2,3-dihydrosqualene, 22,23-epoxy-2-aza-2,3-dihydrosqualene, azasqualene alcohol, 19-aza-18,19,22,23-tetrahydrosqualene, 2,3-epoxy-19-aza-18,19,22,23-tetrahydrosqualene and hexafluorosqualene epoxide . The tests were done by inoculating 10 microliters of Trichophyton mentagrophytes (Robin) Blanchard or Microsporum canis Bodin homogenate into 1 ml of Sabouraud glucose liquid medium containing serial dilutions from 100 to 0.25 micrograms ml-1 of the substance . For each compound the minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) were determined . The most effective compounds were 22,23-epoxy-2-aza-2,3-dihydrosqualene and azasqualene alcohol, with MICs respectively of 3 and 6.25 micrograms ml-1 for each of the two species of dermatophyte . The first of these compounds was the only one to show fungicidal activity over the range of concentrations tested.

J Antimicrob Chemother, 1995 Jul, 36 Suppl A, 43 - 56
A compilation of meropenem tissue distribution data; Hutchison M et al.; Meropenem body fluid and tissue concentration data from both published studies and samples obtained during efficacy evaluation have been compiled and presented according to a consistent format to facilitate comparison . The concentration data have been compared with the mode MIC data available for the pathogens isolated during the clinical evaluation of meropenem . These data support the widespread and rapid penetration of meropenem into the interstitial fluid of those tissues not protected by a tight epithelial barrier . Furthermore, they suggest that the proposed dosages of meropenem 500 mg or 1 g tds would provide an adequate duration of cover at tissue sites for the treatment of a range of commonly occurring pathogens . A higher dosage of 40 mg/kg or 2 g in adults given tds would be recommended for meningitis based on the penetration of meropenem into CSF . Overall, the tissue and body fluid data presented confirm the expectation, based on the plasma concentrations and theoretical arguments, that meropenem is rapidly and readily distributed into the interstitial fluid, thereby producing concentrations in tissues likely to be clinically effective . This is consistent with the available clinical data on the therapeutic efficacy of meropenem.

J Antimicrob Chemother, 1995 Jul, 36(1), 53 - 64
Potent activity of meropenem against Escherichia coli arising from its simultaneous binding to penicillin-binding proteins 2 and 3; Sumita Y et al.; A mutant strain of Escherichia coli with reduced susceptibility to imipenem, designated TL2740, was selected following serial passage of the parent strain, E . coli C600, in broth containing increasing concentrations of the carbapenem; the MIC of imipenem for TL2740 was eight-fold greater than that of the parent strain . The mutant also exhibited reduced susceptibilities to panipenem and biapenem and high-level resistance to mecillinam, but was as susceptible to meropenem, ceftazidime, piperacillin and the other beta-lactams tested as strain C600 . The affinity of penicillin-binding protein (PBP) 2 of TL2740 for imipenem and meropenem was ten-fold less than that of C600, thereby providing an explanation for the mutant's reduced susceptibility to some carbapenems and mecillinam . However, this theory was confounded by the observation that the in-vitro activities of meropenem against both parent and mutant strains were virtually the same and by the fact that PBP 2 is the principal target of the antibiotic . Imipenem and aztreonam, which bind to PBP 2 and PBP 3 respectively, demonstrated synergic activity when tested in combination against both C600 and TL2740 . These results suggest that the potent activity of meropenem against the mutant strain might also be due to a synergic effect resulting from simultaneous binding to both PBP 2 and PBP 3 and that the variable activities of the carbapenems against TL2740 were related to their different PBP binding profiles . Compared with C600, TL2740 appeared shorter on electron microscopy and had a longer generation time, discrepancies which are compatible with defective PBP 2 activities in the mutant strain . We also identified three clinical isolates of E . coli with beta-lactam susceptibility profiles which resembled that of TL2740 i.e . high-level resistance to mecillinam and low-level resistance to carbapenems, with the exception of meropenem to which these strains were susceptible; in common with TL2740, the combination of imipenem and aztreonam was synergic against these isolates . The genetic basis of resistance in all of the mecillinam-resistant strains, including TL2740, mapped close to lip at 15' on the E . coli chromosome with transductional analysis . The results strongly suggest that the reduced susceptibilities of the clinical isolates to carbapenems were due to mutations in the genes encoding the PBP 2s of these strains which affected their affinities for beta-lactam antibiotics.

Mycopathologia, 1995 Jul, 131(1), 9 - 12
A case of cutaneous phaeohyphomycosis caused by Exserohilum rostratum, its in vitro sensitivity and review of literature; Agarwal A et al.; A 40 year old woman presented with the infection of skin of 3 years duration on the upper anterior aspect of fore-arm . Histologic examination of the skin tissue revealed dematiaceous hyphae, aggregated structures or single celled elements . On detailed mycological examination the isolate was identified as Exserohilum rostratum . Among the antimycotic tested in vitro amorolfine was found to be most effective with MIC value of 3 mcg/ml . This is the first report of E . rostratum infection of man from India.

Eur J Clin Microbiol Infect Dis, 1995 Jul, 14(7), 636 - 42
Antibiotic selection factors and description of a hospital-based outpatient antibiotic therapy program in the USA; Craig WA; A variety of pharmacodynamic, pharmacokinetic and drug stability factors can influence the choice of drug, the dosing regimen and the method of drug administration for out-patient parenteral antibiotic therapy (OPAT) . Beta-lactam antibiotics exhibit little if any concentration-dependent killing and produce short-term or no persistent effects with most bacterial pathogens . Optimal dosing regimens for these agents should provide serum levels that continually exceed the minimal inhibitory concentration (MIC) of the pathogen . Beta-lactam agents with long half-lives (greater than 2 hours) can provide these levels with intermittent dosing once or twice daily . Beta-lactam agents with shorter half-lives can be administered by programmable pumps or by continuous infusion providing the drug is sufficiently stable to degradation in solution . Imipenem and ampicillin are examples of drugs with short half-lives that are unstable in solution and must be dosed intermittently . Intramuscular administration slows absorption and can also prolong the length of time during which serum levels exceed the MIC of infecting bacteria . Aminoglycosides and fluoroquinolones, on the other hand, exhibit concentration-dependent killing and produce prolonged persistent effects . Optimal dosage regimens of these drugs should maximize serum levels . Once-daily dosing regimens for the aminoglycosides meet this goal and also appear to reduce drug-induced nephrotoxicity . Application of these principles to drug selection and administration in a hospital-based OPAT program has provided efficacious therapy and a low incidence of adverse reactions in an elderly population distributed over a wide geographic area.

Vet Microbiol, 1995 Jul, 45(2-3), 251 - 8
Effect of heparin on hemagglutination by Akabane and Aino viruses belonging to the Simbu group of bunyaviruses; Jusa ER et al.; Heparin inhibited the hemagglutinin activity of Akabane and Aino viruses . The minimal inhibitory concentration of heparin required to inhibit 8 hemagglutination (HA) U of Akabane and Aino viruses was 10 U/ml . Goose erythrocytes failed to combine with the HA inhibitory factor of heparin . On the other hand, goose erythrocytes treated with heparinase had greatly reduced agglutinability by Akabane virus . Virus-heparin complex formation was observed by sedimenting heparin with the virus particles.

Chemotherapy, 1995 Jul-Aug, 41(4), 276 - 80
Antifungal activity of LY295337 in vitro against clinical isolates of Candida spp; Aller AI et al.; LY295337 is a new antifungal agent derived from the echinocandins; it shows in vitro and in vivo activity against a great variety of pathogenic fungi . In this study, we evaluated the in vitro activity of LY295337 against 201 strains of Candida spp . using two culture media: Sabouraud dextrose broth (SDB) and RPMI 1640; fluconazole was used as reference antifungal agent . The minimum inhibitory concentration (MIC) was determined by the broth microdilution method for LY295337 in SDB and RPMI 1640, and for fluconazole by an agar dilution method . The fungicidal activity of LY295337 was also determined . The MIC-50 as well as MIC-90 values obtained for LY295337 in SDB (range 0.025-0.6 mg/l) were lower than those obtained for RPMI 1640 (0.035-1.25 mg/l) . All the strains resistant to fluconazole were sensitive to LY295337 (MIC < 0.6 mg/l) . These results show that LY295337 is an excellent antifungal agent with a fungicidal activity in vitro against various species of Candida.

Can J Anaesth, 1995 Jul, 42(7), 631 - 5
Sepsis reduces isoflurane MAC in a normotensive animal model of sepsis; Gill R et al.; Patients with sepsis often require anaesthesia for surgical procedures . Anaesthesia can be unpredictable and the most haemodynamically stable agents are used . No data are available for the minimum alveolar concentration (MAC) requirements in such patients or in animal models of sepsis . We have characterized the effect of sepsis on the MAC of isoflurane in a normotensive rodent model of sepsis . The minimum inhibitory concentration (MIC) of isoflurane to an identical stimulus was determined for rodents subjected to caecal ligation and perforation (CLP n = 8), or sham laparotomy (n = 7) . The calculated MAC of isoflurane was reduced in the septic animals compared with the sham animals (MAC of isoflurane, CLP = 0.8%, sham = 1.4% P < 0.003) . No statistical differences were found in the haemodynamic variables measured in either group . Isoflurane leads to haemodynamic stability during anaesthesia in this animal model of sepsis . However, the MAC requirement for isoflurane is reduced by sepsis.

Antimicrob Agents Chemother, 1995 Jul, 39(7), 1454 - 7
Susceptibilities of nontuberculosis mycobacterial species to amoxicillin-clavulanic acid alone and in combination with antimycobacterial agents; Utrup LJ et al.; Neither amoxicillin nor clavulanic acid used alone was active at the highest level tested, i.e., 256.0 micrograms/ml, in vitro against 24 isolates of Mycobacterium fortuitum, Mycobacterium kansasii, and Mycobacterium marinum . However, the MIC of an amoxicillin-clavulanic acid combination of 2:1 was < or = 8.0/4.0 micrograms/ml for 50 percent of the isolates tested, with all isolates being inhibited in the range of 4.0/2.0 to 32.0/16.0 micrograms/ml, respectively . Titration of amoxicillin-clavulanic acid with a fixed 2-micrograms/ml concentration of ethambutol resulted in synergistic activity against 3 of 9 isolates of M . fortuitum, 10 of 10 isolates of M . kansasii, and 5 of 5 isolates of M . marinum . This observation was confirmed in a checkerboard analysis in which fractional inhibitory concentrations were < or = 0.5 for 20 of the 24 isolates . Synergistic activity was observed against the other four isolates in one of two trials . On the other hand, titration of amoxicillin-clavulanic acid in the presence of either one or two fixed concentrations of isoniazid, rifampin, cycloserine, tetracycline, or amikacin failed to result in synergism.

J Chemother, 1995 Jun, 7 Suppl 2, 47 - 52
Once-daily versus multiple-daily dosing of aminoglycosides; Craig WA; The pharmacodynamic characteristics of isepamicin and other aminoglycosides, both in terms of efficacy and toxicity, explain why once-daily administration of these agents should be the optimal dosing regimen . Isepamicin, as with other aminoglycosides, exhibits concentration-dependent bactericidal activity and produces prolonged post-antibiotic effects against susceptible organisms . High concentrations of these drugs would be expected to produce more rapid and extensive bacterial killing than lower levels . Furthermore, the post-antibiotic effect would protect against bacterial regrowth when serum and tissue concentrations fall below inhibitory levels . In animal models, the magnitude of the peak serum concentration or the area under the concentration-time curve, are the important determinants of efficacy for isepamicin and the other aminoglycosides . Isepamicin also exhibits the "first-exposure effect", i.e . initial exposure of bacteria to isepamicin down-regulates subsequent uptake of the drug . During this period of down-regulation, bacteria exhibit decreased killing and shorter post-antibiotic effects . Since the first-exposure effect lasts for several hours, once-daily administration of the aminoglycosides allows for this effect to dissipate completely between doses . High peak concentrations, greater than 8-10 times the minimum inhibitory concentration (MIC), will also decrease the emergence of resistant strains . With regard to toxicity, one of the first steps in the uptake of aminoglycosides into sites of toxicity is their binding to the brush borders of renal cells and to the cochlea and vestibular membranes . Binding to these membranes demonstrates saturable kinetics . As a result, uptake of the aminoglycosides is more efficient with low sustained concentrations than with high intermittent levels . Once-daily dosing of aminoglycosides has consistently been less toxic than more frequent dosing in animals . In clinical studies, once-daily dosing of aminoglycosides compared to two-or three-times daily administration has generally exhibited similar efficacy and toxicity . However, a few studies has shown greater efficacy or lower toxicity with once-daily dosing of aminoglycosides . Once-daily dosing of the aminoglycosides has the potential to enhance efficacy, reduce toxicity, and lower administration costs for this drug class.

Pathol Biol (Paris), 1995 Jun, 43(6), 565 - 7
{Azithromycin and Mycobacterium avium infection}; Perronne C; Mycobacterium avium infection is a frequent complication during the late stage of AIDS . M . avium is resistant or poorly susceptible to classical antituberculosis drugs . Some new macrolide antibiotics such as clarithromycin or azithromycin are bactericidal against M . avium, and their use has dramatically improved the prognosis of this infection . In vitro, azithromycin has MICs against M . avium ranging from 4 to 64 MIC50 being 16 mg/l and a MIC90 being 32 mg/l . Despite low concentrations in serum, close to 0.4 mg/l, very high intracellular concentrations of azithromycin, above the MIC, may be achieved . Azithromycin is active in vitro in the model of macrophage infection . Furthermore, azithromycin is active against murine experimental infection with M . avium . Clinical studies conducted among patients with AIDS have shown that azithromycin was active against disseminated M . avium infection, with a dose of 600 mg/d . Ongoing studies are designed to better determine the ideal dose, to compare its activity with that of clarithromycin and to determine the antibiotics that could be combined to prevent the selection of resistant mutants . Other ongoing studies are evaluating the efficacy of azithromycin for the chemoprophylaxis of M . avium infection in HIV infected patients with a CD4T lymphocyte concentration lower than 100/mm3.

Pathol Biol (Paris), 1995 Jun, 43(6), 534 - 41
{Azithromycin and bronchopulmonary infections}; Leophonte P; Azithromycin is a molecule of the macrolide family, belonging to the azalides class . Several of its characteristics allow for its use in the treatment of the community-acquired lower respiratory tract infections . Commonly isolated pathogens in bronchial infections are most frequently H . influenzae, S . pneumoniae, M . catarrhalis, C . pneumoniae and M . pneumoniae, and more rarely or in the context of a particular background, S . aureus, Gram negative bacteria and L . pneumophila . MIC90 of these germs is generally low or slightly elevated, displaying an inhibitory activity of the azithromycin on these bacteria . Nevertheless, the frequency of macrolide-resistant S . pneumoniae is not negligible and this germ must be considered as inconstantly susceptible to the macrolide family . Pharmacokinetics studies evidenced from high to very high azithromycin concentrations in the pulmonary tissues, reaching values well above MIC of pathogens commonly isolated . Given the long half-life, these concentrations persist a long time after oral administration . As azithromycin concentrates much in polymorphonuclear leucocytes, they release azithromycin after having migrated into the infectious site by chimiotactism, thus allowing to increase the antibiotic concentration at infection site . These requirements have been confirmed in vivo in animal models and in clinical studies . Two experimental models on macrolide susceptible S . pneumoniae, and H . influenzae evidenced a better activity of azithromycin in comparison to other macrolides tested against these two germs.

Hum Pathol, 1995 Jun, 26(6), 639 - 41
Is esthesioneuroblastoma a peripheral neuroectodermal tumor?
Nelson RS, Perlman EJ, Askin FB.
Esthesioneuroblastoma (ENB; olfactory neuroblastoma) is a rare, locally aggressive neoplasm of the sinonasal area and anterior cranial fossa . The histogenesis of the lesion is not clearly delineated, and the broad histological spectrum of ENB has confounded the issue . The location, histological features (neuropil, Homer Wright, and olfactory rosettes), and reported immunocytochemical reactions (neuron-specific enolase (NSE) and chromogranin (CHR) positivity) suggest that ENB may be a neural or neuroendocrine neoplasm derived from the olfactory membrane . Recent demonstration in two of three metastatic putative ENB cell lines of the 11;22 chromosomal translocation, seen in Ewing's sarcoma (ES) of bone and peripheral neuroectodermal tumors (PNET) of bone and soft tissue, has led to the conclusion that ENB may be closely related histogenetically to PNET . The overwhelming majority of cases of ES and PNET express the protein product of MIC-2, a gene located on the pseudoautosomal region of the X and Y chromosomes . This protein can be identified immunocytochemically by antibodies 12E7, HBA71, and ON13 . We studied the expression of MIC-2 using the 12E7 antibody as well as multiple neural markers in 18 ENB samples obtained from the files of The Johns Hopkins Hospital . The patients ranged in age from 19 to 90 years (mean, 47.5; median, 47) and included five men and 13 women . None of the 18 specimens reacted with antibody 12E7, but 16 were positive for NSE, nine reacted to synaptophysin (SYN), and 13 showed antibodies to chromogranin (CHR) . Our studies agree with the previous suggestions that ENB is a primitive neural tumor but fail to support the hypothesis that it is a member of the PNET family.

Infect Immun, 1995 Jun, 63(6), 2236 - 42
Release of tumor necrosis factor alpha and interleukin 6 during antibiotic killing of Escherichia coli in whole blood: influence of antibiotic class, antibiotic concentration, and presence of septic serum; Prins JM et al.; The concentration and accessibility of endotoxin can increase following antibiotic killing of gram-negative bacteria . There are indications that antibiotics may differ in this respect . We measured endotoxin levels in RPMI 1640 and tumor necrosis factor alpha (TNF-alpha) and interleukin-6 production in whole blood ex vivo after exposure of log-phase Escherichia coli to antibiotics belonging to different classes, in a final concentration of 0.5, 5, or 50 times the MIC . After 4 h of incubation at 50 times the MIC, ceftazidime and ciprofloxacin treatment resulted in levels of endotoxin, TNF-alpha, and interleukin-6 significantly higher than those of imipenem and gentamicin (P < 0.001) . Similar differences in cytokine induction were measured after 8 h of incubation . At 0.5 times the MIC, the differences between the antibiotics in measured endotoxin and cytokine levels were small, with levels comparable to the levels in untreated cultures . Polymyxin B and, to a lesser degree, recombinant bactericidal/permeability-increasing protein 21 (rBPI-21) were found to be potent inhibitors of TNF-alpha release, supporting the concept that the differences between the antibiotics in cytokine production were indeed due to differences in amounts of biologically active endotoxin . The presence of serum from patients suffering from untreated sepsis decreased TNF-alpha production significantly, in a concentration-dependent manner.

Ceylon Med J, 1995 Jun, 40(2), 64 - 5
Emergence of penicillin resistant pneumococci in Sri Lanka; de Silva N et al.; Two strains of penicillin resistant (PR) pneumococci were isolated recently from cerebrospinal fluid of two children with meningitis . Penicillin resistance was detected by using a lug disc of oxacillin in the Stokes disc diffusion method . The strains were tested quantitatively for sensitivity to penicillin by an agar dilution technique . The minimum inhibitory concentration (MIC) to penicillin of these strains were 2 micrograms/ml and 0.12 microgram/ml, indicating that respectively they were of frank and intermediate resistance to penicillin . However these strains were sensitive to other antibiotics tested, namely, erythromycin, tetracycline, chloramphenicol, amoxycillin, cephalexin and cefotaxime . Penicillin resistant pneumococci are here in Sri Lanka . Though one strain was of intermediate resistance, therapeutic failure during treatment with penicillin was evident in this case.

Clin Orthop, 1995 Jun, (315), 209 - 11
Sequential levels of ceftriaxone in intervertebral disc removed as part of scoliosis surgery; Lang R et al.; A single intravenous loading dose of 1 g ceftriaxone was injected at different intervals before surgery for correction of spinal scoliosis . Serum and concomitant disc samples were obtained and assay was performed using high-pressure liquid chromatography . Data showed that the antibiotic levels in intervertebral disc space reached 3.5 mcg/mg, which is above the minimum inhibitory concentration for most of the relevant pathogens, as early as 1 hour after intravenous administration . These therapeutic levels were maintained for more than 5 hours, an accepted period for most spinal surgical procedures.

Exp Mycol, 1995 Jun, 19(2), 163 - 5
Resistance to azole drugs in Neurospora crassa; Staben C; Neurospora crassa was susceptible to azole drugs: ketoconazole (MIC 1 microgram/ml), fluconazole (MIC 5 micrograms/ml), and SCH39304 (MIC 5 micrograms/ml) . Mutants of N . crassa resistant to ketoconazole were selected and genetically characterized . The seven characterized resistance mutations represented at least four genetic loci . Some mutants, but not all, were also resistant to fluconazole and to SCH39304.

Antimicrob Agents Chemother, 1995 Jun, 39(6), 1341 - 4
In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis; JI B et al.; In tests with 18 drug-susceptible strains of Mycobacterium tuberculosis, the MIC at which 50% of the strains are inhibited by levofloxacin (LVFX) was one dilution less than that at which 50% of the strains are inhibited by ofloxacin (OFLO), but the MICs at which 90% of the strains are inhibited were similar . The in vivo activity of LVFX against M . tuberculosis was compared with the activities of isoniazid, OFLO, and sparfloxacin (SPFX) . Mice were inoculated intravenously with 1.74 x 10(6) CFU of H37Rv, and treatments began the next day and were carried out six times weekly for 4 weeks . The severity of infection and effectiveness of treatment were assessed by survival rate, spleen weights, gross lung lesions, and enumeration of CFU in the spleen . In terms of CFU counts, the ranking of the anti-M . tuberculosis activities of the treatments used ran in the following order: LVFX (300 mg/kg of body weight) = SPFX (100 mg/kg) > isoniazid > SPFX (50 mg/kg) > OFLO (300 mg/kg) = LVFX (150 mg/kg) > OFLO (150 mg/kg) = LVFX (50 mg/kg) . It seems, therefore, that the in vivo activity of LVFX is comparable to that produced by a twofold-greater dosage of OFLO . It is assumed that the maximal clinically tolerated dosage of LVFX is similar to that of OFLO, i.e., 800 mg daily, which is equivalent to 300 mg of LVFX per kg in mice . Because LVFX displayed powerful bactericidal activity, promising effects against human tuberculosis may be achieved if patients are treated with the maximal clinically tolerated dosage of LVFX.

Antimicrob Agents Chemother, 1995 Jun, 39(6), 1240 - 2
Cefixime penetration in human renal parenchyma; Leroy A et al.; The diffusion of cefixime, a new orally active expanded-spectrum cephalosporin, was studied in 12 patients undergoing nephrectomy after receiving 200-mg oral doses every 12 h for 2 days . The patients were divided into two groups according to the time of perioperative sampling after the last dose: 4 h (group 1) and 12 h (group 2) . Preoperative blood samples were taken just before administration of the last dose of cefixime . Simultaneous blood and tissue samples were collected perioperatively at 4 h (time to peak level) and 12 h (residual level) . The intrarenal concentrations of cefixime were measured by an isocratic reversed-phase high-pressure liquid chromatographic (HPLC) assay . Concentrations in serum were determined by both microbiological and HPLC assays . The mean peak levels in serum were 3.41 +/- 0.43 micrograms/ml (group 1), and the residual levels averaged 1.54 +/- 1.17 micrograms/ml (group 2) . The diffusion in renal parenchyma was not significantly different in the cortexes and medullas of both groups of patients: 5.7 to 6.4 micrograms/g in group 1 and 4.6 to 4.7 micrograms/g in group 2 . The decrease in cefixime concentrations was slower in tissue than in serum; the ratios of concentrations in tissue to those in serum were 3.5 to 3.6 and 1.7 to 1.9 at 4 and 12 h, respectively . The intrarenal concentrations of cefixime remained higher than the MIC for the most susceptible gram-negative bacteria during the time interval between the administration of two doses.

Indian J Med Sci, 1995 May, 49(5), 109 - 13
Antimycotic susceptibility testing of mould-fungi with allylamines by disk diffusion; Venugopal PV et al.; Susceptibility testing of 17 clinical isolates of mould-fungi, which included Aspergillus spp., (8) Penicillium spp., (2) Paecilomyces spp., (1) Cladosporium spp., (1) Pyrenochaeta romeroi (1) Rhizopus spp., 2 . Syncephalastrum spp., (1) and Mortierella spp., (1) were carried out against allylamines-naftifine and terbinafine-(Sandoz Forchungsinstitut) by agar dilution and disk diffusion techniques . Terbinafine was more active than naftifine inhibiting 50 and 90% of the fungi other than zygomycetes at a concentration of 0.5 and 1 microgram/ml whereas the values for naftifine were 2.5 and 10 micrograms/ml . The MIC range for zygomycetes for terbinafine and naftifine were 1-->100 and 100-->100 respectively . The MICs and the sizes of zones of inhibition around the disks correlated well and the degree of correlation was measured by regression analysis . The correlation coefficients for naftifine and terbinafine were-0.9597 and -0.9174 (P < 0.007) respectively.

Microbiology, 1995 May, 141 ( Pt 5), 1081 - 3
Division-inhibition capacity of penicillin in Escherichia coli is growth-rate dependent; Hadas H et al.; Growing bacteria are sensitive to various beta-lactam derivatives due to their interference with peptidoglycan biosynthesis . At low concentrations, penicillin G (benzylpenicillin) blocks cell division without affecting mass growth rate . The MIC for division of Escherichia coli B/r (H266) was found to depend on the growth rate, which was modified by the nutritional conditions . Our hypothesis, that division sensitivity is proportional to the rate of peptidoglycan synthesis for septum formation, as well as to cell circumference, was thus confirmed.

Chemotherapy, 1995 May-Jun, 41(3), 200 - 3
In vitro susceptibility of Mucor ramosissimus Samutsevitsch, a rare fungal pathogen, to antimycotics; Sharma R et al.; The in vitro susceptibility of a rare fungal pathogen, Mucor ramosissimus Samutsevitsch, to antimycotics in clinical use was determined . Minimal inhibitory concentrations (MICs) and minimal fungicidal concentrations (MFCs) were (MIC/MFC, microgram/ml): amphotericin B, 3.125/25; miconazole, 6.25/6.25; clotrimazole, 25/25; fluconazole, 5-fluorocytosine, itraconazole, and ketoconazole, > or = 100/100 . Our results show that amphotericin B and miconazole are the most effective antimycotics.

Farmaco, 1995 May, 50(5), 361 - 4
Synthesis of some N,N-disubstituted carbamodithioic acid esters tested for antifungal activity; Ates O et al.; The synthesis of 12 new 4-{(N,N-disubstituted thiocarbamoylthio)acetamido}antipyrines and their antifungal activity are reported . Of these compounds, only 3e, showed good antifungal activity against C . tropicalis KUEN 1021, C . krusei KUEN 1001, C . stellatoidea KUEN 1018, C . pseudotropicalis KUEN 1012, C . albicans ATCC 10231 when compared with clotrimazole and miconazole (MIC = 12.5 micrograms/ml).

Antimicrob Agents Chemother, 1995 May, 39(5), 1194 - 5
Susceptibilities of Brucella melitensis isolates to clinafloxacin and four other new fluoroquinolones; Garcia-Rodriguez JA et al.; The susceptibilities of 120 clinical isolates of Brucella melitensis and 3 reference strains of the same species to six fluoroquinolones (clinafloxacin, PD 117596, PD 131628, PD 138312, PD 140248, and ciprofloxacin) were examined by agar dilution MIC methodology . Clinafloxacin was the most active compound tested (MIC at which 50% of strains tested were inhibited {MIC50} and MIC90 of 0.06 micrograms/ml) . Its level of activity was slightly higher than that of PD 117596 (MIC50 and MIC90 of 0.12 micrograms/ml) . PD 131628 and ciprofloxacin were less active than clinafloxacin, with MIC50s ranging from 0.12 to 0.25 micrograms/ml and MIC90s of between 0.25 and 0.5 micrograms/ml for the two compounds . The activity levels of PD 138312 and PD 140248, with MIC50s ranging from 1 to 2 micrograms/ml and MIC90s of 4 to 8 micrograms/ml, were lower than those of the other fluoroquinolones tested.

Antimicrob Agents Chemother, 1995 May, 39(5), 1185 - 6
In vitro activity of rokitamycin, a new macrolide, against Borrelia burgdorferi; Cinco M et al.; The activity of rokitamycin, a new macrolide with a 16-member ring, was tested against Borrelia burgdorferi in vitro . The antibiotic had a lower MIC at which 50% of the isolates are inhibited than erythromycin, the parent 14-member macrolide, but the same MIC at which 50% of the isolates are inhibited as the other recent 14- and 15-member macrolides, like clarithromycin and azithromycin . The MBC was equal to the MIC at which 50% of the isolates are inhibited, so rokitamycin can be considered bactericidal against B . burgdorferi . The sensitivity of the Borrelia strains tested was not correlated with the particular species Burgdorferi sensu stricto, B . garinii, and B . afzelii or with the number of subcultures of the isolates.

Antimicrob Agents Chemother, 1995 May, 39(5), 1127 - 33
Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi; Kersten A et al.; Antibiotic therapy with penicillin, doxycycline, and ceftriaxone has proven to be effective for the treatment of Lyme borreliosis . In some patients, however, it was noticed that borreliae can survival in the tissues in spite of seemingly adequate therapy . For a better understanding of this phenomenon, we investigated the different modes of degeneration of Borrelia burgdorferi suspensions during a 96-h exposure to various antibiotics . By dark-field microscopy and ultrastructural investigations, increasing blebbing and the gradual formation of granular and cystic structures could be followed during the exposure time . Although antibiotic concentrations at the MIC at which 90% of organisms are inhibited after 72 h were 80% or even greater, motile organisms were still present after incubation with penicillin and doxycycline but not after incubation with ceftriaxone . By transmission electron microscopy, intact spirochetal parts, mostly situated in cysts, were seen up to 96 h after exposure with all three antibiotics tested . According to experiences from studies with other spirochetes it is suggested that encysted borreliae, granules, and the remaining blebs might be responsible for the ongoing antigenic stimulus leading to complaints of chronic Lyme borreliosis.

J Clin Microbiol, 1995 May, 33(5), 1094 - 7
Comparison of visual and spectrophotometric methods of MIC endpoint determinations by using broth microdilution methods to test five antifungal agents, including the new triazole D0870; Pfaller MA et al.; A study to compare three different methods for reading MIC endpoints tested by the broth microdilution modification of the National Committee for Clinical Laboratory Standards (Villanova, Pa.) reference method was conducted . MICs of amphotericin B, flucytosine, fluconazole, itraconazole, and a new triazole, D0870, were determined for five reference yeast strains and 100 clinical isolates of Candida spp . MICs were read visually according to National Committee for Clinical Laboratory Standards guidelines from microdilution trays that had been (VS) and had not been (V) shaken . MICs were also determined spectrophotometrically (SP) at 492 nm . SP endpoints were determined as the concentrations resulting in a > or = 50% inhibition of growth (flucytosine and azoles) and a > or = 90% inhibition of growth (amphotericin B) relative to control growth . The five reference strains were tested nine times each against all five antifungal agents, and the MIC results for each reading method were compared with a 3-log2 dilution reference range determined by the macrodilution (M27-P) method . Overall, 84 to 100% of the MICs determined by V, 93 to 100% of those determined by VS, and 89 to 100% of those determined by SP fell within the 3-log2 dilution reference range for each reference strain and antifungal agent . Reproducibility was 99% for V and SP and 98% for VS . Agreement among the three methods of reading ranged from 97 to 99% . Excellent agreement among reading methods was also observed for all antifungal agents when tested against 100 clinical isolates . Agreement between the standard V method (no agitation) and VS ranged from 99 to 100%, and that between V and SP ranged from 89 to 99% . The VS and SP reading methods provided more definitive endpoints than the V method, which does not involve shaking.

Anaesthesist, 1995 May, 44(5), 319 - 27
{The effect of mechanical ventilation, thoracotomy, and one-lung respiration on intrapulmonary perfusion distribution . An animal experimental study}; Groh J et al.; The physiological pattern of regional pulmonary blood flow is mainly determined by the relationship of pulmonary arterial, venous, and alveolar pressures . Changes in alveolar pressure and pulmonary geometry may therefore be expected to influence regional perfusion, which is a key determinant of pulmonary gas exchange . Unilateral thoracotomy is usually performed with the patient in the lateral decubitus position . The present study examined the influence of mechanical factors on regional pulmonary blood flow distribution in rabbits in the lateral decubitus position during normoxia and unilateral hypoxia . METHODS . Anaesthetised white New Zealand rabbits (n = 8) weighing 2200-3900 g (mean = 2860 g) received central venous injections of radioactive microspheres while in the left lateral decubitus position during spontaneous breathing (SB) and during mechanical ventilation (two-lung ventilation, 2LV), under closed (2LVC) and open chest (2LVT) conditions, as well as during unilateral hypoxia of the nondependent lung induced by nitrogen inflation (1LVN) or atelectasis (1LVA) . The method used for one-lung ventilation (1LV) has been previously described in detail . Arterial, central venous, and pulmonary arterial pressures were recorded continuously . Lungs were excised, dried in the inflated state, and cut into 16 sagittal slices, which were further divided into lobar components, the lower lobes into center and periphery . The radioactivity of each specimen was measured in a gamma-counter; perfusion of the individual tissue specimens was quantified using the software program MIC III . The Friedman test followed by paired comparisons according to Conover was used for statistical analysis of differences between the experimental phases . Perfusion of central and peripheral parts of isogravitational slices was compared by use of the Wilcoxon matched pairs test . Values are given as means +/- SE; the level of significance was P < 0.05 unless otherwise indicated . RESULTS AND DISCUSSION . Haemodynamic parameters did not differ significantly between the experimental phases (Table 1) . Compared to 2LV, a significant increase in venous admixture (P < 0.05) and a corresponding decrease in PaO2 (P < 0.01) were observed during 1LV . This effect was significantly more pronounced during 1LVA as compared to 1LVN (P < 0.01) . Since inspiratory pressure was kept constant throughout the experiments, moderate respiratory acidosis developed during both phases of 1LV . Regional perfusion (Qr) of the nondependent lung was slightly reduced during 2LVC compared to SB and 2LVT . One-lung ventilation induced a significant decrease in perfusion of the hypoxic lung (P < 0.001 1LVN, 1LVA vs . SB,2LVC,2LVT) . In accordance with the data obtained from blood gas analysis and oximetry, this effect was more pronounced during N2 insufflation than during atelectasis (P < 0.01 1LVN vs . 1LVA) . Among the factors that may account for this effect, PaCO2 did not differ significantly between both phases of 1LV . During N2 insufflation PO2 at the hypoxia-sensitive site is lower than during atelectasis, where it equals mixed-versus PO2 (PvO2) . The difference in local PO2 is unlikely, however, to have caused the changes in regional perfusion between 1LVN and 1LVA, since PvO2 was as low as 40 mmHg during 1LVA and the pulmonary vascular response to hypoxia has been found to reach its maximum in this PO2 range {2, 11} . Enhanced redistribution of regional perfusion during 1LVN as compared to 1LVA is therefore most likely attributed to differences in alveolar pressure and pulmonary geometry . Apart from a radial perfusion gradient in the right lower lobe during 2LVC and 2LVT, no isogravitational Qr gradients were observed . CONCLUSION . We conclude that controlled mechanical ventilation in the lateral decubitus position causes only minor changes in vertical blood flow distribution.

Kansenshogaku Zasshi, 1995 May, 69(5), 602 - 7
{A case of erythroleukemia associated with lung aspergilloma successfully treated with continuous drip infusion of amphotericin B}; Inai K et al.; In September 1990, a 55-year-old female with erythroleukemia was treated with enocitabine, mitoxantrone, vincristine, and etoposide . Despite prophylaxis of infectious diseases by oral administration of 2,400 mg/day amphotericin B (AMPH), 600 mg/day ofloxacin, and 1,500 mg/day kanamycin, pneumonia with refractory pyrexia appeared and developed cystic lesions with air crescent signs thereafter . Finally, the cystic one formed fungus balls . The pneumonia was diagnosed as aspergillus pneumonia by fungus growth in the tissue in the transbronchial lung biopsy specimens and by an elevation of serum anti-Aspergillus antibody . The patient had continuously been administered with AMPH for 16 days, increasing the drug doses every 2 days . The maximum plasma level of AMPH rose up to 0.78 micrograms/ml, the total amount up to 166 mg . The fungus balls disappeared completely without adverse effects except a transient decrease of plasma potassium level . Pharmacological studies had been reported that tissue AMPH levels elevated more than twice as much as that of the plasma . Although the maximum plasma level was less than that of MIC for Aspergillus, the lung tissue drug level was suspected to have been maintained higher by continuous drip infusion . These findings indicate that continuous drip infusion of AMPH is one of the useful treatment for lung aspergillosis.

J Antimicrob Chemother, 1995 May, 35(5), 691 - 6
Disposition of ornidazole and its metabolites during pregnancy; Bourget P et al.; The disposition of ornidazole and its two major hydroxylated metabolites was studied in five pregnant women (gestational ages 25 5/7 to 38 4/7 weeks) with either chorioamnionitis or pyelonephritis treated with ceftriaxone 2 g, tobramycin 3 mg/kg body weight and ornidazole 1 g all administered once-daily . Two series of blood samples were obtained, the first on the first day of treatment and the second at steady-state on day 5 . Local and systemic tolerability of ornidazole was excellent and patients showed complete remission without premature delivery . There was no evidence of ornidazole accumulation, and the pharmacokinetic parameters were very similar to those seen in healthy subjects . The dosage regimen of ornidazole therefore requires no adjustment during pregnancy . Trough concentrations of ornidazole measured at 24 h post dose were above the MIC of sensitive organisms . Children born to the trial patients showed normal initial development and their growth was normal.

J Antimicrob Chemother, 1995 May, 35(5), 675 - 9
In-vitro activity of oxazolidinones against Mycobacterium avium complex; Peters J et al.; Options for treating disseminated Mycobacterium avium complex (MAC) disease have improved . However, efficacy is not always certain, resistance is common and rapidly bactericidal agents would improve efficacy and prevent resistance . Certain oxazolidinones were tested against MAC strains and inhibited growth at expected serum concentrations or lower . Activity correlated with hydrophobicity and one agent was bactericidal at concentrations two to five times greater than the MIC.

J Am Vet Med Assoc, 1995 Apr 15, 206(8), 1200 - 3
Effect of penicillin or penicillin and dexamethasone in cattle with infectious bovine keratoconjunctivitis; Allen LJ et al.; To evaluate the efficacy of penicillin or penicillin and dexamethasone for treatment of infectious bovine keratoconjunctivitis, 6- to 8-month-old beef heifers with clinical signs of infectious bovine keratoconjunctivitis were randomly assigned to 1 of 3 treatment groups: penicillin only, penicillin and dexamethasone, or control . Cattle assigned to the penicillin group (n = 18) were treated with 3 daily subconjunctival injections of procaine penicillin G . Cattle assigned to the penicillin/dexamethasone group (n = 13) were treated with 3 daily subconjunctival injections of procaine penicillin G and dexamethasone sodium phosphate . Control cattle (n = 14) were not treated . Healing times and frequency of recurrence for corneal ulcers; severity, diameter, and surface area measurements of corneal ulcers; and clinical scores did not differ among the 3 groups . Frequency of Moraxella bovis isolation from specimens of ocular secretions from ulcerated and non-ulcerated eyes was similar in all groups . Minimum inhibitory concentration of penicillin G for 95 of the 102 tested M bovis isolates was 0.3 U/ml, and for 7 others was 0.03 U/ml . When first and last specimens from 42 of 45 calves with isolation of M bovis on serial microbial cultures were compared, the susceptibility of each last isolate was similar to that of the corresponding first isolate.

Infect Immun, 1995 Apr, 63(4), 1573 - 80
Borrelia burgdorferi mutant lacking Osp: biological and immunological characterization; Sadziene A et al.; All Borrelia burgdorferi sensu lato isolates characterized to date have one or a combination of several major outer surface proteins (Osps) . Mutants of B . burgdorferi lacking Osps were selected with polyclonal or monoclonal antibodies at a frequency of 10(-6) to 10(-5) . One mutant that lacked OspA, -B, -C, and -D was further characterized . It was distinguished from the OspA+B+ cells by its (i) autoaggregation and slower growth rate, (ii) decreased plating efficiency on solid medium, (iii) serum and complement sensitivity, and (iv) diminished capacity to adhere to human umbilical vein endothelial cells . The Osp-less mutant was unable to evoke a detectable immune response after intradermal live cell immunization even though mutant survived in mouse skin for the same duration as wild-type cells . Polyclonal mouse serum raised against Osp-less cells inhibited growth of the mutant but not of wild-type cells, an indication that other antigens are present on the surface of the Osp-less mutant . Two types of monoclonal antibodies (MAbs) with growth-inhibiting properties for mutant cells were identified . The first type bound to a 13-kDa surface protein of B . burgdorferi sensu stricto and of B . afzelii . The MIC of the Fab fragment of one MAb of this type was 0.2 micrograms/ml . The second type of MAb to the Osp-less mutant did not bind to B . burgdorferi components by Western blotting (immunoblotting) but did not bind to unfixed, viable cells in immunofluorescence and growth inhibition assays . These studies revealed possible functions Osp proteins in borrelias, specifically serum resistance, and indicated that in the absence of Osp proteins, other antigens are expressed or become accessible at the cell surface.

Antimicrob Agents Chemother, 1995 Apr, 39(4), 937 - 40
Prospective randomized comparison of cefepime and cefotaxime for treatment of bacterial meningitis in infants and children; Saez-Llorens X et al.; Ninety infants and children were prospectively randomized to receive cefepime (n = 43) or cefotaxime (n = 47) for therapy of bacterial meningitis . The two treatment groups were comparable in terms of age, duration of illness before enrollment, history of seizures, clinical status on admission, and etiology . Six (7%) patients died--two treated with cefepime and four treated with cefotaxime . Clinical response, cerebrospinal fluid sterilization, development of complications, antibiotic toxicity, and hospital stay were similar for the two treatment regimens . Concentrations of cefepime in cerebrospinal fluid varied from 55 to 95 times greater than the maximal MIC required by the causative pathogens . Audiologic and/or neurologic sequelae were found in 16% of the cefepime-treated patients and 15% of the cefotaxime-treated patients examined 2 to 6 months after discharge . We conclude that cefepime is safe and therapeutically equivalent to cefotaxime for management of bacterial meningitis in infants and children.

Antimicrob Agents Chemother, 1995 Apr, 39(4), 930 - 6
Comparison of ampicillin-sulbactam regimens simulating 1.5- and 3.0-gram doses to humans in treatment of Escherichia coli bacteremia in mice; Lister PD et al.; A mouse model of bacteremia was used to compare the efficacies of 1.5- and 3.0-g intravenous doses of ampicillin-sulbactam . Seven strains of Escherichia coli producing various levels of TEM-1 beta-lactamase were used as the challenge isolates . These strains included six clinical isolates (MICs from 2/1 micrograms/ml {with 2 and 1 microgram/ml being the respective concentrations of ampicillin and sulbactam} to 32/16 micrograms/ml) with similar degrees of virulence in mice and a laboratory genetic transformant (E . coli AFE) which hyperproduces TEM-1 (MIC = 128/64 micrograms/ml) . Human pharmacokinetics were simulated by injecting mice subcutaneously twice (1 h apart) with ampicillin-sulbactam at concentrations of 40 mg/kg of body weight (1.5 g) and 80 mg/kg (3.0 g) . Against two clinical isolates for which ampicillin-sulbactam MICs were < or = 8/4 micrograms/ml, no difference was observed in either the rate or level of killing between the two doses, and both doses were 100% protective against lethal infection . Against the four clinical isolates for which ampicillin-sulbactam MICs were between 16/8 and 32/16 micrograms/ml, a slight delay in killing was noted with three of the strains . This delay was followed by a rapid 2- to 3-log drop in the level of bacteremia, and both doses of ampicillin-sulbactam were 100% protective against lethal septicemia . With strain AFE, no killing was observed with the 40-mg/kg dose compared with a 2-log killing with the 80-mg/kg dose . This difference in killing correlated with a decreased protective efficacy of the 40-mg/kg dose . These data suggest that the 1.5-g preparation of ampicillin-sulbactam is as effective as the 3.0-g dose in the treatment of experimentally induced E . coli bacteremia, as long as ampicillin-sulbactam MICs are 32/16 micrograms/ml or less.

Tuber Lung Dis, 1995 Apr, 76(2), 136 - 40
In vitro activities of 2,2'-bipyridyl analogues against Mycobacterium avium and M . tuberculosis; Dhople AM et al.; SETTING: Because of widespread emergence of resistant Mycobacterium tuberculosis and the high incidence of opportunistic infection caused by M . avium (MAC) in AIDS patients, there is an urgent need for new drugs against these organisms . OBJECTIVE: To evaluate the activity of newly synthesized 2,2'-bipyridyl analogues against MAC and M . tuberculosis . DESIGN: Susceptibility of MAC and M . tuberculosis to VUF-8514 and VUF-8842 were determined by both tube dilution method using 7H9 broth and radiometric (BACTEC) method using 14C-palmitic acid . RESULTS AND CONCLUSIONS: The MICs of 8514 against MAC and M . tuberculosis wee 1 microgram/ml and 0.5 microgram/ml respectively, while for 8842 the respective values were 8 micrograms/ml and 2 micrograms/ml . In general, the MBC values for both drugs were two-fold higher than their corresponding MIC values . However, both drugs exhibited high bactercidal activities against both organisms . The MICs of clinical isolates of both organisms were in the same range as reference strains; furthermore, two isolates of M . tuberculosis that showed resistance to rifampicin were found to be susceptible to 8514 . Thus, these two bipyridyl analogues show great promise in chemotherapy of tuberculosis and M . avium infection.

Indian J Med Res, 1995 Apr, 101, 147 - 9
Comparative in vitro activity of fluoroquinolones against Mycobacterium tuberculosis; Karak K et al.; Sixty clinical isolates of M . tuberculosis, 24 susceptible and 36 resistant to conventional primary antituberculous drugs, were tested against four fluoroquinolones (ciprofloxacin, ofloxacin, pefloxacin and norfloxacin) . Ofloxacin and ciprofloxacin were found to be the most active, with minimum inhibitory concentration (MIC) of 0.6 mg/l or less to all strains tested . Strains resistant to isoniazid and other antitubercular drugs also showed more or less equal MICs for these two drugs . Mycobacterium tuberculosis H37 Rv showed MIC < 0.6 mg/l on each occasion . Other agents viz., norfloxacin and pefloxacin showed lesser activity against all these strains tested in comparison to ciprofloxacin and ofloxacin.

Int J Parasitol, 1995 Apr, 25(4), 531 - 2
Increased antimalarial activity of azithromycin during prolonged exposure of Plasmodium falciparum in vitro; Yeo AE et al.; The minimum inhibitory concentration, MIC, of azithromycin was determined for 2 isolates of Plasmodium falciparum at 48 and 96 h . The MIC at 48 h for the K1 and FC isolates were 6.2 and 8.7 micrograms/ml, respectively . At 96 h, the MIC decreased to 0.08 microgram/ml for the K1 isolate and 0.04 microgram/ml for the FC isolate . The marked reduction in the MIC values between the first and second asexual erythrocytic cycles suggests that the drug acts slowly and that it may have to be used in combination with a faster acting drug.

J Antimicrob Chemother, 1995 Apr, 35(4), 545 - 9
The susceptibility of Helicobacter pylori to the rifamycin, rifaximin; Holton J et al.; Forty strains of Helicobacter pylori had an MIC(50) of 4 mg/L of the non-absorbably antibiotic, rifaximin . Neither synergy nor antagonism was demonstrated when the drug was combined with ampicillin, metronidazole and omeprazole and the rate of spontaneous mutation was less than 1 in 10(8) . With these in-vitro characteristics, rifaximin should now be assessed for clinical efficacy.

J Antimicrob Chemother, 1995 Apr, 35(4), 463 - 71
The in-vitro activities of novel benzoxazinorifamycins against Mycobacterium leprae; Dhople AM et al.; The activities of four newly synthesized benzoxazinorifamycin derivatives, either alone or in combination with ofloxacin, against strains of Mycobacterium leprae were determined by assessing their effects on two biochemical parameters of metabolic activity which served as surrogate markers for growth in vitro . KRM-1648 and KRM-2312 were the most active agents tested against both a rifampicin-susceptible isolate (MICs of 0.05 and 0.1 mg/L respectively) and a rifampicin-resistant isolate (MICs of 0.2 and 0.3 mg/L respectively); both compounds were more active than either rifampicin or rifabutin . The activities of the two other derivatives, KRM-1657 and KRM-1668, against a rifampicin- susceptible strain (MICs of 0.3 mg/L) were similar to that of rifampicin, while the MIC of each of these agents for the rifampicin-resistant strain was 1.0mg/L . In common with rifabutin, both of the more active derivatives demonstrated synergy with ofloxacin against the rifampicin-susceptible isolates . The results of this study suggest that these compounds, in combination with ofloxacin as part of multidrug regimens, warrant further evaluation as treatment for patients with leprosy.

Proc Natl Sci Counc Repub China B, 1995 Apr, 19(2), 80 - 4
The in vitro activity of beta-lactamase inhibitors in combination with cephalosporins against M . tuberculosis; Chen CH et al.; Although there are reports that the addition of a beta-lactamase inhibitor to ampicillin or amoxicillin greatly improves their in vitro activity against M . tuberculosis, there are no written reports about the antituberculosis effects of beta-lactamase inhibitors in combination with cephalosporins against M . tuberculosis . In this report, we have determined the minimal inhibitory concentrations (MIC) of 5 cephalosporins with or without combination with beta-lactamase inhibitor against M . tuberculosis strains isolated from patients before antituberculosis treatment and checked the production of beta-lactamase by bacteria before this procedure . Four strains of M . tuberculosis were contaminated during the experiment, and all the other 16 strains hydrolyzed the nitrocefin disc, thus indicating a beta-lactamase producer . The MICs of cephalosporins alone against M . tuberculosis were 200-400 micrograms/ml for ceforanide, 100-400 micrograms/ml for cephapirin, 400-1600 micrograms/ml for cefamandole, 200-1600 micrograms/ml for cefotaxime, and 800-1600 micrograms/ml for ceftriaxone . After adding the equimolar concentrations of sulbactam, the MICs were reduced to 100-200 micrograms/ml for ceforanide, 12.5-100 micrograms/ml for cephapirin, 100-400 micrograms/ml for cefamandole, 25-200 micrograms/ml for cefotaxime, and 100-800 micrograms/ml for ceftriaxone . We concluded that sulbactam enhanced the antituberculosis effect of cephalosporins.

Ann Oncol, 1995 Apr, 6(4), 347 - 53
Chemotherapy of advanced non-small-cell lung cancer: a comparison of three active regimens . A randomized trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.); Crino L et al.; BACKGROUND: Cisplatin-based chemotherapy is generally considered the most active treatment for advanced non-small-cell lung cancer . The combination of cisplatin and etoposide had for some time been the standard treatment at our center . Of the other active regimens, cisplatin in combination with mitomycin-C, vindesine or ifosfamide (MVP or MIC) showed the highest response rates . We decided to perform a comparative trial of the three 'best' regimens in order to define a possible standard regimen in advanced NSCLC . MATERIALS AND METHODS: From May 1989 to April 1992, 393 consecutive, previously untreated NSCLC patients, stages IIIB and IV, were randomized to receive either cisplatin (120 mg/sqm day 1) + etoposide (100 mg/sqm days 1-3) every 3 weeks (PE) or cisplatin (120 mg/sqm every 4 weeks) + mitomycin-C (8 mg/sqm days 1-29-71) + vindesine (3 mg/sqm days 1-8-15-22) (MVP) or cisplatin (120 mg/sqm day 1) + mitomycin-C (6 mg/sqm day 1) + ifosfamide (3 mg/sqm day 2) every 3 weeks (MIC) . Of these, 382 were evaluable for survival and 360 for response . RESULTS: Response rates were statistically higher for both MIC (40%) and MVP (36%) than for the PE arm (23%) . Survival estimates analyzed by the log-rank test showed a significant benefit (p < 0.04) for patients treated with three-drug regimens (MVP; MIC) as compared to those in the PE arm . The main toxicity was myelosuppression; thrombocytopenia WHO grade 3-4 was worse in the MIC arm; nephrotoxicity grade 3-4 was also more frequent in the MIC arm . CONCLUSIONS: A three-drug cisplatin-based regimen (MVP; MIC) should be considered as reference treatment in NSCLC.

Aliment Pharmacol Ther, 1995 Apr, 9(2), 191 - 6
Maintenance of gastric pH above 6 with intravenous famotidine in patients with a bleeding duodenal ulcer; Delchier JC et al.; BACKGROUND: The secondary prevention of bleeding from ulcers may be improved if antisecretory drugs are able to maintain a 24-h gastric pH close to neutral . AIM: To evaluate the effect of intravenous famotidine at a conventional dose of 40 mg/day on 24-h intragastric pH in patients with a bleeding duodenal ulcer, and to determine the dose required to maintain gastric pH > 6 by use of a Gastrojet (MIC, Switzerland) device (a pH meter-controlled programmable pump) . METHODS: Twelve patients (nine men, three women), aged 24-78 years, admitted for a bleeding duodenal ulcer, were studied after active bleeding had stopped for at least 6 h . Gastric pH was recorded for two consecutive 24-h periods, each starting at 16.00 hours . The patients were fasted during these periods and received an infusion of 2.5 L of isotonic glucose . They were given famotidine, as a continuous i.v . infusion of 40 mg during one period, and at a rate determined by the Gastrojet during the other period (in a random sequence), with the aim of maintaining the gastric pH above 6 . RESULTS: The 24-h median (interquartile range) pH and the mean (+/- S.E.M.) percentage of the 24-h period with a gastric pH > 6 were both significantly higher during the Gastrojet period than during the continuous infusion: 6.4 (6.3-6.5) vs . 5.7 (2.7-6.4) (P < 0.01) and 74 +/- 5% vs . 44 +/- 7% (P < 0.002), respectively . The mean dose of famotidine delivered by the Gastrojet was 172 mg (range: 101-200 mg) . The entire available amount of famotidine (200 mg) was delivered in four of the 12 patients . The percentage of time at pH > 6 (mean +/- S.E.M.) was significantly higher at night (22.00 to 07.00 hours) than during the rest of the day (88 +/- 2 vs . 70 +/- 6%; P < 0.005) and the mean quantity of famotidine delivered per hour was significantly lower during the night (6.3 +/- 0.8 mg/h vs . 8.4 +/- 0.5 mg/h; P < 0.02) . CONCLUSION: We conclude that 40 mg of famotidine delivered as a continuous i.v . infusion is not sufficient to maintain gastric pH > 6 for 24 h in duodenal ulcer patients . Our study with the Gastrojet device shows that it may be possible to achieve this goal by using a much larger dose, preferably delivered during the day.

Pathol Biol (Paris), 1995 Apr, 43(4), 300 - 5
FT-IR spectroscopy study of perturbations induced by antibiotic on bacteria (Escherichia coli); Zeroual W et al.; Fourier transform infrared spectroscopy (FT-IR) is an analysis method which over the spectral absorption, gives information about the molecular structures of systems . Recently, this method is widely used to the investigation of complex systems like cells and bacteria . Characteristic of FT-IR spectrum of bacteria depend closely to physiological and culture parameters . In this study, the infrared bands of intact bacteria are first tentatively attributed to the contribution of the cellular components . Secondly are compared the FT-IR spectra of Escherichia coli bacteria before and after treatment at sub-inhibitrice concentrations (< or = MIC) at penicillin A, penicillin G and nalidixic acid . The observed spectral perturbations are closely depending on the antibiotic treatment and are observed even if bacterial cell mass is far away from cell death . On the other hand, this spectral changes are related to the known mode of action of the used antibiotic.

Lung Cancer, 1995 Apr, 12 Suppl 1, S95 - 106
Trials with mitomycin, ifosfamide and cisplatin in non-small cell lung cancer; Cullen MH; In 1988, we reported a Phase II study of mitomycin, ifosfamide and cisplatin (MIC) in inoperable non-small cell lung cancer . The overall objective response rate was 56% in 66 evaluable cases . An improvement in performance status was observed in responding patients and toxicity was acceptable . Consequently we then embarked upon two major, multicentre randomised trials to test this regimen in cases with localised disease (MIC 1--chemotherapy plus radical radiotherapy versus radical radiotherapy alone) and advanced disease (MIC 2--chemotherapy plus palliative care versus palliative care alone) . These trials are still in progress with targets of 500 and 300 randomised cases, respectively . The present interim analysis is based on 317 cases randomised in MIC 1 and 193 in MIC 2 . The overall response rate (CR + PR) in the MIC 1 trial is 52% with 10% CRs and in the MIC 2 trial is 42% with 5% CRs . Formal symptomatic assessments are monitored in both trials and the present interim analysis indicates symptom improvement in cases randomised to chemotherapy, including patients who fail to achieve an objective PR or CR . Other Phase II studies employing MIC are also reviewed.

Lung Cancer, 1995 Apr, 12 Suppl 1, S125 - 32
Superiority of three-drug combination chemotherapy versus cisplatin-etoposide in advanced non-small cell lung cancer: a randomized trial by the Italian Oncology Group for Clinical Research; Crino L et al.; To evaluate the efficacy of a three-drug regimen vs . a two-drug CDDP based combination in the treatment of NSCLC, we conducted a three-arm randomized parallel trial comparing (a) CDDP (120 mg/m2 day 1) + etoposide (100 mg/m2 days 1-3) every 3 weeks (PE--arm A); (b) CDDP (120 mg/m2 every 4 weeks) + mitomycin (8 mg/m2 days 1, 29, 71) + vindesine (3 mg/m2 days 1, 8, 15, 22 every 2 weeks) (MVP--arm B); and (c) CDDP (120 mg/m2 day 1) + mitomycin (6 mg/m2 day 1) + ifosfamide (3 g/m2 day 2) every 3 weeks (MIC--arm C) . From May 1989 to April 1992, 393 consecutive previously untreated patients with NSCLC Stage IIIB and IV entered the trial; 373 were evaluable for survival and 360 for response . The response rate was significantly better for both the three-drug regimens compared with PE (Table 3) . Logistic regression model showed a significantly better response in patients with a good P.S . and in Stage IIIB . Main toxicity consisted of myelosuppression: neutropenia Grade III-IV was recorded in 14% (arm A), 15% (arm B) and 21% (arm C) . Thrombocytopenia Grade III-IV was worst in arm C: 10% vs . 5% (arm A) and 3% (arm B) . Nephrotoxicity Grade III-IV was more common in arm C: 3.5% . Toxic deaths were 11 (3%: three in arm A, five in arm B, three in arm C) . From our data, the three-drug containing regimens, MVP and MIC, appear more active than the two-drug combination PE in treatment of advanced NSCLC.

Antimicrob Agents Chemother, 1995 Mar, 39(3), 650 - 5
Experience with a once-daily aminoglycoside program administered to 2,184 adult patients; Nicolau DP et al.; Once-daily aminoglycoside (ODA) regimens have been instituted to maximize bacterial killing by optimizing the peak concentration/MIC ratio and to reduce the potential for toxicity . We initiated an ODA program at our institution that utilizes a fixed 7-mg/kg intravenous dose with a drug administration interval based on estimated creatinine clearance: > or = 60 ml/min every 24 h (q24h), 59 to 40 ml/min q36h, and 39 to 20 ml/min q48h . Subsequent interval adjustments are made by using a single concentration in serum and a nomogram designed for monitoring of ODA therapy . Since initiation of the program, 2,184 patients have received this ODA regimen . The median dose was 450 (range, 200 to 925) mg, while the median length of therapy was 3 (range, 1 to 26) days . The median age of the population was 46 (range, 13 to 97) years . Gentamicin accounted for 94% of the aminoglycoside use, and the majority (77%) of patients received the drug q24h . The 36-, 48-, and > 48-h intervals were used for 15, 6, and 2% of this population, respectively . Three patients exhibited clinically apparent ototoxicity . Twenty-seven patients (1.2%) developed nephrotoxicity (the Hartford Hospital historical rate is approximately 3 to 5%) after a median of 7 (range, 3 to 19) days of therapy . On the basis of a prospective evaluation of 58 patients and follow-up of additional patients via clinician reports, we have noted no apparent alterations in clinical response with our ODA program . This ODA program appears to be clinically effective, reduces the incidence of nephrotoxicity, and provides a cost-effective method for administration of aminoglycosides by reducing ancillary service time and serum aminoglycoside determinations.

J Vasc Interv Radiol, 1995 Mar-Apr, 6(2), 179 - 83
Gastrostomy button placement through percutaneous gastrostomy tracts created with fluoroscopic guidance: experience in 27 children; Borge MA et al.; PURPOSE: The authors report their experience with skin level (button) gastrostomy placement through radiologically created gastrostomy tracts . PATIENTS AND METHODS: Fifty-two gastrostomy buttons have been placed in 27 children (average age, 73 months; range, 9-235 months) . All buttons were placed through tracts created during earlier fluoroscopically guided percutaneous gastrostomy . Fifteen Bard mushroom-type buttons and 12 MIC-Key balloon-type buttons were initially placed . Patients have been followed up for an average of 13.4 months . RESULTS: Button placement was successful at the initial attempt in 25 of 27 patients (93%) . Tract age at button placement averaged 18.5 weeks . The average tract length measured 3.5 cm (1.7-6.0 cm) . Tract rupture and peritoneal leakage occurred in three patients; one patient had the button immediately repositioned without sequela, and the remaining two patients underwent replacement of the gastrostomy tube into the stomach and successful button placement approximately 1 week later . There were no major complications . Minor problems (leak, granulation tissue, valve malfunction, balloon breakage) occurred in 19 patients . CONCLUSION: Button gastrostomy is a useful alternative to the traditional gastrostomy tube for the pediatric population . Conversion with use of existing radiologically created tracts is possible and safe . Attention to tract integrity and proper button position is required to avoid complications.

J Antimicrob Chemother, 1995 Mar, 35(3), 381 - 90
Enhancement of drug susceptibility of multi-drug resistant strains of Mycobacterium tuberculosis by ethambutol and dimethyl sulphoxide; Jagannath C et al.; Strategies to augment conventional methods of drug delivery in treatment of multiple drug resistant tuberculosis are needed to achieve optimum results with available drugs . We have studied the effect of sub-minimum inhibitory concentrations (sub-MIC) of ethambutol and dimethyl sulphoxide on drug susceptibility of Mycobacterium tuberculosis strains both in vitro and in macrophages . At sub-MIC ethambutol between caused four and 64 fold increase in susceptibility to isoniazid rifampicin and streptomycin in four M . tuberculosis strains, resistant to these drugs . Incubation of the organisms with isoniazid and sub-MIC of dimethyl sulphoxide (2.5%) resulted in an eight-fold increase in susceptibility to the drug . Previous exposure of the organisms to sub-MIC of dimethyl sulphoxide also caused similar enhancement of susceptibility . Both ethambutol and dimethyl sulphoxide at the sub-MIC of sulphoxide also caused similar enhancement of susceptibility . Both ethambutol and dimethyl sulphoxide at the sub-MIC enhanced the activity of the anti-tuberculosis drugs against multiple drug resistant M . tuberculosis strains growing inside macrophages . Our data indicate that the agents which modify cell wall permeability can enhance the susceptibility of multiple drug resistant strains to drugs to which they were originally resistant . This could provide a new approach to treating drug resistant tuberculosis.

Chemotherapy, 1995 Mar-Apr, 41(2), 149 - 52
Efficacy of roxithromycin in the treatment of mycoplasma pneumonia; Kaku M et al.; Macrolide and tetracycline antibiotics, which are protein synthesis inhibitors, are effective in the treatment of mycoplasma pneumonia . We evaluated the clinical efficacy and safety of roxithromycin, a new macrolide antibiotic, in the treatment of mycoplasma pneumonia . Roxithromycin was administered orally to patients who had been definitely diagnosed through Mycoplasma pneumoniae isolation or serum antibody titer as having mycoplasma pneumonia . The efficacy assessment was based on clinical signs and symptoms of infection as well as bacterial culture from clinical samples . Clinical efficacy was excellent in 6 cases, good in 6 cases and fair in 1 case, with an efficacy rate of 92.3% . The bacteriological effect was evaluated in 6 patients: the organism was eradicated in 4 cases and unchanged in 2 cases . In this study, the MIC of roxithromycin against M . pneumoniae fell in the range 0.0156-0.00625 mg/l . No adverse reaction was observed . As for abnormal laboratory findings, two cases showed elevated serum glutamic-pyruvic transaminase (S-GPT), one elevated serum glutamic-oxaloacetic transaminase and S-GPT, and one reduced neutrophil counts . From our results, we consider that roxithromycin is useful in the treatment of mycoplasma pneumonia.

Nihon Kyobu Shikkan Gakkai Zasshi, 1995 Mar, 33(3), 342 - 7
{A case of chronic necrotizing pulmonary aspergillosis in which intravenous infusion of amphotericin B was effective}; Tabeta H et al.; A 49-year-old man with a history of left upper lung lobectomy for pulmonary asperigilloma developed a productive cough in the middle of April 1992, and his chest X-ray film showed infiltration of the left S6 . Treatment with several different antibiotics was tried, but the shadow expanded and developed a cavity over the following 8 months . A clinical diagnosis of chronic necrotizing pulmonary aspergillosis was made, based on repeated detection of Aspergillus fumigatus in the patient's sputum and in specimens obtained by fiberoptic branchoscopy and percuraneous needle biopsy . Prior lobectomy and a marked idiopathic decrease in ventilation and perfusion in the affected lung are risk factors for this disease . Slow intravenous infusion of amphotericin B eradicated the fungus without any side effects . Measurement of drug concentrations during treatment revealed that the concentration in the sputum was far higher than that in the serum, and was also far higher than the minimum inhibitory concentration for the fungus.

Trop Med Parasitol, 1995 Mar, 46(1), 49 - 53
Activity and structure relationship of acridine derivatives against African trypanosomes; Obexer W et al.; 48 newly synthesized acridine derivatives of different classes were screened for antitrypanosomal activity . They showed a dose dependent effect on Trypanosoma rhodesiense and T . brucei bloodstream forms measured by the inhibition of esterase activity in a fluorescence based in vitro assay . After analysis of the IC50 and MIC values of the investigated acridines it was obvious that no new compound reached the level of the trypanocidal drugs in use (50 ng/ml) . Most of the derivatives had IC50 values in the range of 1 to 10 micrograms/ml . 9 derivatives from different classes of acridines were in vitro active below 1 microgram/ml . Correlations between structure and effect on trypanosomes have been elucidated by comparing the IC50 and MIC values of these compounds, in the course of which no significant differences in the drug susceptibility between T . brucei und T . rhodesiense was noticed . The dialkylaminoalkyl derivatives among the group of the 9-thioacridines were slightly more potent than the mono-alkylated ones . 1,2,3,4-tetrahydro-9-thioacridines showed the influence of higher substituted side chains on the trypanocidal activity in the same way as 9-thioacridines . The corresponding ketones of 9-thioacridines confirmed the tendency of increasing toxicity due to the derivatisation of the dialkylaminoalkyl side chain . Within the series of the 9-aminoacridines the elongation of the side chain did not markedly change the activity, however the IC50 values are generally low between 0.13 and 1.2 micrograms/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Trop Med Parasitol, 1995 Mar, 46(1), 45 - 8
A novel in vitro screening assay for trypanocidal activity using the fluorescent dye BCECF-AM; Obexer W et al.; A cell viability assay, using fluorescence measurements has been developed for the screening of new compounds against African trypanosomes . 2',7'-Bis-(carboxyethyl)-5(6)-carboxyfluorescein-pentaacetoxymethyles ter (BCECF-AM), an esterase substrate, was used in the assay as a marker for cell viability . Fluorescence was quantified using an automated fluorescence scanner for multi-well plates . Trypanosoma brucei rhodesiense, T . congolense, T . evansi and T . equiperdum from continuously growing cultures were exposed to various concentrations of trypanocidal drugs for an incubation period of 72 h at 37 degrees C . Then BCECF-AM was added to the cell suspensions and after 60 minutes the fluorescence of the trypanosome suspension was measured using the Millipore Cytofluor 2300 fluorescence scanner, at 485 nm excitation and 530 nm emission wavelengths . Results of kinetic studies of the hydrolysis of the non-fluorescent BCECF-AM in trypanosomes showed that BCECF-AM is readily cleaved by non-specific esterases to a highly fluorescent product . Drug concentrations causing 50% inhibition of fluorescence (IC50-values) were measured fluorimetrically . Minimum inhibitory concentration (MIC) was determined microscopically.

Int Clin Psychopharmacol, 1995 Mar, 10(1), 39 - 43
Structure-antitubercular activity relationship of phenothiazine-type calmodulin antagonists; Ratnakar P et al.; Six neuroleptic (antipsychotic) phenothiazine derivatives which are calmodulin antagonists were tested for their activity against Mycobacterium tuberculosis H37Rv in order to understand their structure-antitubercular activity relationship . Out of the six derivatives tested (trifluoperazine, chlorpromazine, triflupromazine, thioridazine, acetopromazine and fluphenazine), trifluoperazine appears to be a more potent antitubercular drug than others with a minimum inhibitory concentration (MIC) of 5 micrograms/ml . Chlorpromazine, triflupromazine and thioridazine are also active but less potent and have a higher MIC of 20 micrograms/ml . Acetopromazine and fluphenazine could not completely inhibit the growth even at a high concentration of 20 micrograms/ml . These results indicate that a methylpiperazinylpropyl group attached to the nitrogen (position 10) atom and trifluoromethyl group at the second carbon confer antitubercular activity to the phenothiazine molecule . It is suggested that trifluoperazine or one of its derivatives could be useful as one of the drugs in the multi-drug regimen for the treatment of tuberculosis with psychotic problems or vice versa.

Eur J Clin Microbiol Infect Dis, 1995 Mar, 14(3), 193 - 8
Study of Stomatococcus mucilaginosus isolated in a hospital ward using phenotypic characterization; van Tiel FH et al.; Thirty-one isolates of Stomatococcus mucilaginosus were cultured from the blood (n = 6), throat (n = 23) and sputum (n = 2) of 18 hospitalized patients, 13 of whom were neutropaneic and five of whom were non-neutropaneic . Antibiotic susceptibility testing, performed by means of a broth microdilution method, showed that the minimal inhibitory concentrations (MICs) of ciprofloxacin were > or = 4 mg/l for the isolates collected from neutropaenic patients . All these patients received ciprofloxacin as part of their prophylactic regimen . In contrast, the MICs for four of five isolates collected from non-neutropaenic patients, none of whom were receiving ciprofloxacin, were < or = 2 mg/l . In addition, 14 of the 31 isolates were cultured from seven neutropaenic patients, admitted to the same ward over a 12-week period . To evaluate possible cross-acquisition of strains between patients, cluster analysis of all 31 isolates was performed using phenotypic characteristics, MIC values and acid production from carbohydrates (API 50 CH) . Overall, 22 isolate clusters were distinguished . In five of 18 patients, two or more isolates were cultured which belonged to different clusters . In only one patient, identical isolates were cultured from blood and from the throat . All six isolates of cluster 7 were cultured within the aforementioned 12-week period from three neutropaenic patients . These data support the possibility of cross-acquisition of strains between patients although its frequency seems to be low.

Biochim Biophys Acta, 1995 Feb 22, 1247(1), 121 - 5
beta-Lactamase mutations far from the active site influence inhibitor binding; Bonomo RA et al.; Analysis of the three dimensional structure of the class A beta-lactamases shows that Arg-244, a spatially conserved residue important for inactivation by clavulanic acid, is held in place by a hydrogen (H) bond from the residue at 276 . An Asn276-Gly mutant of OHIO-1, an SHV family class A enzyme, was constructed to investigate the importance of that interaction . Compared to a strain expressing the wild type enzyme, OHIO-1, the MIC of the Asn276-Gly mutant strain was more resistant to clavulanate (0.25 vs . 2.0 micrograms/ml) in the presence of ampicillin (16 micrograms/ml) but was as susceptible to sulbactam or tazobactam plus ampicillin as the OHIO-1 bearing strain . No difference in MICs was observed when other beta-lactams were tested . Consistent with the susceptibility test results, the apparent Ki of clavulanate for the Asn276-Gly enzyme (4.5 microM) was 10-fold greater than OHIO-1 (0.4 microM) . For sulbactam and tazobactam the apparent Ki decreased for Asn276-Gly enzyme (1.0 and 0.1 micrograms/ml, respectively) compared to the wild-type parent (17 and 0.7 micrograms/ml, respectively) . Comparing the Asn276-Gly heta-lactamase with OHIO-1, the Vmax for most substrates except cephaloridine did not change substantially . There was a 2-15 fold decreased affinity (Km) and catalytic efficiency (Vmax/Km) for beta-lactam substrates . These data support the observation and emphasize the role for this H bonding residue in orienting Arg-244 towards the active site.

Nucleic Acids Res, 1995 Feb 11, 23(3), 464 - 6
A new mutation in 16S rRNA of Escherichia coli conferring spectinomycin resistance; Johanson U et al.; We report a novel mutation, C1066U in 16S rRNA which was selected for resistance to spectinomycin, an antibiotic which inhibits ribosomal translocation . The minimal inhibitory concentration (MIC) of spectinomycin determined for this mutant (15 micrograms/ml) is greater than with the wild-type plasmid (5 micrograms/ml) but lower than with the well known C1192U mutation (> 80 micrograms/ml) . The C1066U mutation also increases the cells sensitivity to fusidic acid, another antibiotic which inhibits translation at the translocation stage, whereas C1192U is unchanged relative to the wild type . We discuss why the acquisition of resistance to one of these drugs is often associated with hypersensitivity to the other.

Pharmacoeconomics, 1995 Mar, 7(3), 251 - 67
Pharmacoeconomic analysis of topical treatments for tinea infections; Shear NH et al.; The purpose of this study was to perform a government-perspective economic analysis of the most widely used topical creams {namely, ciclopirox (CIC), clotrimazole (CLO), ketoconazole (KET), miconazole (MIC), and terbinafine (TER)}, for the treatment of 2 types of dermatophyte skin infections: dermatophytosis major (excluding onychomycosis) and dermatophytosis minor . A 3-phase approach was used . In phase I, experts were assembled to identify the standard approach for management of fungal infections and a decision tree was constructed to model the process; in phase II, meta-analysis was used to determine success, failure, and relapse rates; and in phase III, economic analyses were performed including cost of regimen, total expected cost and cost-effectiveness analysis . Sensitivity analyses (robustness analyses) were also performed in phase III . It was found that while TER was successful following 1 week of administration for minor infections and after 2 weeks for major infections, duration of drug treatment was usually twice that time . Other comparators (CIC, CLO, KET and MIC) took 4 weeks to achieve a successful outcome . In addition, an extra 2 weeks were often needed to clear both types of infections because the comparators are fungistatic, whereas TER is fungicidal . In the total expected cost analysis, TER had the lowest overall cost of treating patients for both infection categories . It was also responsible for the highest number of disease-free days and, consequently, the lowest cost per disease-free day . Sensitivity analyses confirmed that TER was the most cost-effective topical agent for treating dermatophytosis major (excluding onychomycosis) and dermatophytosis minor.

Hindustan Antibiot Bull, 1995 Feb-Nov, 37(1-4), 48 - 50
Laboratory evaluation of sensitivity of three keratinophilic fungi to some vicolides; Rai MK et al.; Four vicolides (sesquiterpenoides) isolated from Vicoa indica were evaluated against three keratinophilic fungi, viz., Microsporum gypseum, Chrysosporium tropicum, and Trichophyton terrestris . All the test fungi were found to be sensitive to vicolides . Vicolides A and C showed the maximum efficacy while B and D exhibited moderate activity . The Minimum Inhibitory Concentration (MIC) was observed in the range of 15.62-125 micrograms . The most sensitive fungus tested was C . tropicum followed by T . terrestris and M . gypseum.

Nippon Hinyokika Gakkai Zasshi, 1995 Feb, 86(2), 325 - 32
{Comparative study on minimum inhibitory concentration of gonococcal strains according to their auxogroups and serovars}; Takai K et al.; Auxotypes, serovars and minimum inhibitory concentration (MIC) of various antibiotics are investigated on 85 gonococcal strains isolated from the patient with gonorrhea from 1984 to 1986 in Japanese Red Cross Medical Center . As to the auxotypes 33 strains were identified to be Proto, 33 to be Pro, 10 to be Arg and 9 to be PAU . No AHU strain was identified . Serovars were divided into 1A and 1B . MIC of 22 kinds of antibiotics including penicillins, cephems, spectinomycin, tetracycline and new quinolones were determined . Cumulative MIC curves were found to be shifted to the right according to the order of auxotypes Arg, PAU, Proto, Pro in the most antibiotics . Serovar 1A was found to have lower MIC as compared to 1B, though only 5 strain of 1A were in the study . Seventy-eight % of isolates were Proto or Pro, so-called Asian auxotype which were revealed to have higher MIC not only of penicillin but also of the other antibiotics . Nine strains were identified as PAU which was lately identified in Canada . This might suggest that gonococcal strains are spreading over the world in spite of the local predominance of auxotype distribution.

Acta Orthop Scand, 1995 Feb, 66(1), 14 - 6
Intravenous cefuroxime prophylaxis . Tissue levels after one 3-gram dose in 40 cases of hip fracture; Kaukonen JP et al.; This study consists of 2 series of patients with cervical hip fracture treated with hemiarthroplasty . In a preliminary study, the method, timing of sample collection, and tissue and serum concentrations were studied in 15 patients . In the main study of another 25 patients, only tissue samples were collected . In the preliminary study, 3 g of cefuroxime was infused in 15-25 min and serum, muscle, fascia and bone samples were collected at various times . In the main study, 1 dose of 3 g of cefuroxime was infused in 15 min . Skin, muscle, fascia, and bone tissue samples were collected after 30 and 45 min and the concentrations of cefuroxime were measured by high-performance liquid chromatography . In the preliminary study, serum cefuroxime levels were 61 micrograms/mL and 42 micrograms/mL at 15-30 and 35-50 min, respectively . Cefuroxime levels in various tissues were only slightly less than those in serum . Blood contamination contributed less than 30 percent to the tissue levels of cefuroxime . In the main study, mean cefuroxime levels in the tissues were in the range of 39-58 micrograms/g, and the total range was 5.5-151 micrograms/g at 30 and 45 min . These concentrations are well above the MIC values of the most common bacteria causing wound and bone infections.

Intern Med, 1995 Feb, 34(2), 85 - 8
Percutaneous intracavitary antifungals for a patient with pulmonary aspergilloma; with a special reference to in vivo efficacies and in vitro susceptibility results; Itoh T et al.; A 61-year-old man with pulmonary aspergilloma received two antifungals intracavitarily . Although clinical, serological and roentgenographic improvement were observed with fluconazole therapy, bronchial secretions continuously yielded Aspergillus fumigatus . When fluconazole was switched to amphotericin B, the pathogen was eradicated immediately . The minimal inhibitory concentrations (MICs) of the isolate were 400 micrograms/ml for fluconazole, and 0.2 microgram/ml for amphotericin B . Although the discrepancy between in vitro and in vivo efficacy of antifungals has been argued, it was suggested the drug of choice should be selected on the basis of the MIC results at least in the intracavitary antifungal therapy for pulmonary aspergilloma.

Antimicrob Agents Chemother, 1995 Feb, 39(2), 435 - 9
Enhancement of antibiotic susceptibility and suppression of Mycobacterium avium complex growth by poloxamer 331; Hunter RL et al.; The resistance of Mycobacterium avium complex (MAC) to antibiotics is thought to be enhanced by its outer glycolipid layer, which protects the organisms from antibiotics and host defense mechanisms . We hypothesized that surfactants which disrupt the lipid barrier might be of therapeutic value . We evaluated the ability of 10 poloxamer surfactants to inhibit the growth of MAC organisms and to potentiate antimycobacterial drug activity in broth culture using a radiometric assay . Very large, small, or hydrophilic poloxamers had little or no effect . However, certain hydrophobic poloxamers, especially P331, retarded the growth of most isolates of MAC and produced a synergistic effect with rifampin . The MIC of rifampin required to inhibit the growth of MAC was reduced from a mean of 14.6 micrograms/ml (range, 4 to > 32 micrograms/ml) to 1.4 micrograms/ml (range, < 1.125 to 4 micrograms/ml) by 1.0 mg of P331 per ml (P < 0.01) . Enhancement of antibiotic susceptibility was observed with concentrations of poloxamer as low as 10 micrograms/ml . These studies suggest that P331 might be useful in increasing the effectiveness of antibiotic therapy of MAC infections.

Antimicrob Agents Chemother, 1995 Feb, 39(2), 431 - 4
Amoxicillin pharmacokinetics in preterm infants with gestational ages of less than 32 weeks; Huisman-de Boer JJ et al.; The multiple-dose pharmacokinetics of amoxicillin (AM {administered twice daily in a 25-mg/kg of body weight intravenous dose}) in 17 preterm infants (11 males; gestational age, 29 +/- 1.9 weeks; birth weight, 1,175 +/- 278 g) were evaluated on day 3 of life . Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after the intravenous dose . A high-performance liquid chromatography method was used to determine AM concentrations in serum . AM pharmacokinetics followed a one-compartment open model . The glomerular filtration rates of all patients were simultaneously studied by means of the 24-h continuous inulin infusion technique . The elimination half-life, apparent volume of distribution, and total body clearance of AM (mean +/- standard deviation) were 6.7 +/- 1.7 h, 584 +/- 173 ml, and 62.4 +/- 23.3 ml/h, respectively . The mean (+/- standard deviation) AM peak and trough levels were 53.6 +/- 9.1 and 16.0 +/- 4.9 mg/liter, respectively . All infants had a serum trough level above 5 mg/liter . The total body clearance and apparent volume of distribution of AM and the clearance of inulin increased significantly with increasing gestational age . The total body clearance of AM (1.0 +/- 0.4 ml/min) and the clearance of inulin (1.0 +/- 0.3 ml/min) were similar . The total body clearance of AM increased significantly with increasing clearance of inulin . We conclude that an AM dose of 25 mg/kg every 12 h given to preterm infants in the first week of life with gestational ages of less than 32 weeks results in serum levels well above the MIC for major microorganisms involved in neonatal infections.

J Craniomaxillofac Surg, 1995 Feb, 23(1), 38 - 41
Perioperative antibiotic prophylaxis with cefuroxime in oral-maxillofacial surgical procedures; Alfter G et al.; A study was carried out to investigate the suitability of cefuroxime for perioperative antibiotic prophylaxis in maxillofacial surgical procedures . Serum and tissue samples were taken, to determine the intraoperative cefuroxime concentration, from 40 patients who had been given 1.5 g cefuroxime (Zinacef) i.v . during maxillofacial surgery . The time between i.v . administration and taking the blood and tissue samples varied between 10 and 260 min . The serum tissue kinetics were determined using an HPLC method in the jaw area, particular emphasis being given to the concentrations measured in bone . It was demonstrated that concentrations of cefuroxime were reached which are above the MIC values for many of the pathogens in the maxillofacial area and therefore adequate protection during intraoperative bacterial contamination is guaranteed . Maximum serum levels averaging 80 mg/l were measured within 30 min of administration . An average of 15 mg/l could still be demonstrated after 4 h . The bone samples gave maximum levels of 8-9 mg/kg 90 min after administration . Average levels of 1-3 mg/kg were still measurable after 4 h . It is only possible to describe trends due to the wide variation in the values, particularly of the bone samples . No postoperative wound infection was seen under prophylaxis with cefuroxime . Cefuroxime is suitable for perioperative prophylaxis during maxillofacial surgery procedures because of its favourable kinetics and broad spectrum of action.

Biochim Biophys Acta, 1995 Jan 3, 1254(1), 98 - 104
Certain properties of isoniazid inhibition of mycolic acid synthesis in cell-free systems of M . aurum and M . avium; Quemard A et al.; In Mycobacterium tuberculosis isoniazid (INH)-susceptibility and the presence of a thermolabile catalase-peroxidase (T-catalase) are nearly always associated . It is shown in this study that an INH-susceptible strain of M . aurum had a T-catalase activity while its resistant mutants did not, but an in vitro susceptible strain of M . avium had a strong catalase activity without any detectable peroxidase properties . Synthesis of mycolic acids is a genus-specific target for INH and there is an excellent parallelism between INH-susceptibility of intact cells and that of a cell-free system synthesizing mycolic acids . We investigated whether the INH-inhibition of mycolic acid cell-free synthesis was dependent on a T-catalase activity in M . aurum and M . avium: no catalase activity was detectable in any of the cell-free systems tested, and addition of T-catalase from susceptible M . aurum strain to an INH-resistant system did not render it sensitive . So INH can inhibit mycolic acid synthesis independently of the presence of a T-catalase . An INH-susceptible cell-free system prepared from INH-treated (at the MIC) cells was progressively and irreversibly inhibited, while incubation of the same susceptible system in the presence of INH did not result in a significant irreversible inhibition . The possible participation of T-catalase in the irreversible effect of INH is discussed.

Cell Mol Biol Res, 1995, 41(6), 575 - 81
Cell wall synthesis specific cytocidal effect of Hansenula mrakii toxin-1 on Saccharomyces cerevisiae; Takasuka T et al.; HM-1 toxin produced by Hansenula mrakii kills sensitive Saccharomyces cerevisiae . We found that the budding cells and the cells that responded to mating factor were sensitive to HM-1 toxin . These findings indicate that the target sites of HM-1 toxin are developing buds and conjugating tubes . The in vitro activity of beta-1,3-glucan synthase solubilized and partially purified from S . cerevisiae membranes was inhibited by HM-1 toxin at a concentration (around 50 nM, 0.5 micrograms/ml) that coincided well with its minimum inhibitory concentration for the growth of yeast cells . These data indicate that the HM-1 toxin perturbs the synthesis of yeast cell walls by inhibiting the glucan synthesis occurring at a budding site or a conjugating tube, which results in cell lysis.

Med Tr Prom Ekol, 1995, (11), 32 - 4
{Setting standards for laser radiation}; Ushkova IN et al.; The article presents principles of a universal theory of hygienic regulation, proves a principle of regulation warranty . Maximal allowable level of laser irradiation (wavelength 0.63 and 10.6 mic) was subjected to feedback test, i.e . health state of the examinees was evaluated after the norm setting . The test proved that the Maximal Allowable Level for laser irradiation needs adjustment.

Braz Dent J, 1995, 6(2), 103 - 9
Hydroxylapatite and tricalcium phosphate implants in the dental alveolus of rats . A histometric study; Rosa AL et al.; The objective of the present study was to analyze histomorphometrically the biological behavior of microgranular hydroxylapatite (HA 40), and tricalcium phosphate (TCP) implanted in the dental alveolus of rats . All three materials retarded alveolar repair when compared to controls, since less bone was formed during all periods of study . Nevertheless, MIC and TCP showed higher compatibility than HA 40.

Braz Dent J, 1995, 6(1), 29 - 32
Susceptibility of Actinobacillus actinomycetemcomitans strains to norfloxacin; Avila-Campos MJ et al.; The minimal inhibitory concentration of norfloxacin to Actinobacillus actinomycetemcomitans strains isolated from patients with localized juvenile periodontitis was determined by using an agar dilution method . All the tested strains, including the three reference strains, were susceptible at concentrations lower than the breakpoint used, with 90% of the strains susceptible to 0.125 micrograms/ml.

Ann Oncol, 1995, 6 Suppl 3, S45 - 7
Chemotherapy in advanced non-small-cell lung cancer . The experience of Italian Cooperative Groups; Crino L; The clinical experience of Italian Cooperative Groups in the treatment of advanced non-small-cell lung cancer began in the early 1980's with several phase II trials on cisplatin-etoposide (PE) combination . PE was chosen and widely used also in neoadjuvant trials on the basis of several randomized studies showing a favourable safety-efficacy profile of this combination with respect to other chemotherapy regimens . Recently, in order to improve therapeutic results in NSCLC the Italian Oncology Group for Clinical Research compared PE versus mitomycin, ifosfamide and cisplatin (MIC) and mitomycin, vindesine and cisplatin, the three-drug regimens most widely used in clinical trials . This trial showed a significant difference in response rate and a survival benefit for MIC and MVP; therefore, we considered MIC or MVP as the reference treatment is advanced NSCLC.

Medinfo, 1995, 8 Pt 2, 1111 - 5
Adaptive control of therapeutic drug regimens relations between clinical situations: outcomes and simulations using nonlinear dynamic models; Maire PH et al.; With Bayesian modeling and adaptive control of drug dosage regimens, serum and peripheral drug concentrations can be predicted in clinical situations using linear pharmacokinetic compartmental models (PK) . Recently, several pathophysiologic and pharmacodynamic nonlinear models (PD) have been developed . The present report illustrates both their utility and limits for the computation of effects in clinical situations in the setting of actual routine and acute patient care . Patients who received therapy with aminoglycosides or/and vancomycin were selected . For each patient, after estimation of individual pharmacokinetic parameters, the computed outputs of the linear compartmental pharmacokinetic model were used as inputs for 2 different a priori nonlinear dynamic models: 1) the EFFECT modeling program, using a Hill model, and 2) the BACTCIDE program, which is a combination of a simple growth model for the organism and a Hill effect model considering both the microorganism, the antibiotic, and the patient's minimal inhibitory concentration (MIC) . The programs (1) and (2) can use as inputs the computed concentrations from any of three compartments: central, peripheral, or a spherical diffusion compartment to compute drug diffusion into endocardial vegetations or abscesses . The EFFECT program can be used alone for the evaluation of drug effects . The BACTCIDE program illustrates differences in activity between concentration-dependent and time-dependent antibiotics . Such nonlinear programs are very sensitive to the MIC values.

Scand J Infect Dis, 1995, 27(5), 469 - 74
In vivo and in vitro study of several pharmacodynamic effects of meropenem; Fuentes F et al.; Several pharmacodynamic parameters are being studied and applied to the design of dosage regimens . The thigh infection model in neutropenic mice has been used in this study to investigate the in vivo postantibiotic effect (PAE) of meropenem against S . aureus, E . coli and P . aeruginosa . The sub-minimum inhibitory concentration (sub-MIC) postantibiotic effect (PA SME) of 1/2, 1/4 and 1/8 x MIC was also determined in vitro on S . aureus and E . coli after pre-exposure of these microorganisms to 10 x MIC of meropenem . The in vitro PAE was also determined . In vivo killing curves using 2 different short dosage regimens were also studied to relate the lethal effect to the time that serum levels were above the MIC . No significant in vivo and in vitro PAEs were observed . The PA SMEs were higher for S . aureus than for E . coli . The 2 short dosage regimens, in vivo, were equally effective in killing S . aureus, but not E . coli . These results suggest that the pharmacodynamics of meropenem on Gram-negative strains may need further study to elucidate the mechanisms and characteristics of these parameters . On the other hand, we need to standardize a reliable in vitro method to monitor regrowth with a good correlation with the in vivo conditions.

Dermatology, 1995, 191(4), 311 - 4
The antifungal activity of a coal tar gel on Malassezia furfur in vitro; Nenoff P et al.; OBJECTIVE: Seborrhoeic dermatitis is associated with Malassezia furfur, but the exact role of this lipophilic yeast is still unclear . The in vitro antifungal activity of a coal tar gel, the base of the gel and coal tar (Stantar) itself has been evaluated against 54 different M . furfur strains, isolated from patients suffering from dandruff, seborrhoeic dermatitis and pityriasis versicolor . METHODS: Minimum inhibitory concentrations (MICs) of the tested agents were measured by the agar dilution technique . RESULTS: The coal tar gel was found to be able to inhibit growth of 52 out of 54 investigated M . furfur isolates in vitro at MIC values between 625 and 10,000 micrograms/ml-corresponding to 3-5 micrograms/ml coal tar . However, the gel base also appears to be a less potent inhibitor of in vitro growth of M . furfur . In addition, it could be demonstrated that coal tar alone has an antifungal potential on M . furfur in vitro . MIC values from 250 to 5,000 micrograms/ml for coal tar were found . Presumably, both coal tar as the active ingredient and the gel base contribute to the in vitro activity of the coal tar gel against M . furfur . CONCLUSIONS: It is suggested that the effect of coal tar gel ointment in dandruff and seborrhoeic dermatitis therapy in vivo may be at least partly due to an antifungal activity of the coal tar but also of the gel base.

Arch Toxicol, 1995, 69(10), 694 - 7
Effect of methyl isocyanate on rabbit cardiac Na+, K(+)-ATPase; Jeevaratnam K; The present study describes the effect of methyl isocyanate (MIC) on rabbit cardiac microsomal Na+, K(+)-ATPase . Addition of MIC in vitro resulted in dose-dependent inhibition of Na+, K(+)-ATPase, Mg(2+)-ATPase and K(+)-activated p-nitrophenyl phosphatase (K(+)-PNPPase) . Activation of Na+, K(+)-ATPase by ATP in the presence of MIC showed a decrease in Vmax with no change in Km . Similarly, activation of K+ PNPPase by PNPP in the presence of MIC showed a decrease in Vmax with no change in Km . The circular dichroism spectral studies revealed that MIC interaction with Na+, K(+)-ATPase led to a conformation of the protein wherein the substrates Na+ and K+ were no longer able to bind at the Na(+)- and K(+)-activation sites . The data suggest that the inhibition of Na+, K(+)-ATPase was non-competitive and occurred by interference with the dephosphorylation of the enzyme-phosphoryl complex.

Yao Xue Xue Bao, 1995, 30(8), 567 - 72
{Effects of tetrahydroprotoberberines on cytosolic free calcium in cultured rat single myocardial cells}; Li XT et al.; Effect of tetrahydroberberine (THB), l-tetrahydropalmatine (THP) and l-stepholidine (SPD) were supposed to be related to the blocking of calcium influx . In this paper, using Fura-2/AM and AR-CM-MIC cation measurement system, the effects of THB, THP and SPD on cytosolic free calcium ({Ca2+}i) in cultured rat single myocardial cells were examined and compared with verapamil (Ver) . THB, THP and SPD (10-100 mumol.L-1) were found to increase resting {Ca2+}i gently, which was not depressed by tetrodotoxin . THB, THP and SPD (1-100 mumol.L-1) were also shown to inhibit the KCl-induced {Ca2+}i elevation, the IC50 values of THB and SPD were 50.9 (95% confidence limits: 18.5-140) mumol.L-1 and 23.5 (95% confidence limits 7.6-73.4) mumol.L-1, respectively . THB, THP and SPD 30 mumol.L-1 were also shown to inhibit the elevation of {Ca2+}i induced by high extracellular calcium and norepinephrine; but the inhibitory effects of these drugs were weaker than those of Ver . The three compounds showed no significant effect on ouabain induced {Ca2+}i increase . These results suggest that the inhibitory effects of THB, THP and SPD on {Ca2+}i in myocite by blocking voltage-dependent calcium channels were similar but inferior to Ver.

Med Dosw Mikrobiol, 1995, 47(1-2), 101 - 6
{Antifungal activity of fluconazole in vitro}; Pawlik B et al.; The susceptibility of 97 fungal strains to fluconazole was evaluated using the dilution method . Forty-three of the strains were C . albicans, fifty-three other Candida species and one S . cerevisiae . The MIC values varied from 0.1 mg/l to 100 mg/l . However, the growth of 75.2% of the strains was considerably inhibited at 0.1 mg/l . Forty-nine strains were tested using both the dilution and disk-diffusion methods . The findings were consistent . The latter method may be performed on YNB medium and is of practical value.

Chemotherapy, 1995 Jan-Feb, 41(1), 1 - 4
Collagen shields delivery of netilmicin: a study of ocular pharmacokinetics; Dorigo MT et al.; Collagen shields have been used as therapeutic contact lenses to promote corneal epithelial healing and to deliver hydrosoluble drugs . In albino rabbits, we studied the ocular pharmacokinetics of netilmicin, an aminoglycoside antibiotic, released by a 24-hour collagen shield immersed for 10 min in commercially available eye solution of netilmicin, at the standard concentration of 3 mg/ml . The animals were sacrificed after 0.5, 1, 6 and 18 h . The antibiotic concentrations were measured by the microbiological method . The drug levels remained above the MIC for the usual pathogens for 18 h in the cornea and for 6 h in the aqueous humor . In the iris and ciliary body the peak concentration was reached 1 h after shield application, netilmicin concentration decreased thereafter rapidly . The lens and the vitreous did not appear to be permeated by the drug . In the conjunctiva, drug concentrations were low, showing a negligible lateral diffusion of netilmicin released by shields . In conclusion, our findings show, that if the collagen shields are used as delivery systems, a very concentrated drug solution is not required to obtain high and persistent levels of netilmicin in cornea.

J Antibiot (Tokyo), 1995 Jan, 48(1), 31 - 5
Disorazol A, an efficient inhibitor of eukaryotic organisms isolated from myxobacteria; Irschik H et al.; A new antibiotic, disorazol, was isolated from the culture broth of the myxobacterium, Sorangium cellulosum strain So ce 12 . It is a macrocyclic compound containing two oxazole rings . The antibiotic acted against many fungi and mammalian cell cultures . The latter responded to extremely low doses (MIC 3-30 pg/ml) . None of the tested bacteria and yeasts were inhibited.

J Antibiot (Tokyo), 1995 Jan, 48(1), 21 - 5
Gephyronic acid, a novel inhibitor of eukaryotic protein synthesis from Archangium gephyra (myxobacteria) . Production, isolation, physico-chemical and biological properties, and mechanism of action; Sasse F et al.; A new antibiotic compound, gephyronic acid was isolated from the culture broth of the myxobacterium, Archangium gephyra strain Ar 3895 . Up to 3 mg/liter was produced during the logarithmic and stationary growth phase . The compound is an aliphatic acid, which tends to form a hemiacetal . Both forms inhibited growth of yeasts and molds (MIC 1-25 micrograms/ml) and had a cytostatic effect on mammalian cell cultures (IC50 10-60 ng/ml) . Gephyronic acid is a specific inhibitor of eukaryotic protein synthesis showing an IC50 of 1-2 x 10(-7) mol/liter in an in vitro translation assay.

J Infect Dis, 1995 Jan, 171(1), 240 - 5
Rapid identification of a point mutation of the Mycobacterium tuberculosis catalase-peroxidase (katG) gene associated with isoniazid resistance; Cockerill FR 3rd et al.; The complete catalase-peroxidase (katG) gene DNA sequence was determined for 15 strains of Mycobacterium tuberculosis with a wide range of susceptibility to isoniazid . Five of 9 strains with isoniazid MICs > or = 1.0 microgram/mL had one or more missense mutations and all 5 strains had a common G-->T transversion in codon 463, causing the replacement of arginine with leucine and the loss of an NciI or MspI restriction site . None of 6 strains with an isoniazid MIC < 1.0 microgram/mL had mutations affecting codon 463 . Restriction analysis of 43 strains with isoniazid MICs > or = 1.0 microgram/mL showed that 19 (44.2%) had lost the NciI-MspI restriction site at the locus of codon 463 while only 1 of 32 strains with isoniazid MICs < or = 1.0 microgram/L had this restriction polymorphism . These results indicate that the mutation arginine-->leucine in codon 463 of the catalase-peroxidase gene occurs in a significant fraction (44.2%) of M . tuberculosis strains with isoniazid MICs > or = 1.0 microgram/mL.

J Infect Dis, 1995 Jan, 171(1), 237 - 40
Catalase expression, katG, and MIC of isoniazid for Mycobacterium tuberculosis isolates from São Paulo, Brazil; Ferrazoli L et al.; The MIC of isoniazid, peroxidase-catalase expression, and the presence of the katG gene for 102 Mycobacterium tuberculosis isolates from patients in Sao Paulo were compared . Fifty-three isoniazid-resistant and 49 isoniazid-sensitive isolates were analyzed by polymerase chain reaction (PCR) for the presence of katG sequences . All isoniazid-sensitive and 43 (81%) isoniazid-resistant isolates expressed catalase (P = .001) . None of isoniazid-sensitive and 4 (7%) of 53 isoniazid-resistant isolates lacked katG sequences . Among 6 isolates with MICs > 50 micrograms/mL, 5 (83%) did not express catalase and 2 lacked katG sequences; only 1 had complete gene deletion shown by Southern blot analysis . These findings indicate a correlation between loss of catalase and isoniazid resistance among highly resistant isolates, but these isolates were a small proportion of resistant clinical M . tuberculosis isolates from Sao Paulo.

Diagn Microbiol Infect Dis, 1995 Jan, 21(1), 51 - 4
Cross-resistance analysis for DU-6859a, a new fluoroquinolone, compared to six structurally similar compounds (ciprofloxacin, clinafloxacin, fleroxacin, levofloxacin, ofloxacin, and sparfloxacin); Cormican MG et al.; Emerging resistance to the current fluoroquinolones has encouraged synthesis of new compounds in this class . We have evaluated the activity of DU-6859a, a novel halogenated quinolone, against a panel of 300 bacteria, relative to the activity of ciprofloxacin, clinafloxacin, fleroxacin, levofloxacin, ofloxacin, and sparfloxacin . DU-6859a was the most active of the fluoroquinolones studied and retains potentially useful activity against 80% of isolates resistant (minimum inhibitory concentration, > or = 4 micrograms/ml) to ciprofloxacin . Continued clinical investigation of DU-6859a and similar new quinolones is urged.

Infection, 1995, 23 Suppl 1, S39 - 43
Roxithromycin in the treatment of Lyme disease--update and perspectives; Gasser R et al.; Spirochaetal infections have been successfully treated with penicillin; more recently, erythromycin has been used in cases with known penicillin allergy . The discovery of the spirochaete Borrelia burgdorferi and the elaboration of a new generation of macrolides with properties that differ from older macrolides have led to new ways of treating spirochaetal disease with these compounds . This paper presents data on the in vitro and in vivo efficacy of a combination of roxithromycin and co-trimoxazole against B . burgdorferi . In vitro (checkerboard technique; B . burgdorferi strain B31; modified BSK II medium) it was found that while roxithromycin showed excellent efficacy against B . burgdorferi (MIC 0.031 mg/l), co-trimoxazole had no effect . However, the combination of both chemotherapeutics led to a minor synergistic effect, decreasing the MIC for roxithromycin by one dilution step at concentrations of co-trimoxazole from 256 to 8 mg/l . In addition, a clearly reduced growth of microorganisms was seen at concentrations of roxithromycin as low as 0.015 mg/l in combination with 256 to 4 mg/l co-trimoxazole, when compared to the positive controls . Most interestingly, however, the motility of B . burgdorferi was markedly reduced even when the two drugs were combined at very low concentrations . In an in vivo, non-randomised, open, prospective pilot study it was found that of 17 patients with confirmed late Lyme borreliosis (stage II/III), treated with combined roxithromycin (300 mg b.i.d.) and co-trimoxazole for 5 weeks, 13 (76%) recovered completely by the end of treatment, and four continued to have symptoms on follow-up at 6 and 12 months . This success rate is similar to that seen with i.v . penicillin and ceftriaxone . It appears that the reduced motility of B . burgdorferi makes the pathogen more accessible to the immune system.

J Ethnopharmacol, 1995 Jan, 45(1), 43 - 52
The antiamoebic effect of a crude drug formulation of herbal extracts against Entamoeba histolytica in vitro and in vivo; Sohni YR et al.; The antiamoebic effect of a crude drug formulation against Entamoeba histolytica was studied . In the traditional system of medicine in India, the formulation has been prescribed for intestinal disorders . It comprises of five medicinal herbs, namely, Boerhavia diffusa, Berberis aristata, Tinospora cordifolia, Terminalia chebula and Zingiber officinale . The dried and pulverized plants were extracted in ethanol together and individually . In vitro amoebicidal activity was studied to determine the minimal inhibitory concentration (MIC) values of all the constituent extracts as well as the whole formulation . The formulation had a MIC of 1000 micrograms/ml as compared with 10 micrograms/ml for metronidazole . In experimental caecal amoebiasis in rats the formulation had a curative rate of 89% with the average degree of infection (ADI) reduced to 0.4 in a group dosed with 500 mg/kg per day as compared with ADI of 3.8 for the sham-treated control group of rats . Metronidazole had a cure rate of 89% (ADI = 0.4) at a dose of 100 mg/kg per day and cured the infection completely (ADI = 0) when the dosage was doubled to 200 mg/kg per day . There were varying degrees of inhibition of the following enzyme activities of crude extracts of axenically cultured amoebae: DNase, RNase, aldolase, alkaline phosphatase, acid phosphatase, alpha-amylase and protease.

Zentralbl Bakteriol, 1995 Jan, 282(1), 83 - 5
Metronidazole susceptibility testing of Helicobacter pylori with the PDM epsilometer test (E test); von Recklinghausen G et al.; The bacteriostatic activity of metronidazole against Helicobacter pylori was determined with the PDM epsilometer test (E test) and with an agar dilution test . Both methods correlated in the minimum inhibitory concentration (MIC) ranges (< or = 0.5- > 32 mg/l) and in the MIC 50 (E test: 1 mg/l; agar dilution test: 2 mg/l) and MIC 90 (> 32 mg/l) values . However, comparison of test results of single strains revealed that 14 out of 105 strains (13.3%) were classified as resistant by one method but classified susceptible by the other . The correlation coefficient of 0.71 also indicated a low congruence of test results . It is concluded that both methods should be used in order to ascertain all strains resistant to metronidazole.

Antimicrob Agents Chemother, 1995 Jan, 39(1), 250 - 2
Explanations for high rates of eradication with triple therapy using metronidazole in patients harboring metronidazole-resistant Helicobacter pylori strains; van Zwet AA et al.; In 4 of 17 Helicobacter pylori strains obtained from antral biopsy samples, the registered primary resistance (MIC, > 32 microgram/ml) appeared to be nonstable after prolonged microaerophilic incubation . In all resistant strains tested, susceptibility could be obtained when culture under normal microaerophilic conditions was preceded by a period of anaerobic incubation . Both of these findings may explain the observed discrepancy between the results of in vitro susceptibility tests and the eradication obtained in vivo.

Antimicrob Agents Chemother, 1995 Jan, 39(1), 145 - 9
Single amino acid replacements at positions altered in naturally occurring extended-spectrum TEM beta-lactamases; Blazquez J et al.; By directed mutagenesis, we constructed a set of seven TEM-1 derivatives containing single replacements in each one of the amino acids substituted in naturally occurring extended-spectrum TEM beta-lactamases . The exact contribution of each mutation to the resistance phenotype was determined . In addition, mutant enzyme production and stabilities were studied . Five of seven mutations determined to some extent variations in cephalosporin and/or monobactam activity . Dramatic changes in the hydrolysis of ceftazidime and aztreonam occurred when a serine was at position 164 . Changes at positions 104, 238, and 240 showed more leaky variation in activity towards cephalosporins and aztreonam . Replacements at positions 237 and 265 caused no variation in susceptibility to cephalosporins . Interestingly, the change from Gln to Lys at position 39 found in TEM-2, classically considered a neutral change, slightly but consistently increased the MIC of ceftazidime and aztreonam . The in vitro construction of mutations appearing in naturally occurring TEM-beta-lactamases, studied in the same genetic context, may help to understand the evolution of extended-spectrum beta-lactamases.

Mycopathologia, 1995, 130(1), 3 - 9
In vitro susceptibilities of clinical yeast isolates to three antifungal agents determined by the microdilution method; Pfaller MA et al.; A comparative evaluation of the in vitro susceptibilities of 597 clinical yeast isolates to amphotericin B, fluconazole, and 5-fluorocytosine (5FC) was conducted . The broth macrodilution reference method of the National Committee for Clinical Laboratory Standards (NCCLS, M27-P) was adapted to the microdilution method . Microdilution endpoints for amphotericin B were scored as the lowest concentration in which a score of 0 (complete absence of growth) was observed and for 5FC and fluconazole as the lowest concentration in which a score of 2 (prominent decrease in turbidity; MIC-2) was observed compared to the growth control . The MIC values were read after 24 and 48 h incubation . A broad range of MIC values was observed with each antifungal agent . Amphotericin B was very active (MIC90 < or = 1.0 microgram/ml) against all of the yeast isolates with the exception of C . lusitaniae (MIC90 > or = 2.0 micrograms/ml) . Fluconazole was most active against C . parapsilosis (MIC90 of 1.0 microgram/ml) and least active against C . krusei (MIC90 of 32 micrograms/ml) . 5FC was most active against C . albicans, C . parapsilosis, C . tropicalis, and T . glabrata (MIC90 < or = 1.0 microgram/ml) and was least active against C . krusei and C . lusitaniae (MIC90 > or = 16 micrograms/ml) . These data indicate that the microdilution method, performed in accordance with M27-P, provides a means of testing larger numbers of yeast isolates against an array of antifungal agents and allows this to be accomplished in a reproducible and standardized manner . Given these results, it appears that the microdilution method may be a useful alternative to the macrodilution reference method for susceptibility testing of yeasts.

Mycoses, 1995 Jan-Feb, 38(1-2), 59 - 67
In vitro susceptibility of Candida species isolated from patients with haematological malignancies; Morace G et al.; Candida spp . (83 isolates including C . (Torulopsis) glabrata) were tested in vitro for their susceptibility to 5-fluorocytosine, amphotericin B, ketoconazole, itraconazole, fluconazole, and miconazole . The yeasts were isolated from clinical specimens, mostly from the lower respiratory tract, of 30 oncologic patients, 27/30 with haematological malignancies, during a 6-month period (December 1991-May 1992) . Minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values of the 6 drugs were obtained for each yeast using a microdilution broth method developed in our laboratory . Amphotericin B, and 5-fluorocytosine were active against the majority of the yeasts with MIC90/MFC90 values within achievable serum concentrations (3.12/6.25 micrograms ml(-1) and 0.625/0.625 micrograms ml(-1) respectively) . Azole derivatives showed a species-specific activity . MFC values were two to four times higher than those of the MICs, confirming the fungistatic rather than fungicidal activity of azole derivatives . An interesting correlation was found when the in vitro susceptibility values of the isolates were compared with data of patients with or without antifungal prophylaxis or therapy during that period . In general, with respect to fluconazole, C . albicans strains isolated from patients who received no treatment showed MIC and MFC values lower than those obtained from patients who were under prophylaxis or treatment with this drug . Fluconazole administration appears to influence in vitro susceptibility testing.

Mycoses, 1995 Jan-Feb, 38(1-2), 23 - 7
Growth inhibition of Malassezia species by pharmacological concentrations of polidocanol; Mayser P et al.; In vitro antifungal properties of polidocanol (Thesi), a hydroxypolyethoxydecan, were investigated against various yeasts at concentrations of 0.05-10% (w/w) by means of the agar diffusion test; in the case of lipophilic Malassezia furfur, polidocanol-containing olive oil was used additionally for sensitivity study . Six strains of M . furfur of different clinical origin were tested as well as strains of C . albicans (3), C . krusei (3), C . parapsilosis (2), C . robusta (2), Tr . cutaneum (2) and one strain each of C . guilliermondii, C . glabrata, C . tropicalis and M . pachydermatis . Both test systems revealed predominantly fungistatic activity against M . furfur, with a minimal inhibitory concentration (MIC) of 1% polidocanol (w/w), while yeasts of other genera (Candida species, Trichosporum species) showed no or only transitory (C . krusei) inhibition of growth . M . pachydermatis was also found to be sensitive with a MIC of 0.1%; this suggests a specific inhibitory effect against the genus Malassezia . Polidocanol, which has been used for decades as an antipruritic and analgesic in various topical preparations at concentrations between 3% and 5%, might therefore be suitable for prophylaxis of recurrent pityriasis versicolor or in veterinary medicine.

Zhonghua Yi Xue Za Zhi, 1995 Jan, 75(1), 11 - 4, 60
{Susceptibility study on urogenital Chlamydia trachomatis to 19 kinds of antibiotics}; Bai H et al.; We detected the minimal inhibitory concentrations (MIC) and minimal bacteriocidal concentrations (MBC) of 19 kinds of antibiotics against urogenital chlamydia trachomatis (CT) from sexually transmitted disease (STD) patients . The results were as follows: (1) The mean MICs of tetracycline, doxycycline, minocycline, erythromycin, josamycin, medimycin, lomexacin and ofloxacin were lower than 0.08 microgram/ml . Clindamycin was lightly inhibitant to CT . Steptomycin, cephaloradine, chloramiphonic, metronidazole, ciprofloxacin, sulfamethaxazole and trimethoprim showed no activitis to urogenital CT . (2) The values of the MICs and MBCs of the standard strains were among those of the isolated ones . Another the differences in drug susceptibility of different serovars were observed . (3) The MIC detected method is also discussed.

Arch Orthop Trauma Surg, 1995, 114(5), 295 - 7
Pharmacokinetic study of fibrin clot-ciprofloxacin complex: an in vitro and in vivo experimental investigation; Tsourvakas S et al.; We prepared a composite of fibrin clot and ciprofloxacin for use as a biodegradable antibiotic delivery system with sustained effect for the treatment of chronic osteomyelitis . In vitro, ten experiments were performed in which 10 mg of ciprofloxacin were incorporated into 4 ml of fibrin clot . The clots were preserved in nutrient broth and incubated at 37 degrees C for a total of 60 days . Every 24 h a broth specimen was obtained, and the ciprofloxacin concentration was determined by microbiological assay . The maximum level of antibiotic was noted on the first day (49.9 +/- 5.1 mg/l) . The ciprofloxacin-fibrin clot complexes usually disintegrated after 60 days . In vivo, the fibrin-ciprofloxacin clots were made as previously described . The composite was implanted in the medullary canal of rabbit tibiae, and the antibiotic concentration was measured in bone, muscle, skin and serum . In all tissues around the implant, the concentration of antibiotic exceeded the minimum inhibitory concentration against the common causative organisms of osteomyelitis for 10 days . The implant caused no systemic side-effects, and it is likely to prove clinically useful as a drug delivery system for treating chronic osteomyelitis.

Antonie Van Leeuwenhoek, 1995, 67(4), 333 - 7
Inorganic-ion resistance by bacteria isolated from a Mexico City freeway; Vaca Pacheco S et al.; Bacteria were isolated from soil samples, containing high exchangeable lead concentrations, obtained from a busy freeway in the Mexico City metropolitan area . Forty-five selected strains (86.7% Gram-positive) had a single MIC distribution pattern for lead (800-1600 micrograms/ml lead nitrate) and were considered lead-resistant . The isolates showed variable levels of resistance to arsenate (86.7%), chromate (66.7%), cadmium (57.6%), and mercury (31.1%) ions . Multiple inorganic-ion resistance was shown by all strains.

Medicina (B Aires), 1995, 55(1), 59 - 68
{Dolichoectatic intracranial arteries . Advances in images and therapeutics}; Casas Parera I et al.; Dolichoectasia of intracranial arteries is an infrequent disease with an incidence less than 0.05% in general population . It represents 7% of all intracranial aneurysms . Commonly seen in middle age patients with severe atherosclerosis and hypertension, the affected arteries include the basilar artery, supraclinoid segment of the internal carotid artery, middle, anterior and posterior cerebral arteries; males are more frequently affected . The clinical features of these fusiform aneurysms are divided in three categories: ische-mic, cranial nerve compression and signs from mass effect . Hemorrhage may also occur . Nine patients with symptomatic cerebral blood vessel dolichoectasias are presented . Six of them were males with moderate or severe hypertension . Lesions were confined to the basilar artery in 3 cases, carotid arteries and the middle cerebral artery in 1 case, and both systems were affected in 4 patients . Middle cerebral arteries were affected in 5 cases and the anterior cerebral artery in one . An isolated fusiform aneurysm of the posterior cerebral artery is also presented (case 8) (Table 3) . Motor or sensory deficits, ataxia, dementia, hemifacial spasm and parkinsonism were observed . One patient died from cerebro-meningeal hemorrhage (Table 2) . All patients were studied with computerized axial tomography of the brain, 5 cases with four vessel cerebral angiography, 4 cases with magnetic resonance imaging (MRI) and case 5 with MRI angiography . Clinical symptoms depend on the affected vascular territory, size of the aneurysm and compression of adjacent structures . The histopathologic findings are atheromatous lesions, disruption of the internal elastic membrane and fibrosis of the muscular wall . The resultant is a diffuse deficiency of the muscular wall and the internal elastic membrane . Recent advances in neuroimaging such as better resolution of CT scan, magnetic resonance images (MRI) and MRI angiography increased the diagnosis of this pathology showing clearly the affected vessels . This avoids the use of conventional or digital subtraction angiography, reserved only for diagnosing suspected saccular aneurysm, evidence of subarachnoid hemorrhage or planning surgical treatment . The treatment of this entity may be medical or surgical . There is evidence suggesting a more favorable outcome with anticoagulation therapy, although antiaggregation is a reasonable alternative . In our experience no difference in clinical outcome was evident . Surgical treatment of this type of aneurysm includes intra- or extracranial occlusion of parent artery, clipping or aneurysm trapping, tourniquet occlusion, and circumferential wrapping with clip reinforcement . Endovascular occlusion has been accomplished with detachable balloon technique or coils . No surgical attempt was done in our cases . The prognosis is variable depending on the patients age, vessels involved and clinical complications.(ABSTRACT TRUNCATED AT 400 WORDS)

Eur Arch Otorhinolaryngol, 1995, 252(4), 236 - 8
Amoxicillin concentrations in nasal secretions of patients with acute uncomplicated sinusitis and in paranasal sinus mucosa of patients with chronic sinusitis; Kment G et al.; In this prospective randomized clinical study a total of 59 patients of both sexes (above 18 years of age) were enrolled . Thirty patients with acute sinusitis were randomly allocated to two treatment groups, one group receiving 1000 mg amoxicillin every 12 h for 10 days and the other group receiving 500 mg amoxicillin every 8 h for 10 days . The median concentration of amoxicillin in nasal secretions was 2.34 micrograms/ml in the 12-h administration group and 1.95 micrograms/ml in the 8-h administration group . Median bioavailability of antibiotic at 8-24 h did not show any statistical differences between the two treatment schemes {probability (Z) = 0.2} . Twenty-nine patients with chronic sinusitis were then randomly allocated to three groups, with patients receiving 1000 mg amoxicillin at 12, 8 or 6 h before nasal and/or sinus surgery was carried out . The mean amoxicillin concentrations in mucosal tissues removed intraoperatively ranged from 0.69 to 0.99 microgram/g samples . Statistical evaluation by analysis of variance did not show any statistically significant differences among the three treatment groups {probability (F) = 0.1705} . In all cases of acute and chronic sinusitis, amoxicillin concentrations exceeded minimum inhibitory concentration values for pathogens common in sinusitis . Our results indicate that 1000 mg amoxicillin administered twice daily produces tissue concentrations high enough to be clinically effective in patients with either acute or chronic sinusitis.

J Immunol, 1995 Jan 1, 154(1), 26 - 32
The E2 molecule (CD99) specifically triggers homotypic aggregation of CD4+ CD8+ thymocytes; Bernard G et al.; We have previously described E2 as a 32-kDa transmembrane glycoprotein displaying an isomorphism, as two epitopes (defined by mAbs O662 and L129) are widely distributed on T cells whereas two epitopes are restricted to T cell subsets (defined by mAbs D44 and 12E7) . E2, the MIC-2 gene product, is involved in T cell adhesion because anti-E2 mAbs against pan T epitopes block spontaneous T cell rosettes . Pan T E2 mAbs are also able to induce exposure of the phosphatidylserine at the thymocyte surface but not at the surface of mature T lymphocytes, an event most likely linked to adhesion phenomena . We now show here that the anti-E2 mAbs (0662 and L129) that block rosettes and induce phosphatidylserine exposure at the thymocyte surface, and not those reacting with epitopes not involved in adhesion, also trigger aggregation of certain immature T cell lines and no other cell lines tested . Among the normal cells tested, anti-E2 mAbs exclusively induce homotypic aggregation of CD4+ CD8+ human thymocytes . This phenomenon is temperature, energy, and Mg++ dependent, and requires an intact cytoskeleton . These adhesion properties are rather characteristic of integrins . Nevertheless, mAb against beta 1, beta 2, and beta 3 integrin chains, as well as those against alpha-chains known to be present on thymocytes, are unable to block corticothymocyte aggregation . We conclude that E2 triggers on corticothymocytes and no other T cells a homotypic adhesion pathway most likely mediated by an uncharacterized integrin.

Int J Clin Pharmacol Res, 1995, 15(1), 23 - 5
Effects of cardiopulmonary bypass on teicoplanin serum disposition; Miglioli PA et al.; The time course of teicoplanin (T) serum concentrations was determined in 6 patients who had undergone cardiopulmonary bypass (CPB) . The drug was given i.v . (12 mg/kg) 85-140 min before starting CPB . Serum concentrations of T were measured with an automated fluorescence polarization immunoassay, at appropriate times before, during and after CPB (total sampling interval: 12 h) . Five min after initiating CPB, T serum concentrations decreased, on average, by 29% and remained less than the expected values (values extrapolated from the decay curve, measured excluding the CPB period) over the subsequent 60 min . When CPB was discontinued, the T serum concentrations rebounded to the expected values within 5 min . The mean area under the curve (AUC) during CPB was significantly lower than the mean extrapolated AUC . It was concluded that CPB reversibly reduced T serum concentrations, probably due to drug redistribution . Nevertheless, T serum levels were always above the mean inhibitory concentration (MIC) of the most common pathogenic organisms associated with CPB surgery infections.

Vet Rec, 1994 Dec 3, 135(23), 548 - 52
Pharmacokinetics of oxytetracycline in goats: modifications induced by a long-acting formulation; Escudero E et al.; The pharmacokinetics of oxytetracycline were studied in goats, after the intravenous and intramuscular injection of a conventional and long-acting formulation . The antibiotic was distributed according to an open two-compartment model . The apparent volume of distribution (Vz) and the central compartment volume (Vc) were 1.443 litres/kg and 0.453 litre/kg, respectively, and the total body clearance was 0.156 litre/kg/hour . The mean half-lives (T1/2 lambda z) of the conventional formulation after intravenous and intramuscular administration were six hours 28 minutes and 10 hours 38 minutes, respectively, whereas the long-acting formulation had half-lives of six hours 36 seconds and 29 hours, respectively, after intravenous and intramuscular injection . From the results of these single administrations two intramuscular dosage regimens can be proposed that achieve minimum concentrations of over 0.5 mg/litre (the minimum inhibitory concentration for most susceptible pathogens): with the conventional formulation by administering an initial dose of 10 mg/kg and a maintenance dose of 8.5 mg/kg every 24 hours, and with the long-acting formulation by administering an initial dose of 20 mg/kg and a maintenance dose of 14 mg/kg every 48 hours.

Anesth Analg, 1994 Dec, 79(6), 1049 - 55
Effect of n-alkane kinetics in rats on potency estimations and the Meyer-Overton hypothesis; Liu J et al.; Neither lipophilicity nor vapor pressure of larger n-alkanes appear to correlate with their anesthetizing partial pressures in inspired gas . Such results suggest that the Meyer-Overton hypothesis and Ferguson's rule may not apply to these compounds . An alternative explanation might be that a large difference in inspired-to-arterial partial pressure exists, i.e., that the inspired partial pressure misrepresents the effective partial pressure . To test this explanation, we investigated the kinetics of five consecutive even-numbered n-alkanes (C2H6 to C10H22) in rats . The ratio of end-tidal-to-inspired (PA/PI), arterial-to-end-tidal (Pa/PA), and arterial-to-inspired (Pa/PI) partial pressures decreased with increasing carbon chain length, consistent with our separate finding that blood solubility increased . Using Pa/PI and the minimum inspired concentration (MIC) obtained previously, we calculated the true effective potency, minimum alveolar anesthetic concentration (MAC); of these n-alkanes as (Pa/PI)(MIC) . This markedly improved, but did not perfectly correct, the correlation of MAC with lipid solubility (the Meyer-Overton hypothesis) and vapor pressure (Ferguson's rule) . A coefficient of variation of 76.7% was found for the product of MAC and the olive oil/gas partition coefficient . More importantly, the correlation of the logarithm of MAC and oil solubility had a slope of -0.724 (i.e., deviated from -1.0), whereas the slope for eight conventional anesthetics was -1.046 (approached-1.0) . These data imply that olive oil does not adequately mimic the nature of the anesthetic site of action of n-alkanes.

Mycopathologia, 1994 Dec, 128(3), 135 - 7
In vitro susceptibility to 9 antifungal agents of 14 strains of Zygomycetes isolated from clinical specimens; Otcenasek M et al.; Fourteen clinical isolates of Zygomycetes were tested for their in vitro susceptibility to nine antifungal agents . Susceptibility assessment was performed using a microtiter broth dilution method . Synthetic broth with YNB and glucose was used for 5-fluorocytosine and BHI broth for all the other antimycotics . Amphotericin B exhibited the strongest activity against all isolates tested . MIC values of other two polyenes--nystatin and pimaricin--ranged within the susceptibility limits, with a little pronounced higher activity of pimaricin . The isolates of the genus Absidia and Syncephalastrum were well sensitive to all antimycotics with the exception of 5-fluorocytosine and naftifine . A very weak or zero growth inhibitory effect against all members of the genera Mucor and Rhizopus was found in azoles, 5-fluorocytosine and naftifine.

Mycopathologia, 1994 Dec, 128(3), 129 - 33
Discrepancies between MIC and MLC values of amphotericin B against isolates of Aspergillus species; Colombo AL et al.; There is little information addressing the phenomena of discrepancy between minimal inhibitory concentrations (MIC) and minimal lethal concentrations (MLC) values of amphotericin B (AMB) to clinical isolates of fungi . This study assessed in vitro activity of AMB against 70 clinical isolates of aspergilli: 30 strains of Aspergillus fumigatus, 20 strains of Aspergillus flavus and 20 strains of Aspergillus niger . Susceptibility tests were accomplished using a macro broth dilution procedure, with special emphasis on ascertainment of MLCs . AMB exhibited low MIC values against all clinical isolates . While we did not identify any AMB resistant isolates among 70 Aspergillus spp . studied as judged by MIC levels, analysis of the data demonstrated a clear discrepancy between the MIC and MLC levels of AMB obtained against clinical isolates of Aspergillus spp . The MLC values of AMB were significantly higher than the MIC values with MIC 50 and MIC 90 of 0.29 and 0.5 microgram/ml, respectively, at the second reading time, and MLC 50 and MLC 90 of 2.31 and 9.24 micrograms/ml, respectively (p < 0.001) . Additionally, minimal lethal concentrations in 36/70 (51%) of aspergillal isolates studied produced drug concentrations above those which can usually be sustained in patient plasma or tissue.

Eur J Gastroenterol Hepatol, 1994 Dec, 6 Suppl 1, S109 - 12
Non-steroidal anti-inflammatory drugs associated with gastroduodenal injury and Helicobacter pylori; Mizokami Y et al.; OBJECTIVE: To clarify the relationship between non-steroidal anti-inflammatory drug (NSAID)-associated gastroduodenal mucosal injury and Helicobacter pylori infection . DESIGN AND METHODS: The incidence of H . pylori infection was determined in a group of patients treated with NSAID for rheumatoid arthritis for > or = 3 months and in a control group of patients with mainly abdominal symptoms but without rheumatoid arthritis and not being treated with NSAID . The incidence of H . pylori infection was also determined in patients treated with different NSAID and antirheumatic drugs . In addition, the minimum inhibitory concentration of several NSAID against H . pylori was investigated . RESULTS: The incidence of H . pylori infection in the NSAID group tended to be lower than in the control group, and was significantly lower in patients with gastric ulcers . The incidence of infection did not differ between patients treated with one or with more than one NSAID . Differences in the infection rate were found between individual NSAID, with indomethacin being associated with a particularly low rate . No differences in the infection rate were found between different antirheumatic drugs . The minimum inhibitory concentration of ibuprofen was low . CONCLUSION: H . pylori appears to have little effect on gastroduodenal mucosal injury associated with long-term NSAID administration.

Allergy, 1994 Dec, 49(10), 861 - 5
The surface membrane antigen phenotype of human blood basophils; Fureder W et al.; Basophils are effector cells of allergic reactions and express a unique profile of cellular antigens (Ag) . Using a combined toluidine-blue/immunofluorescence staining method, we were able to study the cell membrane Ag phenotype of normal human blood basophils with monoclonal antibodies (mAbs) against established and novel CD antigens . According to previous findings, basophils express CD9 (p24), CD11a (LFA-1 alpha-chain), CD11b (C3biR), CD11c (CR4), CD13 (aminopeptidase N), CDw17 (lactosylceramide), CD18 (beta-chain of beta 2), CD25 (IL-2R alpha-chain), CD26 (dipeptidylpeptidase), CD31 (PECAM), CD35 (CR1), CD38 (T10), CD43 (leukosialin), CD44 (Pgp-1), CD45 (pan-leukocyte Ag), and CD63 (basophil activation Ag) . Various novel CD Ags were detected on basophils, including membrane cofactor protein (MCP) (CD46), the N-linked glycan CD47, decay-accelerating factor (DAF) (CD55), membrane attack complex inhibitory factor (MACIF) (CD59), LFA-3 (CD58), ICAM-2 (CD 102), ICAM-3 (CD50), C5a receptor (CD88), MIC-2/E2 (CD99), and the interleukin-1 (IL-1) R type II (CD121b) . These data provide further evidence that basophils express a unique profile of surface membrane receptors for cytokines and immunomodulating compounds, as well as adhesion molecules and surface glycolipids.

Acta Trop, 1994 Dec, 58(3-4), 187 - 97
Induction of resistance to melarsenoxide cysteamine (Mel Cy) in Trypanosoma brucei brucei; Pospichal H et al.; A population of Trypanosoma brucei brucei with reduced sensitivity to melarsenoxide cysteamine (Mel Cy) was produced in immunosuppresed mice using subcurative drug treatment . Melarsenoxide cysteamine resistance was stable after cyclical transmission through Glossina morsitans centralis . In vitro, the blood-stream forms showed 15-fold higher values for the minimal inhibitory concentration as compared with the parental clone . Cross-resistance could be determined with another arsenical drug, melarsoprol (14-fold) and to two different diamidines (diminazene aceturate: 47-fold; pentamidine methanesulphonate: 34-fold), but not to suramin . When cells were transformed to procyclic forms and tested in vitro, the sensitivity of the resistant population to melarsenoxide cysteamine was only 6-fold lower than that of the parent, but comparatively high cross-resistance could be shown to other drugs (melarsoprol; 85-fold; pentamidine methanesulphonate: 17-fold; quinapyramine sulphate: 40-fold) . Selection of the resistant trypanosomes from non-resistant ones was possible under pentamidine methanesulphonate pressure in cell culture.

Antimicrob Agents Chemother, 1994 Dec, 38(12), 2908 - 9
In vitro activities of 2,2'-bipyridyl analogs against Mycobacterium leprae; Dhople AM et al.; In vitro susceptibility of Mycobacterium leprae to two bipyridyl analogs was studied by using two biochemical parameters to measure the metabolic activity of the organism . VUF-8514 at 0.16 micrograms/ml, but not VUF-8842, completely inhibited the metabolic activity of M . leprae, and the action was bactericidal . When compared to rifampin (MIC 0.3 micrograms/ml), VUF-8514 was equally bactericidal against M . leprae.

Antimicrob Agents Chemother, 1994 Dec, 38(12), 2877 - 82
In vitro and in vivo antimycobacterial activities of a new quinolone, DU-6859a; Saito H et al.; A new fluoroquinolone, DU-6859a, was studied for its in vitro and in vivo antimycobacterial activities . MIC determination by the agar dilution method with 7H11 medium revealed that DU-6859a had MICs at which 90% of M . kansasii (0.78 microgram/ml), M . marinum (1.56 micrograms/ml), M . scrofulaceum (1.56 micrograms/ml), M . fortuitum (0.39 microgram/ml), M . chelonae subsp . abscessus (6.25 micrograms/ml), and M . chelonae subsp . chelonae (1.56 micrograms/ml) were inhibited were 4 to 32 times lower than those of ofloxacin and sparfloxacin . The MICs of DU-6859a at which 90% of M . tuberculosis (0.2 microgram/ml) and M . avium-M . intracellulare complex (12.5 micrograms/ml each) were inhibited were comparable to those of sparfloxacin but were four- to eightfold lower than those of ofloxacin . Thus, DU-6859a possessed more potent in vitro activity than sparfloxacin and ofloxacin against most mycobacterial species . DU-6859a exerted significant efficacy against infections caused by M . intracellulare and M . chelonae subsp . abscessus induced in mice when it was given at a dose of 1 mg per mouse (ca . 50 mg/kg of body weight) in terms of reducing the frequency of occurrence and the degree of gross pulmonary or renal lesions and bacterial loads in the lungs, spleens, or kidneys . The efficacy of DU-6859a was greater than that of ofloxacin and was more pronounced against M . chelonae infections than against M . intracellulare infections.

Asian Pac J Allergy Immunol, 1994 Dec, 12(2), 131 - 6
Standardization of methacholine inhalation challenge by a reservoir method; Wongtim S et al.; Standardization of methacholine inhalation challenge (MIC) by a reservoir method was performed at Respiratory Unit, Chulalongkorn Hospital . One hundred subjects, including 20 non-smoking healthy subjects, 20 patients with isolated chronic cough, 20 patients with isolated allergic rhinitis, 20 patients with stable chronic obstructive bronchitis, and 20 patients with mild bronchial asthma, were scheduled to perform the test . The aerosolized methacholine was produced by an atomized nebulizer of the Provocation test I (Pari-Starnberg) and the aerosol was kept in a reservoir bag . It was inhaled by each subject via a slow vital capacity . Increasing concentrations of methacholine (0, 0.5, 1, 5, 10, and 25 mg/ml were used . None of the healthy subjects had increased bronchial hyperresponsiveness (BHR) . Sixty percent of patients with chronic cough, 60% of patients with allergic rhinitis, 95% of patients with chronic obstructive bronchitis, and 100% of patients with asthma were found to be positive in the MIC tests . No serious effect from methacholine during and after the tests was found . It was concluded that MIC can be easily performed by a reservoir with reproducible results to demonstrate BHR.

Cas Lek Cesk, 1994 Nov 21, 133(22), 702 - 5
{A female patient with near-tetraploid acute myeloid M4 leukemia}; Lemez P et al.; BACKGROUND . Acute myeloid leukemias (AML) are a heterogeneous group of diseases, several types of them are well characterized by typical morphologic, immunologic and cytogenetic features of their leukemic blasts in the MIC classification . We have recently described 2 patients with a new AML type--poorly differentiated near-tetraploid AML L0 . The occurrence of very large blasts in a heterogeneous blast population seemed to be a morphological sign of this new type of AML . RESULTS . The same morphologic characteristics were observed by us when we studied blasts of another 80-year-old patient with a near-tetraploid karyotype . However, 34% of blasts were positive for myeloperoxidase and they exhibited in 24-33% surface myelomonocytic markers CD11b, CD13, CD15 and CD14 . The illness was classified as acute myelomonoblastic leukemia M4 without significant dysplastic changes in erythroid and megakaryocytic lineages . The growth of granulocyte-macrophage bone marrow progenitors CFU-GM was low . The patient refused cytotoxic chemotherapy and expired 3 months later on supportive treatment . CONCLUSIONS . The finding of very large blasts is a typical sign in cases of near-tetraploid AML . Precise classification of leukemia type is essential for successful therapy.

MMWR Morb Mortal Wkly Rep, 1994 Nov 11, 43(44), 807 - 10
Erythromycin-resistant Bordetella pertussis--Yuma County, Arizona, May-October 1994; Strain delineation and antifungal susceptibilities of epidemiologically related and unrelated isolates of Candida lusitaniae; Department of Pathology, University of Iowa College of Medicine, Iowa City 52242Candida lusitaniae is an important nosocomial pathogen that may express resistance to one or more antifungal agents including amphotericin B . We investigated the genotypic diversity and antifungal susceptibility among 47 clinical isolates from 33 patients hospitalized in 12 different medical centers . Strain delineation was performed by restriction endonuclease analysis of genomic DNA (REAG) with the restriction enzyme Sfi I followed by pulsed-field gel electrophoresis and by electrophoretic karyotyping (EK) . Antifungal susceptibility of the isolates to amphotericin B, 5-fluorocytosine (5FC), fluconazole, and itraconazole was determined using National Committee for Clinical Laboratory Standards standard methods . Minimum inhibitory concentration (MIC)90 values ranged from 0.5 micrograms/ml for itraconazole to 512 micrograms/ml for 5FC . In general, isolates from a given patient or epidemiologically related isolates from a nosocomial cluster were identical by molecular typing methods . Epidemiologically unrelated isolates were all distinctly different by both EK and REAG typing methods . Although elevated amphotericin B MICs ( > or = 2 micrograms/ml) were observed in only three isolates, extended incubation (72 h) revealed amphotericin B MICs of 2-16 micrograms/ml in a subset of isolates suggesting potential amphotericin B resistance . These data document the genetic diversity, nosocomial transmission, and antifungal susceptibility of clinical isolates of C . lusitaniae.

Pharm Res, 1994 Nov, 11(11), 1605 - 9
A new bioerodible polymer insert for the controlled release of metronidazole; Gates KA et al.; This study evaluates a new class of bioerodible polymers as periodontal inserts for the controlled release of metronidazole . The system is based on association polymers formed from compatible blends of cellulose acetate phthalate (CAP) and a hydrophobic block copolymer of polyoxyethylene and polyoxypropylene, Pluronic L101 . In addition to characterizing these polymers by thermal analysis, their erosion and metronidazole release characteristics were determined both in vitro, and in vivo using a rat model . The results show that increasing the concentration of Pluronic L101 in the blend to 50% and above leads to a sharp reduction in the rates of polymer erosion and metronidazole release . The characteristics of these slowly eroding films are potentially suitable for use as periodontal drug inserts with an effective duration of up to several days . Depending on the blend composition, the mechanism of metronidazole release was found to range from a surface erosion-controlled process to an erosion-modulated diffusion process . In all in vivo experiments, no signs of adverse tissue reactions were detected . Based on these results, prototype delivery inserts were designed and subsequently evaluated in volunteer patients . Preliminary results from this pilot study show that the metronidazole concentration in the gingival crevicular fluid was significant throughout the sampling period of up to 3 hr and remained well above the minimum inhibitory concentration for most periodontal pathogens . In addition, no discomfort or irritation was reported by the test subjects.

Histopathology, 1994 Nov, 25(5), 447 - 54
Effects of chemotherapy on ultrastructure of oesophageal squamous cell carcinoma; Antonakopoulos GN et al.; Seven oesophageal squamous carcinomas, treated with pre-operative chemotherapy (mitomycin-C, ifosfamide and cisplatin-MIC), with a course finishing 21 days prior to resection, were examined by electronmicroscopy . In one treated case detailed light microscopy failed to reveal any tumour . Five of the remaining six tumours showed cytotoxic damage in that apoptosis and unusual necrotic changes were observed in almost all the neoplastic cells . These features were not seen in untreated cases . In four additional cases, who received one pulse of MIC followed by biopsy or resection within 3-6 days, apoptotic changes were very pronounced and extensive and most neoplastic cells presented unusual degeneration with characteristic derangement of the cytoskeleton, destruction of organelles and accumulation of glycogen . The ultrastructural appearance of 18 untreated resected oesophageal squamous carcinomas was studied for comparison with the treated tumours . The study has demonstrated ultrastructural changes resulting from chemotherapy . Results suggest that the regimen is more effective against squamous carcinomas than against adenocarcinomas of the oesophagus, as judged by comparison with the results of a previous study.

Rozhl Chir, 1994 Nov, 73(7), 328 - 30
{Short-term prophylaxis with ceftriaxone in planned intrathoracic operations}; Vyhnanek F et al.; The purpose of the investigation was to evaluate the effect of short-term prophylaxis with a cephalosporin of the IIIrd generation, ceftriaxone, in 20 patients with an elective intrathoracic operation . The investigation comprised patients operated on account of bronchogenic carcinoma, metastases in the lungs, relapsing spontaneous pneumothorax and carcinoma of the distal cesophagus . ceftriaxone - 1 g was administered before the introduction to anaesthesia . The second 1 g dose was administered after 12 hours . In addition to the microbiological examination of the bronchial secretion and evaluation of the minimal inhibitory concentration of ceftriaxone to the isolated bacteria the ceftriaxone serum level was assessed in the patients and its concentration in the pulmonary parenchyma . Postoperative inflammatory complications/pneumonia/ were detected in two patients . With regard to the long serum half-life/longer than surgery/ ceftriaxone is suitable for short-term prophylaxis in thoracic surgery . The serum level and ceftriaxone penetration into the pulmonary parenchyma is higher than the minimal inhibitory concentration in the majority of isolated bacteria.

Infection, 1994 Nov-Dec, 22(6), 401 - 6
Ultrastructure of Borrelia burgdorferi after exposure to benzylpenicillin; Schaller M et al.; The aim of this study was to investigate the morphological changes of Borrelia burgdorferi associated with penicillin treatment . An isolate of B . burgdorferi from an erythema migrans lesion was cultivated in BSK II medium and exposed to increasing concentrations (0.0625 mg/l-2 mg/l) of penicillin G for 5 days . The in vitro minimal inhibitory concentration (MIC) was determined to be 0.5 mg/l by broth dilution method . The morphological structures of untreated spirochetes, as well as their characteristic ultrastructural changes when exposed to penicillin, were observed by electron microscopy . The following alterations were discovered: (i) Numerous outer sheath blebs at a penicillin concentration of 0.0625 mg/l . (ii) A characteristic irregular waveform of the borrelial cells and complete loss of the outer sheath at a penicillin concentration of 0.125 mg/l . (iii) The presence of "spheroplasts" at the same concentration . (iv) Structural changes of the protoplasmic cylinder complex which showed an irregular pattern at a penicillin concentration of 0.125 mg/l . (v) Disruption of the protoplasmic cylinder complex into several parts at penicillin concentrations of 0.25 mg/l and 0.5 mg/l . (vi) Severe cytolysis at penicillin concentrations of 1 mg/l and 2 mg/l.

Clin Ther, 1994 Nov-Dec, 16(6), 1016 - 27
Experimental study on bacterial colonization of fibrin glue and its prevention; Tanemoto K et al.; To assess the possibility of bacterial colonization of fibrin glue and the effects of adding local sustained-release antibiotics, we conducted in vivo and in vitro preliminary studies . The in vitro experiments revealed that, although there was no colonization of the fibrin glue plates by the eight strains of bacteria tested, the fibrin mesh can serve as a culture medium when blood mingles with it, as is the case in clinical use . Adding dibekacin sulfate (DKB; 3570 micrograms/mL) to fibrin glue decreased the likelihood of colonization of the fibrin mesh . The pharmacokinetics of the added DKB were investigated by adding DKB-supplemented fibrin glue directly to muscle and vascular tissue in male rats . The DKB rapidly eluded from the fibrin glue (less than 0.2% remained after 24 hours) . Because the amount remaining after 7 days (2.03 micrograms/mL) was greater than the minimum inhibitory concentration for most clinical pathogens, a 7-day preventive effect against colonization of the fibrin glue and the surrounding tissue can be anticipated at the concentration used in the present experiments . Experiments using the dermis layer of porcine skin strips showed that the added DKB did not affect the adhesive strength of the fibrin glue.

Int J Dermatol, 1994 Oct, 33(10), 733 - 7
In vitro evaluation of griseofulvin, ketoconazole, and itraconazole against various dermatophytes in Singapore; Goh CL et al.; BACKGROUND . Superficial cutaneous fungal infection, principally dermatophytosis, is an extremely common skin disease . Various in vitro test systems have been developed in recent years to determine the antifungal activity of various drugs . The minimum inhibitory concentration (MIC) obtained may give an indication of the in vivo potency of the drugs . METHODS . One hundred patients (69 men and 31 women) with a clinical diagnosis of dermatophytosis were entered into the study . Direct microscopy and culture were done on all patients . The MICS were determined using the broth dilution method . RESULTS . The age range was 1-76 years . The most common diagnosis was tinea corporis (36%), followed by tinea cruris (22%), and tinea pedis (19%) . The most common fungus isolated was T . rubrum (58%), followed by E . floccosum (14%), and T . mentagrophytes (10%) . The majority of the isolates was sensitive to the three drugs tested (griseofulvin, ketoconazole, and itraconazole) . Of the isolates, 82% were sensitive to griseofulvin, 78% to ketoconazole, and 81% to itraconazole, all at a concentration of < 0.25 micrograms/mL . For T . rubrum, there were four isolates that had an MIC of > or = 64 micrograms/mL to griseofulvin, seven isolates and nine isolates with an MIC > or = 64 micrograms/mL to ketoconazole and itraconazole, respectively . T . interdigitale was relatively resistant to the three drugs in vitro with four of seven isolates having an MIC > or = 4 micrograms/mL with griseofulvin, one of seven isolate with an MIC > or = 64 micrograms/mL with ketoconazole, and three of seven isolates with an MIC > or = 32 micrograms/mL with itraconazole . CONCLUSIONS . The in vitro antifungal activity of griseofulvin, ketoconazole, and itraconazole are similar against dermatophytes in Singapore . Griseofulvin may be given as the first-line drug for treating such infections in Singapore.

Int J Dermatol, 1994 Oct, 33(10), 730 - 2
Disk diffusion susceptibility testing of dermatophytes with allylamines; Venugopal PV et al.; BACKGROUND . Allylamines are a newly developed group of drugs possessing a broad spectrum of activity against a wide range of fungi . With the advent of new antifungal drugs, susceptibility testing of fungi is receiving increased attention as important laboratory procedures for aiding in the selection of appropriate drug therapy . METHODS . In vitro susceptibility testing of 43 clinical isolates of dermatophytes which included Microsporum sp., (18) Trichophyton sp., (23) and Epidermophyton floccosum (2) were carried out against the two allylamine derivatives, naftifine and terbinafine, by agar dilution and disk diffusion methods . RESULTS . Terbinafine was found to be more active minimal inhibitory concentration (MIC range < or = 0.0001-0.1 micrograms/mL), inhibiting 50% (MIC 50) and 90% (MIC 90) of the isolates at 0.01 and 0.1 micrograms/mL, respectively . The MIC 50s and MIC 90s of naftifine were 0.1 micrograms/mL (MIC range 0.001-0.5 micrograms/mL) . Both the drugs showed good correlation between the MIC and sizes of zones of inhibition around the disks . Regression analysis was used to measure the degree of correlation between the MIC values and matched averaged zones of inhibition; the correlation coefficients for both terbinafine and naftifine were -0.6841 (P < 0.001) and -0.5455 (P < 0.001), respectively . CONCLUSIONS . The allylamines, naftifine and terbinafine, could be used successfully for susceptibility testing of dermatophytes by the disk diffusion method . With proper standardization of the test conditions, in vitro susceptibility testing of filamentous fungi by disk diffusion would become a useful laboratory procedure in the near future for determining the best drug therapy.

Indian J Pathol Microbiol, 1994 Oct, 37(4), 381 - 8
Antidermatophytic activity of allylamine derivatives; Venugopal PV et al.; The allylamine derivatives are a new class of synthetic antifungal agents . The antidermatophytic activity of the two main compounds, naftifine and terbinafine were compared in vitro with those of ketoconazole and itraconazole by agar dilution . Eighty eight clinical isolates of dematophytes comprising of Microsporum canis (50), M . audouinii (5), Trichophyton rubrum (6) T . mentagrophytes (5), T . violaceum (12), T . simii (5), T . verrucosum (1), T . soudanense (1), T . erinacie (1) and Epidermophyton floccosum (2) were tested . Terbinafine was found to be most active, inhibiting 68 of the 88 isolates at a concentration of 0.01 ug ml-1 and all at 0.1 ug ml . (Minimum inhibitory concentration - MIC range < or = 0.0001-0.1 ug ml-1) . Naftifine inhibited 84 isolates at a concentration of 0.1 ug ml-1 and all at 0.5 ug ml-1 (MIC range 0.001-0.5 ug ml-1) . Itraconazole required 0.1 ug ml-1 for inhibiting 50 isolates and 0.5 ug ml-1 for 85 isolates (MIC range 0.01-1 ug ml-1) whereas ketoconazole inhibited 71 isolates at 1 ug ml-1 and 87 at 2.5 ug ml-1 (MIC range 0.01-5 ug ml-1).

Endosc Surg Allied Technol, 1994 Oct, 2(5), 279 - 81
Automated processing of endoscopic surgical instruments; Roth K et al.; This paper deals with the requirements for automated processing of endoscopic surgical instruments . After a brief analysis of the current problems, solutions are discussed . Test-procedures have been developed to validate the automated processing, so that the cleaning results are guaranteed and reproducable . Also a device for testing and cleaning was designed together with Netzsch Newamatic and PCI, called TC-MIC, to automate processing and reduce manual work.

New Microbiol, 1994 Oct, 17(4), 337 - 40
Netilmicin influences siderophores production and iron receptor expression in Escherichia coli; Mignini F et al.; This study investigated the effect of subinhibitory concentrations of netilmicin on the phenolate (enterochelin), hydroxamate (aerobactin) and total siderophores production and on the 81-kDa and 74-kDa receptors expression in Escherichia coli . Netilmicin at 1/40 MIC reduces total siderophores by 40%; the cathecols by 50% and the hydroxamate by 80% . Concomitant with siderophores reduction, the antibiotic induces the upregulation of the 81-kDa protein receptor . Both effects reduce the ability of the bacterium to survive in the host.

Antimicrob Agents Chemother, 1994 Oct, 38(10), 2477 - 9
Association between double mutation in gyrA gene of ciprofloxacin-resistant clinical isolates of Escherichia coli and MICs; Vila J et al.; The mutations in the quinolone resistance-determining region of the gyrA and gyrB genes from 27 clinical isolates of Escherichia coli with a range of MICs of ciprofloxacin from 0.007 to 128 micrograms/ml and of nalidixic acid from 2 to > 2,000 micrograms/ml were determined by DNA sequencing . All 15 isolates with ciprofloxacin MICs of > or = 1 micrograms/ml showed a change in Ser-83 to Leu of GyrA protein, whereas in clinical isolates with a MIC of > or = 8 micrograms/ml (11 strains), a double change in Ser-83 and Asp-87 was found . All isolates with a MIC of nalidixic acid of > or = 128 micrograms/ml showed a mutation at amino acid codon Ser-83 . Only 1 of the 27 clinical isolates of E . coli analyzed showed a change in Lys-447 of the B subunit of DNA gyrase . A change in Ser-83 is sufficient to generate a high level of resistance to nalidixic acid, whereas a second mutation at Asp-87 in the A subunit of DNA gyrase may play a complementary role in developing the strain's high levels of ciprofloxacin resistance.

Antimicrob Agents Chemother, 1994 Oct, 38(10), 2357 - 61
Standardization of disk diffusion test and its clinical significance for susceptibility testing of metronidazole against Helicobacter pylori; Xia H et al.; Susceptibilities of 121 clinical Helicobacter pylori strains to metronidazole were determined by both a 5-micrograms metronidazole disk diffusion test and a plate dilution method in duplicate and after different periods of incubation . The distribution of MICs of metronidazole against H . pylori among the strains was found to be bimodal . The diameters of inhibitory zones obtained by the disk diffusion test and the MICs obtained by the plate dilution method correlated well, especially after 4 days of incubation (r = 0.77) . An inhibitory zone diameter of 20 mm was found to correspond to a MIC of 8 micrograms/ml and is recommended as a suitable zone for differentiating susceptibility and resistance with a 5-micrograms metronidazole disk . Three interpretive categories of susceptibility results were defined; strains with inhibitory zone diameters of more than 26 mm were defined as susceptible (MIC, < 4 micrograms/ml), strains with zone diameters of 20 to 26 mm were deemed intermediate (MIC, 4 to 8 micrograms/ml), and those with zone diameters of less than 20 mm were deemed resistant (MIC, > 8 micrograms/ml) . Furthermore, 76 H . pylori-positive patients with duodenal ulcers or nonulcer dyspepsia were treated with a 1 week of triple therapy (colloidal bismuth subcitrate, metronidazole, and tetracycline) . H . pylori strains were isolated before treatment from antral biopsies from those patients, and the metronidazole susceptibilities of the strains were determined by the disk diffusion test . H . pylori status was evaluated again 4 weeks after completion of treatment . The eradication rates for susceptible, intermediate, and resistant strains were 95.9% (47 of 49), 62.5% (5 of 8), and 52.6% (10 of 19), respectively . It is included that the 5-micrograms disk diffusion test is easy to perform and gives final results similar to those of the plate dilution method . The three interpretive categories of susceptibility may be of benefit for clinical choice of chemotherapy in eradicating H . pylori.

Antimicrob Agents Chemother, 1994 Oct, 38(10), 2296 - 9
In vitro and in vivo activities of azithromycin, a new azalide antibiotic, against chlamydia; Niki Y et al.; The in vitro and in vivo activities of azithromycin against chlamydia were investigated . The MIC of azithromycin for five standard strains of different species of chlamydia and six wild-type strains of Chlamydia pneumoniae was 0.125 microgram/ml, which was superior to that of erythromycin but inferior to those of clarithromycin and minocycline . However, the therapeutic effect of a 7-day course of azithromycin at a dose of 10 mg/kg of body weight administered orally once daily to mice with experimental Chlamydia psittaci pneumonia was excellent, with a 100% survival rate at 14 days after infection, which was the same as that for treatment with minocycline administered at 10 mg/kg twice daily; all erythromycin treated animals died within 10 days . When treatment was discontinued 3 days after the infection, the survival rate for mice treated with azithromycin was 90% and that for mice administered minocycline was 30% . These results suggest that azithromycin may be useful in the treatment of respiratory infections caused by intracellular pathogens, including chlamydia because of its excellent accumulation within host cells.

Pharmacology, 1994 Oct, 49(4), 226 - 37
Interaction between Helicobacter pylori and human gastric epithelial cells in culture: effect of antiulcer drugs; Wagner S et al.; A human in vitro model to study the interaction between Helicobacter pylori and gastric epithelial cells was developed using primary cultures of gastric mucosal cells (isolated from gastric biopsies or operative specimen and maintained in culture for 2 weeks) as well as the well-differentiated human gastric carcinoma cell line HM02, the undifferentiated gastric tumour cell line HM51, and the laryngeal epithelial cell line HEp-2 . Primary cultures and all cell lines were exposed to seven isolates of H . pylori isolated from gastritis and duodenal ulcer patients . Microbial adherence was assessed by microscopical evaluation of Giemsa-stained preparations and by culturing the viable bacteria attached to the epithelial cells . All H . pylori isolates adhered to the gastric cells in primary culture, to HM02 cells, and to HEp-2 cells with the greatest binding affinity found in primary gastric cells . No adherence was detected in HM51 cells . H . pylori adherence was dependent on bacterial load, incubation time, and temperature . There was no difference in microbial binding between H . pylori isolates derived from gastritis and duodenal ulcer patients . The effect of antiulcer drugs on H . pylori adherence was investigated by pre-incubating isolates of H . pylori with omeprazole, cimetidine, and bismuth subcitrate . Omeprazole and cimetidine failed to significantly influence microbial adherence . In contrast, bismuth subcitrate already in concentrations below the MIC range decreased H . pylori adherence in gastric epithelial cells and in HEp-2 cells substantially . Our study shows that primary cultured human gastric mucosal cells and the human gastric carcinoma cell line HM02 provide suitable in vitro models for the study of the interactions between H . pylori and the gastric epithelium . This gastric cell model is characterized by a high affinity for H . pylori binding.

East Afr Med J, 1994 Oct, 71(10), 624 - 7
Resistance of E . coli strains, recovered from chickens to antibiotics with particular reference to trimethoprim-sulfamethoxazole (septrin); Bebora LC et al.; Thirty-seven strains of E . coli recovered from cases of septicaemia in chicken were tested for sensitivity to 6 antibiotics . Minimum inhibitory concentration (MIC) determinations done on the strains showed resistance to trimethoprim-sulfamethoxazole (septrin) (100%), ampicillin (62.2%), tetracycline (51.4%), kanamycin (13.5%) and gentamicin (2.7%) . All were sensitive to chloramphenicol . Conjugation studies showed easy transfer of the resistance factor for septrin to the recipient sensitive strain, K12F-, a 60 megadalton plasmid was transferred in most of the cases (a number of plasmids moved across to K12F- strains) . Septrin was chosen as a referral antibiotic because it is used extensively for treating diarrhoeal cases in children in Kenya . The results expressed the possibility of the chicken being the possible source of the septrin resistance gene (plasmid) for humans, and vice versa.

Jpn J Med Sci Biol, 1994 Oct-Dec, 47(5-6), 241 - 52
Cure with cisplatin (II) or murine malaria infection and in vitro inhibition of a chloroquine-resistant Plasmodium falciparum isolate; Nair L et al.; Antiplasmodium properties of cisplatin {cis-platinum (II) diamine dichloride}, a neoplastic drug, have been assessed in in vivo and in vitro model systems of malarial parasite . A well-tolerated dose of 6 mg/kg body weight of the compound cured the mice infected with Plasmodium berghei and the amount of cisplatin required for in vitro inhibition (IC50) of a chloroquine-resistant Plasmodium falciparum isolate was smaller than either chloroquine or quinine . The minimum inhibitory concentration (MIC) needed to prevent the in vitro multiplication of asexual blood parasites was 30 ng/ml . Late ring and trophozoite stages of the erythrocytic cycle were the most susceptible, whereas schizont and early ring stages were the least sensitive to the toxic effect of cisplatin . Multiple smaller doses were more effective in curing malaria in mice than a single large dose . In a few of the mice treated with a single intraperitoneal large dose of 6 mg/kg body weight, there was a delay in appearance of parasitemia but most of them recovered completely but slowly . This compound exerts its toxicity mainly by randomly damaging and cross-linking DNA strands as shown by Southern hybridization with a synthetic oligonucleotide probe, which is a repeat sequence in the falciparum genome . The report clearly demonstrates the antimalarial potentials of this compound and suggests a closer evaluation of this and other related compounds, specially in combination with antimalarial drugs to probe their synergistic properties.

Epidemiol Mikrobiol Imunol, 1994 Sep, 43(3), 120 - 3
{Occurrence and characteristics of gram-negative rods with marginal sensitivity and resistance to ofloxacin}; Kolar M et al.; In the submitted paper the authors focused their attention on the characteristics of Gram-negative bacteria with a marginal sensitivity and resistance to ofloxacin (MIC > or = 2 mg.l-1) isolated from clinical materials in the Olomouc Faculty Hospital . They give an account of their sensitivity (based on assessment of the minimal inhibitory concentration-MIC) to 20 other antibiotics and chemotherapeutic agents and the percentage ratio of different species according to department, clinical material and diagnosis.

Epidemiol Mikrobiol Imunol, 1994 Sep, 43(3), 104 - 6
{Radiometric determination of Mycobacterium avium-intracellulare and Mycobacterium xenopi sensitivity to antitubercular agents}; Kubin M et al.; Using the macrodilution radiometric technique in a BACTEC 460 apparatus, the authors assessed in 25 strains of the M . avium complex and 20 strains of M . xenopi the MIC of the following chemotherapeutic agents: Ciprofloxacine, clofazimine, rifampin, cycloserine, kanamycin, etionamide, ethambutol and amikacin . In all instances wild strains isolated in the Czech Republic in 1991-1992 were involved . In strains of the M . avium complex in the majority of drugs a major predominance of slightly or completely resistant strains was found . However, in addition to resistant strains there were also sensitive strains and strains with a reduced sensitivity in the group . The highest ratio of sensitive strains was recorded in clofazimine and amikacin . Strains of M . xenopi had, as compared with avian mycobacteria, lower MIC values with the exception of cycloserine and ethambutol in all the remaining chemotherapeutic agents . The applied radiometric technique was evaluated as a suitable method for assessment of the sensitivity of mycobacteria to chemotherapeutic agents, in particular because it provides results within a short time, i.e . within 8 days after inoculation and because of the quantitative evaluation of MIC values . It was therefore recommended for centralized assessment of sensitivity in the Czech Republic.

Zhonghua Zhong Liu Za Zhi, 1994 Sep, 16(5), 360 - 3
{Detection and analysis of multidrug resistance in 100 cases of acute leukemia}; Luan FJ et al.; Bone marrow specimens from 100 cases of acute leukemia (AL) diagnosed by MIC were detected with fluorescence microscopy for their mdr-1 expression using monoclonal antibody JSB-1 against P-glycoprotein (P-170) . The results showed that almost all subtypes of AL had P-170 expression and M5 of ANLL had a significantly higher expression rate in the newly diagnosed group . The MDR expression highly correlated with the clinical drug resistance and prognosis . The Positive rate of P-170 (20.8% +/- 14.9%) and MDR expression (78.9%) of refractory group were significantly higher than newly diagnosed group (7.5% +/- 9.8% and 18.2% respectively) . Cases with MDR expression had poor response to chemotherapy and bad prognosis.

J Chemother, 1994 Sep, 6 Suppl 4, 7 - 15; discussion 23-4
Antibiotic-resistant pneumococci--facts and fiction; Appelbaum PC; The effective treatment of infections caused by penicillin-resistant pneumococci is dependent upon the rapid and accurate laboratory assessment of bacterial susceptibility . The most reliable methods for the susceptibility testing of pneumococci are those of minimum inhibitory concentration (MIC) determination, disk diffusion and the more recently developed E-test . The E-test, in particular, has made pneumococcal testing much easier and allows results to be obtained more rapidly . Current breakpoint recommendations for the susceptibility of pneumococci to penicillin and cephalosporins have been criticised and continue to be the subject of debate . Evidence suggests that strains of pneumococci with an MIC value of 0.06 mg/L for penicillin should be classified as being of intermediate susceptibility . Many of these strains produce zone diameters less than the susceptible breakpoint in oxacillin/methicillin disk procedures . Other proposed changes to NCCLS guidelines are also discussed . Surveys of susceptibility patterns of pneumococci to antibiotics are important in assessing the value of agents in the management of infectious disease . Susceptibility studies have demonstrated that older drugs such as amoxycillin and piperacillin have low MICs against pneumococci, and may therefore be effective in the treatment of infection due to penicillin-intermediate and possibly even penicillin-resistant strains.

Infection, 1994 Sep-Oct, 22(5), 343 - 6
Penetration of ciprofloxacin into the human pancreas; Isenmann R et al.; The aim of this study was to determine the concentrations of ciprofloxacin in human pancreatic tissue and juice . Concentrations were measured by high-pressure liquid chromatography (HPLC) . Two hundred mg of ciprofloxacin were administered as a short i.v . infusion (30 min) . The median ciprofloxacin concentrations 140 min (median) after the start of infusion in pancreatic tissue as well as in pancreatic juice were 0.9 mg/kg (mg/l) . The penetration ratio was 1.0 for pancreatic tissue and 0.83 for pancreatic juice . With regard to the minimal inhibitory concentrations (MIC) for the respective bacteria, ciprofloxacin seems to be an appropriate drug for the treatment of septic complications in necrotizing pancreatitis . Future clinical trials are necessary to prove this assumption.

Antimicrob Agents Chemother, 1994 Sep, 38(9), 2213 - 4
In vitro activity of dirithromycin against Chlamydia trachomatis; Segreti J et al.; Dirithromycin is a new macrolide antibiotic with an active metabolite, erythromycylamine . We evaluated the in vitro activities of both drugs against 16 isolates of Chlamydia trachomatis and compared them with that of doxycycline . In vitro susceptibility testing was performed with McCoy cell monolayers . The MIC was defined as the lowest concentration of antibiotic without inclusions . The MBC was defined as the lowest concentration of antibiotic yielding no inclusions after passage onto 24-h-old antibiotic-free McCoy cell monolayers . Dirithromycin and erythromycylamine appeared to be equally effective against these 16 strains of C . trachomatis (MIC for 90% of strains tested, 1 mg/ml; MBC for 90% of strains tested, 2 micrograms/ml) . Both were less active than doxycycline (MIC for 90% of strains tested, 0.06 micrograms/ml; MBC for 90% of strains tested, 0.12 micrograms/ml) . The combination of dirithromycin and erythromycylamine appeared to be additive.

J Wound Ostomy Continence Nurs, 1994 Sep, 21(5), 195 - 8
The MIC-KEY experience with the pediatric patient; Borkowski S; A gastrostomy, creation of a gastrocutaneous fistulous tract, may be indicated for the pediatric patient with a functional gastrointestinal tract who is unwilling or unable to consume sufficient nutrition to meet caloric needs for optimal growth and development . A gastrostomy may also be used for medication administration, decompression, or access . Several pediatric conditions or anomalies may necessitate gastrostomy . Traditionally, a silicone catheter with a mushroom tip was placed through a gastrostomy . Recently, however, alternative gastrostomy devices have become available . The MIC-KEY device (Medical Innovations Corporation, Milpitas, Calif.) is one such device . This article introduces the ET nurse to the MIC-KEY device as an option and discusses its advantages and disadvantages in the pediatric patient.

Schweiz Med Wochenschr, 1994 Aug 9, 124(31-32), 1385 - 90
{Eradication of metronidazole-resistant Helicobacter pylori: is omeprazole/amoxicillin a therapeutic alternative?}; Zala G et al.; Recommended therapies with the highest eradication rates for Helicobacter pylori (HP) are triple therapies comprising bismuth salts, nitroimidazole and amoxicillin or tetracycline . Primary and secondary resistance of HP to nitroimidazole, however, represents a major problem of this treatment since it is the main cause of eradication failure . In these cases therapeutic regimes without nitroimidazole could prove more successful . High dose omeprazole/amoxicillin has been suggested as a simple and effective therapy with few side effects . The effectiveness of this combination in eradicating metronidazole resistant HP has not been established so far . The aim of this study was to evaluate high dose omeprazole/amoxicillin in eradicating metronidazole resistant HP in our population . 33 patients (6 women, 27 men, mean age 39 {range 21-68}) with recurrent duodenal ulcer and gastric colonization by metronidazole resistant HP were examined . Smokers were defined as patients currently smoking > 10 cigarettes/day . Exclusion criteria were: gastric surgery or intake of antibiotics, omeprazole bismuth salts and NSAIDs within four weeks before study entry endoscopy . Biopsy specimens were obtained in a standardized manner: 5 from the gastric antrum (1 CLO, 1 culture, 3 histology: H & E, Giemsa) and 2 from the gastric body (histology) . Resistance testing for penicillin, amoxicillin and metronidazole was performed using a disk diffusion test (E-test, AB Biodisk, Sweden) . Metronidazole resistance was defined as a minimal inhibitory concentration (MIC) of metronidazole of > 8 micrograms/ml . Eradication therapy consisted of oral omeprazole (40 mg bid) and amoxicillin solute (750 mg tid) for 10 days . Subsequently, for ulcer treatment, patients were given omeprazole (20 mg per day) for 20 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Nature, 1994 Aug 4, 370(6488), 389 - 91
Rapid evolution of a protein in vitro by DNA shuffling; Stemmer WP; DNA shuffling is a method for in vitro homologous recombination of pools of selected mutant genes by random fragmentation and polymerase chain reaction (PCR) reassembly . Computer simulations called genetic algorithms have demonstrated the importance of iterative homologous recombination for sequence evolution . Oligonucleotide cassette mutagenesis and error-prone PCR are not combinatorial and thus are limited in searching sequence space . We have tested mutagenic DNA shuffling for molecular evolution in a beta-lactamase model system . Three cycles of shuffling and two cycles of backcrossing with wild-type DNA, to eliminate non-essential mutations, were each followed by selection on increasing concentrations of the antibiotic cefotaxime . We report here that selected mutants had a minimum inhibitory concentration of 640 micrograms ml-1, a 32,000-fold increase and 64-fold greater than any published TEM-1 derived enzyme . Cassette mutagenesis and error-prone PCR resulted in only a 16-fold increase.

Biochem Pharmacol, 1994 Aug 3, 48(3), 587 - 94
Effect of carbamate thioester derivatives of methyl- and 2-chloroethyl isocyanate on glutathione levels and glutathione reductase activity in isolated rat hepatocytes; Kassahun K et al.; The present study examined the effects of S-(N-methylcarbamoyl)glutathione (SMG), S-(N-methylcarbamoyl)-L-cysteine (L-SMC) and some analogs of these S-linked conjugates of methyl isocyanate (MIC) on the activity of glutathione reductase (GR) in freshly isolated rat hepatocytes and on the levels of reduced and oxidized glutathione (GSH and GSSG) in exposed cells . Both SMG and its monoethyl ester (0.5 mM) were found to inhibit GR weakly, although L-SMC proved to be an effective inhibitor of the enzyme (60 +/- 4% activity remaining after a 4-hr incubation at 0.5 mM) . The cysteine adduct (SCC) of 2-chloroethyl isocyanate (CEIC) was a strong inhibitor of GR (27 +/- 1% activity remaining after a 1-hr incubation at 0.1 mM) and was essentially equipotent with the antitumor agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) . L-SMC depleted intracellular GSH in a time- and concentration-dependent manner up to 2 hr of incubation, beyond which time GSH levels began to recover . Exposure of cells to the enantiomeric conjugate, D-SMC, led to a similar concentration- and time-dependent inhibition of GR and fall in intracellular GSH, but in this case the depletion of GSH was extensive and was sustained throughout the 5-hr incubation period . Only a small amount (less than 10%) of the GSH that was lost from cells exposed to SMC was recovered in the medium, indicating that SMC did not cause efflux of GSH (most of the free cysteine released during breakdown of SMC was recovered in the medium) . Experiments with hepatocytes exposed for 5 hr to SCC (0.1 mM) demonstrated that GSSG levels were elevated by 32 +/- 5% relative to controls . Collectively, these results indicate that carbamate thioester conjugates of MIC and CEIC inhibit GR, probably via release of the free isocyanate at the cell surface, which then penetrates the hepatocyte . The inhibitory effects of the isocyanates on GR, coupled with their propensity to react spontaneously with GSH, combine to deplete significantly intracellular stores of GSH.

Arch Environ Contam Toxicol, 1994 Aug, 27(2), 272 - 5
In vitro and in vivo effects of methyl isocyanate on rat brain mitochondrial respiration; Jeevaratnam K et al.; The present study deals with the in vitro and in vivo effects of methyl isocyanate (MIC) on rat brain mitochondrial function . Addition of MIC to tightly coupled brain mitochondria in vitro resulted in a mild stimulation of state 4 respiration, abolition of respiratory control, decrease in ADP/O ratio, and inhibition of state 3 oxidation . The oxidation of NAD(+)-linked substrates (glutamate + malate) was more sensitive (fourfold) to the inhibitory action of MIC than succinate while cytochrome oxidase was unaffected . Administration of MIC subcutaneously at a lethal dose affected respiration only with glutamate+malate as the substrate (site I) and caused a 20% decrease in state 3 oxidation leading to a significant decrease in respiratory control index while state 4 respiration and ADP/O ratio remained unaffected . As both the malondialdehyde and iron contents of brain mitochondria were not altered, it may be inferred that the observed in vivo inhibition of state 3 oxidation is induced by MIC through systemic stagnant hypoxia leading to ischemia of brain, which further contributes to the cerebral hypoxia.

Ann Neurol, 1994 Aug, 36(2), 190 - 9
Chromosomal fragility associated with familial Alzheimer's disease; Ettinger S et al.; To test whether chromosomal instability is associated with familial Alzheimer's disease, we examined breakage on X chromosomes of fibroblasts derived from patients with familial Alzheimer's disease, using gene cotransfer methodology . The X chromosome is a convenient target for analyzing DNA breakage because of its numerous markers and ease of selection in rodent-human hybrid cells . Patients with familial Alzheimer's disease, including the large Nova Scotia Alzheimer's kindred, show a significantly lower cotransfer of the X-linked glucose-6-phosphate dehydrogenase (G6PD) gene with the selected HPRT gene in hybrid cells, indicating breakage between the markers . Lower cotransfer of the more distant X-linked gene, MIC-2, was statistically significant in this kindred, but not in other patients with familial Alzheimer's disease . The distance between MIC2 and HPRT is sixfold to ninefold greater than that between HPRT and G6PD, suggesting that there may be a "hot spot" for breakage in the latter interval on the X chromosome of patients with familial Alzheimer's disease . The somatic cell hybrid model provides insights into underlying mechanisms for chromosomal breakage induced by the Alzheimer defect . A hypothesis implicating a candidate gene, C1-THF synthase, in the generation of chromosome instability in the pathogenesis of familial Alzheimer's disease, is presented.

Tuber Lung Dis, 1994 Aug, 75(4), 283 - 5
Chloroquine does not enhance the activity of clarithromycin against multiplication of Mycobacterium avium within human macrophages; Lazard T et al.; SETTING: Chloroquine, an alkalinizing lysosomotropic agent, enhances the intracellular activity of antibiotics against Mycobacterium tuberculosis or Coxiella burnetii . OBJECTIVE: To determine if chloroquine modifies the activity of clarithromycin, less effective at acidic pH, against intracellular Mycobacterium avium . DESIGN: The activity of clarithromycin (4 micrograms/ml) against the MO-1 strain of M . avium was evaluated within human macrophages in presence of chloroquine (5 micrograms/ml) . The minimal inhibitory concentration of clarithromycin for the strain was 2 micrograms/ml . RESULTS: While clarithromycin alone did decrease the intracellular infection at day 7 of culture (P < 0.01), chloroquine alone did not impede the intracellular growth of M . avium, and did not enhance the activity of clarithromycin . CONCLUSION: Chloroquine should not improve clarithromycin treatment against M . avium infection.

J Chemother, 1994 Aug, 6(4), 238 - 42
Chlamydia trachomatis genitourinary infections: laboratory diagnosis and therapeutic aspects . Evaluation of in vitro and in vivo effectiveness of azithromycin; Chiarini F et al.; Chlamydia trachomatis (C.t.) cell culture represents a sensitive method for the diagnosis of chlamydial infection and the only one which makes it possible to determine the susceptibility of an isolate to antibiotics so that an appropriate drug can be selected for individual treatment . In 11 patients, affected by urethroprostatitis and suspected of treatment failure with standard drug regimens, either due to lack of compliance with therapy or antibiotic resistance, C.t . was isolated in McCoy cell culture from urethral swabs, after prostatic massage . The in vitro activity of azithromycin against these isolates and the in vivo efficacy of the drug in the patients treated with a single 1 g dose have been evaluated . All the C.t . strains tested were susceptible to the action of azithromycin (MIC range 0.125-1.0 microgram/ml) . Bactericidal values were one dilution higher (MBC range 0.25-2.0 microgram/ml) . These in vitro results are consistent with clinical observations as all the patients treated had negative culture at a 4-week follow-up visit.

J Antimicrob Chemother, 1994 Aug, 34(2), 223 - 30
Comparison of methodologies used in assessing the postantibiotic effect; MacKenzie FM et al.; The postantibiotic effect (PAE) of the carbapenem antibiotic meropenem was determined for the reference strains of Escherichia coli NCTC 4174 and E . coli NCTC 12210 . Regrowth of bacteria after antibiotic exposure was determined by viable counting and bioluminescence alone and in combination with an impedance technique and a morphological technique was also employed . Different methods of calculating the PAE were also used . After exposure of E . coli to 0.1-100 x MIC of meropenem for 2 h, concentration dependent differences in counts by bioluminescence, and viable counting were observed, the latter always being lower . The unexposed control of E . coli NCTC 4174 yielded counts of 1.1 x 10(6) +/- 1.1 x 10(5) and 1.3 x 10(6) +/- 4.7 x 10(5) by viable counting and bioluminescence respectively and E . coli NCTC 12210 gave counts of 4.2 x 10(6) +/- 1.8 x 10(6) and 1.1 x 10(7) +/- 4.3 x 10(6) by the same methods . After exposure to 100 x MIC of meropenem, NCTC 4174 yielded counts of 1.28 x 10(3) +/- 5.35 x 10(2) and 2.59 x 10(5) +/- 8.61 x 10(4) and NCTC 12210 gave counts of 5.22 x 10(3) +/- 9.74 x 10(2) and 5.21 x 10(6) +/- 1.45 x 10(6) by viable counting and bioluminescence, respectively . The discrepancies were due to the inability of the viable counting procedure to detect spheroplasts . Falsely low post exposure counts led to falsely low determinations of PAE by viable counting alone and in combination with the impedance technique.(ABSTRACT TRUNCATED AT 250 WORDS)

Lett Appl Microbiol, 1994 Aug, 19(2), 110 - 3
Antifungal action and antiaflatoxigenic properties of some essential oil constituents; Mahmoud AL; The effect of 20 essential oil constituents on Aspergillus flavus growth and aflatoxin production was tested at the level of 1000 ppm . Some of the tested oils exhibited inhibitory effects on fungal growth and toxin formation . Five oils, namely geraniol, nerol and citronellol (aliphatic oils), cinnamaldehyde (aromatic aldehyde) and thymol (phenolic ketone), completely suppressed growth and aflatoxin synthesis . Trials for determining the minimum inhibitory concentration (MIC) of these oils revealed that geraniol, nerol and citronellol were effective at 500 ppm, while thymol and cinnamaldehyde were highly effective at doses as low as 250 and 200 ppm, respectively . It was observed that citral, citronellol and eugenol prevented fungal growth and toxin formation for up to 8 d . However, after 15 d of incubation, toxin production was greater than the controls.

Antibiot Khimioter, 1994 Aug, 39(8), 37 - 40
{Cefoperazone in the prevention and treatment of experimental plague caused by typical and fraction-free pathogen strains in white mice}; Pasiukov VV et al.; The high susceptibility of the plague microbe to cefoperazone (MIC of 0.1-0.25 microgram/ml) did not depend on the causative agent ability to produce fraction I . Cefoperazone, a 3rd generation cephalosporin, was highly active in the treatment of experimental plague caused by the plague microbe strain typical in the antigen composition: the drug daily dose of 250-500 mg/kg provided an 80-100 percent survival of the albino mice . The efficacy of cefoperazone lowered when the infection was caused by the strain defective in the capsule antigen . The use of the antibiotic for more prolonged periods provided better results of the etiotropic therapy.

Proc Natl Acad Sci U S A, 1994 Jul 5, 91(14), 6259 - 63
A second lineage of mammalian major histocompatibility complex class I genes; Bahram S et al.; Major histocompatibility complex (MHC) class I genes typically encode polymorphic peptide-binding chains which are ubiquitously expressed and mediate the recognition of intracellular antigens by cytotoxic T cells . They constitute diverse gene families in different species and include the numerous so-called nonclassical genes in the mouse H-2 complex, of which some have been adapted to variously modified functions . We have identified a distinct family of five related sequences in the human MHC which are distantly homologous to class I chains . These MIC genes (MHC class I chain-related genes) evolved in parallel with the human class I genes and with those of most if not all mammalian orders . The MICA gene in this family is located near HLA-B and is by far the most divergent mammalian MHC class I gene known . It is further distinguished by its unusual exon-intron organization and preferential expression in fibroblasts and epithelial cells . However, the presence of diagnostic residues in the MICA amino acid sequence translated from cDNA suggests that the putative MICA chain folds similarly to typical class I chains and may have the capacity to bind peptide or other short ligands . These results define a second lineage of evolutionarily conserved MHC class I genes . This implies that MICA and possibly other members in this family have been selected for specialized functions that are either ancient or derived from those of typical MHC class I genes, in analogy to some of the nonclassical mouse H-2 genes.

Chemotherapy, 1994 Jul-Aug, 40(4), 245 - 51
Multicenter evaluation of ATB fungus: a standardized micromethod for yeast susceptibility testing; Quindos G et al.; The micromethod for yeast susceptibility testing, ATB Fungus, was evaluated with 30 reference strains in three laboratories . Ready-to-use strips with 5-fluorocytosine, amphotericin B, nystatin, miconazole, econazole and ketoconazole were used . The test allowed the categorization of each strain as susceptible, intermediate or resistance to all the antifungals tested, and 5-fluorocytosine and amphotericin B MIC determination . The results were compared with the MIC for each reference strain obtained by a microdilution method on RPMI 1640 buffered with MOPS . The repeatability and intralaboratory and interlaboratory reproducibility were evaluated . ATB Fungus was a reliable and reproducible method with a repeatability of 96.6%, a reproducibility of 95.4% and showed an excellent correlation 91.7%) with reference MICs.

Nippon Rinsho, 1994 Jul, 52(7), 1937 - 46
{Large scale multicenter cooperative study for cardiovascular therapy (Japan Multicenter Investigation for Cardiovascular Drugs/Therapies, J-MIC)--results and perspectives}; Kawai C et al.; With rapidly progressing therapeutic methods in the cardiovascular medicine, scientific evaluations for newly developed cardiovascular drugs and therapies have become mandatory . We have launched five large scale multicenter cooperative studies, namely, Japan Multicenter Investigation for Cardiovascular Drugs/Therapies, J-MIC (I), (B), (M), (S), and (K) . The aims of studies include to investigate: the best therapeutic approach in patients with acute myocardial infarction who underwent thrombolytic therapy with or without any adjunctive treatment (I), the long-term comparative study (3 years) of nifedipine (extended release tablet) with ACE inhibitor in patients with essential hypertension and ischemic heart disease (B), the long-term effect (3 years) of trapidil and/or ethyl icosapentate in patients with ischemic heart disease with or without arteriosclerotic obstructive disease in terms of progression or regression of atherosclerotic changes in coronary as well as peripheral arteries (M), the efficacy and safety of pravastatin to prevent post-PTCA restenosis (S), and regression of atherosclerotic lesion of coronary arteries in patients with familial hypercholesterolemia by LDL apheresis (K).

Leuk Res, 1994 Jul, 18(7), 493 - 7
Near-tetraploid poorly differentiated acute myeloid leukemia M0 diagnosed by short-term cultures with a phorbol ester TPA; Lemez P et al.; Leukemic blasts of two patients with acute leukemia exhibited similar characteristics . They were heterogeneous in size with a diameter of 14-30 microns in smears and unclassifiable by morphological, cytochemical, immunophenotypic and ultrastructural examinations . Cytogenetic examinations of both revealed a near-tetraploid karyotype . Blasts from both patients differentiated into macrophages in cultures with 10 ng/ml 12-O-tetradecanoylphorbol-13-acetate (TPA) which is a feature specific for myeloid blasts and the cases were thus classified as poorly differentiated acute myeloid leukemias (AML M0) . Near-tetraploid poorly differentiated acute myeloid leukemias M0 seem to be a special category of AML in the morphologic, immunologic and cytogenetic (MIC) classification . The presence of very large blasts in the heterogeneous blast population in acute unclassified leukemias could be a morphological sign of near-tetraploid leukemias AML M0.

Gynecol Oncol, 1994 Jul, 54(1), 19 - 22
Gastrostomy tubes after gynecologic oncologic surgery; Gleeson NC et al.; In order to prevent the complications of long-term nasogastric suctioning and increase patient comfort, we have been using gastrostomy tubes (G-tubes) in gynecologic oncology patients who are deemed to be at risk for protracted postoperative bowel dysfunction . This study describes our patient selection criteria and evaluates the results with 35 MIC (Medical Innovation Corporation, Milpitas, CA) gastrostomy tubes inserted between September 1, 1992 and April 30, 1993 . The procedure is technically easy and adds approximately 10 min to operating time . The tubes were well tolerated by the patients over periods ranging from 5 to 135 days . All tubes were used for postoperative gastric drainage and in addition, eight tubes were used for short-term enteral feeding . One patient with short bowel syndrome continued enteral nutritional supplementation at home . Twenty patients were discharged with their G-tubes in situ . Five of these patients required continuous gastric drainage because of obstruction of gastric emptying or small bowel by advanced tumor, and four of them were taking full liquids orally prior to discharge from the hospital . Gastrostomy tubes are convenient adjuncts to postoperative care of the gynecologic oncology patient and afford palliation with few complications to patients dying with bowel obstruction.

Antimicrob Agents Chemother, 1994 Jul, 38(7), 1604 - 7
Treatment of disseminated Torulopsis glabrata infection with DO870 and amphotericin B; Atkinson BA et al.; Torulopsis glabrata, an opportunist pathogen in immunosuppressed patients, is resistant to many antifungal agents, and there are no established treatment regimens for this organism . The mouse model was used to evaluate treatment with DO870, amphotericin B, fluconazole, and their combination . Mice were immunosuppressed with 5 mg of gold sodium thiomalate given intraperitoneally 1 day prior to intravenous infection with 10(8) T . glabrata cells . Treatment with a new antifungal triazole, DO870, at doses ranging from 1 to 50 mg/kg of body weight administered per os either daily or on alternate days; fluconazole at 100 mg/kg twice a day per os; or amphotericin B at 3 mg/kg/day intraperitoneally was begun 1 day after infection . Treatment for 5 days was followed by sacrifice 2 days later for determining CFU counts in spleen and kidney tissue . For a fluconazole-sensitive isolate (MIC of DO870, < 1.25 micrograms/ml), DO870 at 5 mg/kg/day significantly reduced counts in kidney and spleen tissue (P < 0.05), amphotericin B was modestly effective, and the combination of DO870 (25 mg/kg) and amphotericin B (3 mg/kg) was markedly more effective than either drug alone (P < 0.01) . Three additional isolates were resistant in vitro to DO870 (MIC, 4 micrograms/ml) . No reduction in CFU in kidney or spleen tissue was observed with DO870 when compared with counts in control tissue . DO870 is effective in vivo against at least some isolates of T . glabrata and when combined with amphotericin B can exert additive effects.

Antimicrob Agents Chemother, 1994 Jul, 38(7), 1588 - 9
Susceptibilities to clarithromycin and erythromycin of isolates of Chlamydia pneumoniae from children with pneumonia; Roblin PM et al.; We tested in vitro 49 isolates of Chlamydia pneumoniae obtained from 35 children with community-acquired pneumonia against clarithromycin and erythromycin . The children were part of a treatment study comparing the two drugs . Clarithromycin was 2- to 10-fold more active than erythromycin, with a MIC for 90% of strains tested and minimal chlamydiacidal concentration for 90% of strains tested of 0.031 microgram/ml compared with 0.125 microgram/ml for erythromycin . Eight of these children, two of whom were treated with erythromycin and six of whom received clarithromycin, remained culture positive after treatment . We were able to test 21 isolates from these children . All were susceptible to both drugs, and the MICs did not change after therapy.

Hautarzt, 1994 Jul, 45(7), 464 - 7
{Effect of anti-seborrhea substances against Pityrosporum ovale in vitro}; Nenoff P et al.; Thirty strains of the lipophilic yeast Pityrosporum ovale were isolated from patients suffering from seborrhoeic dermatitis and dandruff and tested for susceptibility both to some classic antifungal agents and to several primarily non-antimycotic drugs . Minimal inhibitory concentrations (MIC) of altogether eleven agents were measured by the agar dilution technique . As expected, the tested imidazoles showed a good inhibition of growth of Pityrosporum . The most effective agents were ketoconazole (MIC 0.1 microgram/ml) and itraconazole (MIC 0.05 microgram/ml for some strains) . MIC for fluconazole, clotrimazole and tioconazole were also low, indicating a good inhibition of Pityrosporum . In contrast, the range of MIC for bifonazole was moderate to high (for some strains 12.5-25 micrograms/ml) . For zinc pyrithion a very good in vitro efficacy (MIC 0.78-1.56 micrograms/ml) was dedicated . The MIC for selenium disulphide was 1.56-3.13 micrograms/ml . The antipsoriatic drugs dithranol and liquor carbonis detergens also inhibited growth of all Pityrosporum ovale strains investigated but only at higher concentrations.

Diagn Microbiol Infect Dis, 1994 Jul, 19(3), 179 - 81
Etest for susceptibility testing of Mycobacterium tuberculosis and Mycobacterium avium-intracellulare; Wanger A et al.; Methods currently used for susceptibility testing of Mycobacterium, including agar dilution and the Bactec radiometric method, are based on the proportion technique using a single critical concentration of antibiotic . Preliminary studies were conducted with Mycobacterium species by using the Etest method, a gradient minimum inhibitory concentration technique, well described for susceptibility testing of other fastidious and slow-growing organisms . Excellent correlation was demonstrated between Etest and agar dilution with rifampin-susceptible and -resistant isolates of M . tuberculosis and ciprofloxacin-resistant and -susceptible isolates of Mycobacterium avium-intracellulare.

Indian J Physiol Pharmacol, 1994 Jul, 38(3), 202 - 6
Histobiochemical changes in lung of protein deficient rats following repeated exposures of MIC vapour; Bose M et al.; Adult male albino rats, maintained on normal or protein deficient diets from weanling, were exposed to repeated doses of MIC vapour (0.32 mg/L for 8 min for 5 consecutive days) under static conditions . Histopathology and the activities of alkaline and acid phosphatases and GSH content of lung were studied upto day 14 after exposure . Mild but repeated exposures of MIC vapour caused severe pulmonary lesions like denudation of bronchiolar epithelial lining tissue, cellular infiltration, edema, emphysema followed by hyperplasia, hypertrophy, fibrosis and intraluminal fibroplasia . The activities of alkaline and acid phosphatases were increased at earlier intervals while GSH content decreased significantly and remained low throughout the experimental duration . Protein deficiency was found to aggravate the toxic potentials of MIC in present condition.

Mycoses, 1994 Jul-Aug, 37(7-8), 271 - 4
Aspergillus chevalieri (Mangin) Thom and Church: a new opportunistic pathogen of human cutaneous aspergillosis; Naidu J et al.; Three cases of opportunistic cutaneous aspergillosis caused by Aspergillus chevalieri are described . The lesions were erythematous and hyperkeratotic with vesicopapular eruptions and scaling . Histopathology revealed granulomatous reaction showing polymorphonuclear leucocytes around fungal hyphae, which were broad, septate, branched and aggregated in the epidermal area . Oxiconazole and amorolfine, with a minimum inhibitory concentration of 10 micrograms ml-1, were the most active drugs against A . chevalieri 'in vitro' . A . chevalieri is, for the first time, documented as opportunistic pathogen of man.

Semin Oncol, 1994 Jun, 21(3 Suppl 4), 34 - 41
Trials of radical radiotherapy versus chemotherapy plus radical radiotherapy in non-small cell lung cancer; Cullen MH; Currently available treatments for patients with inoperable non-small cell lung cancer have had little impact on long-term survival . Cisplatin-containing chemotherapy regimens have achieved the best response rates (ie, 30% to 50%) in this disease, but trials using these have, for the most part, been too small to detect significant improvements in survival . Two randomized trials have shown a significant impact on survival, including the largest trial published to date (353 cases) . Other trials have shown a trend in favor of the combined-modality arm . The only two trials with a trend in favor of radiotherapy alone were those with the smallest number of randomized cases (48 and 65 patients) . A meta-analysis of trials of cisplatin-containing chemotherapy plus radiotherapy versus radiotherapy alone is thus likely to show a small survival advantage for the combined-modality approach when published in early 1994 . In addition, a multicenter trial of mitomycin/ifosfamide/cisplatin (MIC) plus radiotherapy versus radiotherapy alone being performed in the United Kingdom is expected to accrue 500 patients . Preliminary results obtained in 150 patients randomized to receive the combined modality show an objective response rate to chemotherapy of 51%, which supports the findings of the phase 2 study using this regimen . Moreover, both responders and nonresponders to MIC experienced symptomatic improvement (a parameter largely ignored in previous trials) following treatment . Consequently, the MIC trial will be large enough to detect worthwhile survival improvements, should they exist, as well as illustrate the impact of treatment on patients' symptoms.

Antimicrob Agents Chemother, 1994 Jun, 38(6), 1402 - 3
In vitro activities of OPC-17116, a new quinolone; ofloxacin; and sparfloxacin against Chlamydia pneumoniae; Roblin PM et al.; The in vitro susceptibilities of 12 strains of Chlamydia pneumonia to a new quinolone, OPC-17116; ofloxacin; and sparfloxacin were determined . OPC-17116 was slightly less active than sparfloxacin but more active than ofloxacin, with a MIC for 90% of strains tested and a minimal chlamydiacidal concentration for 90% of strains tested of 0.5 micrograms/ml.

Antimicrob Agents Chemother, 1994 Jun, 38(6), 1284 - 91
Characterization of fluoroquinolone-resistant mutants of escherichia coli selected in vitro; Heisig P et al.; Wild-type mutants highly resistant to fluoroquinolones were selected in vitro from a quinolone-susceptible Escherichia coli isolate by stepwise exposure to increasing concentrations of nalidixic acid and ciprofloxacin (CIP) either in liquid medium or on solid medium . Mutant R17 was selected by serial passage in liquid medium; the MIC of CIP for mutant R17 was 256 micrograms/ml . On solid medium, consecutive mutants MI, MII, MIII, MIVa, and MIVb were selected in four steps . The frequencies of mutations were between 10(-9) and 10(-11), and the MICs of CIP ranged from 0.5 microgram/ml (for mutant MI) to 256 micrograms/ml (for mutant MIVb) . From the results of a dominance test with the gyrB+ plasmid (pBP547), no gyrB mutations were detectable . In the first step, mutant MI, a mutation from a Ser to a Leu residue at position 83 (a Ser-83-->Leu mutation), was detected in the quinolone resistance-determining region of the gyrA gene . In addition, the second-step mutation was associated with a reduced uptake of CIP and an altered outer membrane protein profile . The third mutation was identified as an Asp-87-->Gly mutation in the quinolone resistance-determining region of the gyrA gene . Concomitantly, a slight increase in the doubling time was detected . For two different four-step mutants, mutants MIVa and MIVb, the MICs of only some quinolones, including CIP, increased . The accumulation of CIP in the mutants was comparable to that in their parent MIII . The doubling time of mutant MIVa was similar to that of mutant MIII, but differed by a factor of 3 from that of the very slow growing mutant MIVb . In contrast, a clinical isolate of E.coli (isolate 205096) described previously (P . Heisig, H . Schedletzky, and H . Falkenstein-Paul, Antimicrob . Agents Chemother . 37:696-701, 1993) which has the same double mutation in gyrA had a doubling time comparable to that of the wild-type isolate.

Nippon Eiseigaku Zasshi, 1994 Jun, 49(2), 616 - 20
{Effects of mercury compounds on growth, cell composition and glucose uptake in Tetrahymena pyriformis}; Fukuda M; The effects of the mercuric compounds methylmercuric chloride (MMC) and mercuric chloride (MC) on growth, cell composition, and glucose uptake were studied in the ciliate protozoan Tetrahymena pyriformis GL . MMC was the most effective growth inhibitor of Tetrahymena among mercuric compounds and sulfhydryl inhibitors; it completely inhibited growth of Tetrahymena at concentrations of 1/30-1/3000 of the others . The growth inhibition of Tetrahymena was inversely proportional to concentrations of chemicals in medium . Particularly in the case of MMC and MC the relationship between the concentrations and growth were S-curved in shape . Contents of RNA and DNA in cells were shown to accumulate proportionally to the MMC concentration . Cell division was probably delayed by MMC . The value of the ratio of RNA to DNA content shown by DNA synthesis was inhibited more strongly than RNA at MIC/4 of MMC . MMC inhibited glucose uptake, and the inhibition was likely due to altered permeability of cell membranes . However, no difference was found in lipid compositions between control and MMC cells by thin-layer chromatography.

Am J Respir Crit Care Med, 1994 Jun, 149(6), 1452 - 6
Refractory period during provocation with eucapnic hyperventilation and methacholine; Hurwitz KM et al.; Eucapnic voluntary hyperventilation (EVH) and methacholine inhalation challenge (MIC) both cause bronchoconstriction in asthmatics . A refractory period, or time when the response to bronchoprovocation in a series of challenges is diminished, has been found after hyperventilation or exercise but not after MIC . We investigated whether EVH or MIC blunted the response to the other test . Sixteen asthmatics were studied on 2 d, taking both tests each day . They were randomized to either EVH or MIC first on Day 1, then the opposite order on Day 2, 6 to 14 d apart . After EVH as a first test, the mean decline in FEV1 from baseline was 18.66 +/- 4.76% (mean +/- SEM), but when EVH followed MIC, the response to EVH was reduced by 30%, to a decline in FEV1 of only 13.02 +/- 3.75% (p = 0.0026) . During MIC, the mean provocation dose to cause 20% decrease in FEV1 (PD20) given as the initial challenge was 54.77 +/- 21.60 breath units, compared with 46.94 +/- 19.55 breath units when MIC followed EVH (p = 0.54) . However, the subset of patients most sensitive to methacholine (PD20 < 0.1 breath unit) had changes suggestive of a refractory period after EVH, with a mean increase in the PD20 from 0.06 +/- 0.01 to 3.35 +/- 1.43 (p = 0.069) . Our data show that MIC attenuates the response to subsequent challenge with EVH . Conversely, EVH may only affect subsequent MIC in those most sensitive to methacholine.

Tuber Lung Dis, 1994 Jun, 75(3), 208 - 12
In vitro and in vivo synergistic effect of isoniazid with streptomycin and clofazimine against Mycobacterium avium complex (MAC); Reddy MV et al.; SETTING: Isoniazid (INH), the powerful antituberculosis drug, has also been used in regimens for treating disease caused by Mycobacterium avium complex (MAC), an important opportunistic pathogen encountered in AIDS patients . Its use for treatment of MAC disease has also been endorsed by the American Thoracic Society . However some controversy has emerged recently in medical literature, discounting its role and even implying that its use is contraindicated in chemotherapy of MAC disease . OBJECTIVE: In view of the controversy, we investigated its in vitro and in vivo activity in combination with streptomycin (SM) and clofazimine (CFM) against MAC . DESIGN: In the in vitro studies, the minimal inhibitory concentrations (MIC) of individual drugs or combinations of INH and SM as well as INH and CFM were determined in a checker-board type study by both conventional and radiometric (BACTEC) methods . In vivo studies assessed the efficacy of chemotherapy with INH alone or in combination with either SM or CFM against MAC infection in beige mice . RESULTS AND CONCLUSIONS: While MICs of INH and SM were 12.5 micrograms/ml and 6.25 micrograms/ml respectively, complete inhibition of growth was seen at 1.56 micrograms/ml with the combination of both drugs . The synergistic effect was observed both in conventional and BACTEC methods . In vivo studies demonstrated elevated activity when INH was given along with SM or CFM . Based on these observations we stress that isoniazid has still a place in chemotherapy of MAC disease, at least until other potent drugs are discovered.

Am J Respir Crit Care Med, 1994 May, 149(5), 1335 - 41
Initial clarithromycin monotherapy for Mycobacterium avium-intracellulare complex lung disease; Wallace RJ Jr et al.; Sputum conversion rates in Mycobacterium avium-intracellulare (MAI) complex lung disease have ranged from only 50 to 80% despite the use of three to five antituberculosis agents . We initiated a prospective, open, noncomparative trial of initial clarithromycin monotherapy at 500 mg twice a day for 4 months in HIV-negative patients with MAI lung disease . The primary study end point was microbiologic improvement . Of 30 patients enrolled, 20 completed therapy . This latter group was predominantly male (60%), smokers (70%), older than 45 yr of age (90%), infected with Mycobacterium intracellulare (70%) and with bilateral disease (85%) . Of 19 patients with pretreatment minimum inhibitory concentrations (MIC) for clarithromycin < 16 micrograms/ml, 58% became sputum-negative, and 21% showed significant reductions in sputum positivity . Heavily positive sputum cultures (> 200 colonies) were reduced from 30 to 47 samples pretherapy (64%) to three of 54 (6%) post-therapy (p < 0.0001); 18 of 19 patients (95%) showed an improvement in sputum cultures, chest radiographs, or both . Only two patients (7%) discontinued the drug because of adverse events . Only three (16%) of 19 isolates developed clarithromycin resistance (MIC > 32 micrograms/ml) . Clarithromycin-susceptible and -resistant MAI isolates from the same patient had identical DNA large-restriction fragment patterns . Clarithromycin is the first single agent to be shown efficacious in the treatment of MAI lung disease.

Eur J Clin Microbiol Infect Dis, 1994 May, 13(5), 406 - 9
Culture of Helicobacter pylori under aerobic conditions on solid media; Xia HX et al.; The aim of the present study was to culture Helicobacter pylori under aerobic conditions and to investigate the characteristics of the organism when cultured aerobically . Most (22 of 23) of the Helicobacter pylori isolates grew under aerobic conditions, but with reduced viable cell counts . Blood agar was more suitable than chocolate agar . The morphological and enzymatic characteristics as well as the protein profiles of each organism were identical under aerobic and microaerophilic conditions . However, haemolysis of Helicobacter pylori was delayed under aerobic conditions . The MIC of metronidazole was slightly lower for some strains under aerobic conditions . These findings indicate that Helicobacter pylori is not only a microaerophilic organism but also adapts to aerobic conditions, which may have some important implications in microbiological and epidemiological studies.

Antimicrob Agents Chemother, 1994 May, 38(5), 1200 - 2
Rifabutin and sparfloxacin but not azithromycin inhibit binding of Mycobacterium avium complex to HT-29 intestinal mucosal cells; Bermudez LE et al.; Organisms of the Mycobacterium avium complex (MAC) cause disseminated disease in patients with AIDS, and evidence points to the gastrointestinal tract as the major route of infection . Since MAC can bind to and invade intestinal mucosal cells, we examined whether subinhibitory concentrations of antibiotics which have anti-MAC activity in vitro affect the interaction between MAC and HT-29 intestinal mucosal cells . MAC isolates were exposed to subinhibitory concentrations of rifabutin (MIC, 2.6 micrograms/ml), sparfloxacin (MIC, 8.4 micrograms/ml), or azithromycin (MIC, 32 micrograms/ml) for 30 to 120 min, washed, and incubated with HT-29 cell monolayers for 2 h at 4 degrees C . HT-29 cell monolayers were then washed to remove unbound bacteria and were subsequently lysed . The number of MAC isolates that bound to the HT-29 cells was determined by plating the cell lysate onto 7H10 agar . Preincubation of the MAC isolates with rifabutin at concentrations of 1 and 2 micrograms/ml reduced MAC binding to HT-29 cells by 80 to 90%, while MAC exposed to sparfloxacin at 1 and 7 micrograms/ml inhibited binding by 77 to 93% . Azithromycin at concentrations of 2, 10, and 30 micrograms/ml had no effect on MAC binding to HT-29 cells . Inhibition of MAC binding to the gastrointestinal mucosa may be one underlying mechanism for the prophylactic effects of rifabutin and quinolones.

Diagn Microbiol Infect Dis, 1994 May, 19(1), 9 - 13
Multicenter comparison of a colorimetric microdilution broth method with the reference macrodilution method for in vitro susceptibility testing of yeast isolates; Pfaller MA et al.; This multicenter study was performed to compare a colorimetric microdilution method with the NCCLS M27-P reference macrodilution method for the testing of yeast isolates against amphotericin B, fluconazole, and 5-fluorocytosine (5FC) . Testing was performed on ten yeast isolates in five independent laboratories . All sites tested each isolate a total of 20 times with both methods . MICs were read after 48 h incubation . The macrodilution MIC reference range was defined as the modal MIC +/- 1-log2 dilution for each organism-antifungal agent combination . Agreement between the M27-P reference range results and the microdilution MICs was 86% with amphotericin B, 90% with fluconazole, and 93% with 5FC . Based on these data, it is apparent that new approaches, such as the colorimetric microdilution method, will provide MIC values comparable to the M27-P macrodilution method in a format that is more practical for use in a busy clinical laboratory.

Indian J Med Res, 1994 May, 99, 231 - 5
Acute histopathological changes induced by methyl isocyanate in lungs, liver, kidneys & spleen of rats; Jeevaratnam K et al.; Methyl isocyanate (MIC), inhaled or administered subcutaneously (sc) at lethal concentration/dose caused essentially similar histopathological changes in all the viscera except for the lungs . The observed congestion of the viscera, foci of hepatocellular necrosis with widening of Disse's spaces in the liver and tubulo-rhexis with degeneration in the kidneys are attributable mostly to the initial shock . In addition, the lungs revealed more distinct route specific patterns of histopathological lesions . Inhaled MIC caused acute eosinophilic necrosis of the bronchial epithelium and frank alveolar edema, while MIC administered sc led to prominent vascular endothelial damage and severe interstitial pneumonitis with normal bronchial epithelium . The differential loci of damage in the lungs may be attributed to the immediate contact surface available for interaction with MIC.

Rev Prat, 1994 Apr 15, 44(8), 1068 - 73
{Resistance of pneumococcus}; Goldstein FW; Resistance of S . pneumoniae to penicillin G and other useful antibiotics has sharply increase during the last years in many countries and especially in France . Resistance to penicillin G is due to an unpredictable qualitative and quantitative modification of several penicillin binding proteins . All the beta-lactams are affected but the level of cross-resistance depends upon the affinity of the beta-lactam for the modified penicillin binding proteins . As a consequence, the minimal inhibitory concentration of penicillin G and other useful beta-lactams have to be determined against S . pneumoniae isolated from serious infection, responsible for a clinical failure or resistant to penicillin G.

Pathologe, 1994 Apr, 15(2), 103 - 12
{Molecular genetic detection of t(11;22)(q24;12) translocation in Ewing sarcoma and malignant peripheral neuroectodermal tumors}; Dockhorn-Dworniczak B et al.; Ewing's sarcomas and malignant peripheral neuroectodermal tumors (MPNTs) show very little evidence of differentiation and lack characteristic morphological features at the light-microscopic level . These malignancies have always presented a significant differential diagnostic challenge to the pathologist . Electron microscopy, immunohistochemical staining for neural antigens such as neuron-specific enolase (NSE), Leu 7, synaptophysin and, more recently, the detection of Mic-2 gene expression have been included in the routine histopathological diagnostic procedure . However, the expression of these antigens is not restricted to this entity . Thus, further modalities are required to prove diagnostic reliability . One consistent feature of the Ewing's sarcoma family is the presence of the reciprocal chromosomal t(11;22)(q24;q12) translocation . Recent cloning of the t(11;22) break point has led to the identification of the genes involved in this translocation . This provides the possibility of molecular genetic detection of the t(11;22) translocation in Ewing's sarcomas and MPNTs . We have established a method using reverse transcription and the polymerase chain reaction (RT-PCR) for the detection of the specific gene fusion transcript caused by the 11;22 translocation . The validity of our approach was proved by analyzing Ewing's tumor cell lines and tissue material obtained from primary biopsies and tumor resections . Molecular genetic detection of the 11;22 translocation by RT-PCR analysis should perhaps be included in the diagnostic work-up of suspected Ewing's sarcoma and MPNT.

FEMS Microbiol Lett, 1994 Apr 1, 117(2), 203 - 6
Effects of sub-minimal inhibitory concentrations of EDTA on growth of Escherichia coli and the release of lipopolysaccharide; Pelletier C et al.; Release of lipopolysaccharide from E . coli was studied in the presence of sub-minimal inhibitory concentrations of ethylenediaminetetraacetic acid (EDTA) . In untreated cells no release was detected with 50 mM Mg2+ in the medium, but a steady release of over 50% of the synthesized lipopolysaccharide was observed with 0.1 mM Mg2+ . EDTA at MIC/8 led to a 2- to 3-fold higher release, presumably by an adjustment of the concentration of unchelated Mg2+ to a value still sustaining normal growth but giving rise to a highly unstable outer membrane . No structural difference was observed between cell-bound and released lipopolysaccharide.

Gynecol Oncol, 1994 Apr, 53(1), 109 - 13
Conservative therapy for microinvasive carcinoma of the uterine cervix; Ueki M et al.; The purpose of this study was to evaluate conservative therapy for microinvasive carcinoma (MIC) of the cervix . Large contact Nd-YAG laser conization (laser cone) with contact vaporization using contact probes was performed on 90 cases of MIC and 21 cases of early invasive carcinoma (early IC), with long-term postoperative follow-up for patients at Osaka Medical College, Osaka, Japan . The cure rates of MIC and early IC were 96.7 and 80.9%, respectively . The rates of incomplete excision and true residuation in cases with MIC were 17.8 and 10.0% and those in cases with early IC were 76.2 and 19.0% . Therefore, the spontaneous cure rate following incomplete excision of MIC and early IC was 43.7 and 75.0% . Hysterectomy was performed, for various indications, after cone in 5 patients (5.6%) with MIC, none of the patients with IC of less than 3 mm, 2 (22.2%) of the patients with IC of 3.1 to 5 mm, and 7 patients (87.5%) whose IC was 5.1 mm or more in depth . Combining the data from our department and those in the literature collected an incidence of lymph node metastasis of 0.15% for MIC and of 1.13% of IC of less than 5 mm . In conclusion, conservative therapy is indicated for MIC, and the contact laser cone with contact vaporization is considered to be an excellent therapeutic conservative method.

Nippon Ganka Gakkai Zasshi, 1994 Apr, 98(4), 352 - 6
{Conservative therapy for retinoblastoma--effect of melphalan on in vitro electroretinogram}; Ueda M et al.; The effect of melphalan (an alkylic anti-cancer drug) on rabbit and human in vitro ERGs was studied to establish the non-toxic concentration of melphalan in chemo-thermotherapy for retinoblastoma . The ERGs were recorded before and 15 min after the perfusate was changed from the control solution to a melphalan-containing solution . Melphalan 10 micrograms/ml and 40 micrograms/ml caused no significant effect on the a-wave, the b-wave, or the oscillatory potential in either the rabbit or the human in vitro ERG . Melphalan 50 micrograms/ml significantly reduced the b-wave, but the change was reversible . Considering the minimum inhibitory concentration of melphalan against retinoblastoma cells on colony assay (4 micrograms/ml), melphalan is one of the most effective drugs for the conservative treatment of retinoblastoma.

Chest, 1994 Apr, 105(4), 1082 - 8
Retrospective analyses of methacholine inhalation challenges; Goldstein MF et al.; We retrospectively analyzed 198 methacholine inhalation challenges (MICs) of symptomatic patients with normal results of lung examinations, spirometry, and chest radiographs . During MIC, five parameters (FEV1, FEF25-75%, FVC, sGaw, TGV) were measured . Using established changes in these parameters at < or = 8 mg/ml methacholine, there were 175 positive tests (no false positives) and 23 negative tests (15 true negatives, 5 false negatives, and 3 unavailable for follow-up) . The MIC sensitivity determined by FEV1 responses was significantly lower than the sensitivity using responses in either three (FEV1, FEF25-75%, and FVC; p < 0.001) or five (FEV1, FEF25-75%, FVC, sGaw, and TGV; p < 0.001) parameter sets . Sensitivities were 60.6 percent, 91.1 percent, and 97.2 percent, respectively . All positive MICs (100 percent) were identified by examining changes in the five-parameter set vs 97.3 percent in the three-parameter set; it was a significant difference at p < 0.01 . We conclude that the measurement and analysis of non-FEV1 parameters in addition to FEV1 significantly increases the sensitivity of the MIC.

J Med Microbiol, 1994 Apr, 40(4), 252 - 5
Effect of inoculum size on the in-vitro susceptibility to beta-lactam antibiotics of Moraxella catarrhalis isolates of different beta-lactamase types; Yeo SF et al.; The effect of inoculum size on the results of agar dilution MIC tests was assessed for 20 Moraxella catarrhalis isolates with BRO-1 enzyme, 20 with BRO-2 enzyme and 15 isolates that did not produce beta-lactamase . The compounds tested were ampicillin, coamoxiclav, cefaclor, cefixime and cefetamet, and the inocula were 10(4), 10(5), 10(6) and 10(7) cfu/spot . The MICs of ampicillin for BRO-1 and BRO-2 producers were consistently higher than those for non-producers at inocula of 10(7) cfu/spot but overlapped with those for non-producers at lower inocula . A small beta-lactamase-related inoculum effect was seen with coamoxiclav; small inoculum effects also occurred with cefaclor and cefixime but were not related to enzyme presence or type . MICs of cefetamet were the least affected by the inoculum size . For all the compounds, the degree of correlation between MICs and the inhibition zones observed in disk diffusion tests was independent of the inoculum used in the MIC tests . These data suggest that high inocula should be used to determine MICs of ampicillin for M . catarrhalis but that this precaution is unnecessary with the cephalosporins tested or with coamoxiclav.

J Antimicrob Chemother, 1994 Apr, 33(4), 757 - 64
In-vitro activity of six intracellular antibiotics against Legionella pneumophila strains of human and environmental origin; Reda C et al.; The activity of six intracellular antibiotics, doxycycline, erythromycin, clarithromycin, azithromycin, rifampicin and ciprofloxacin, was tested against 60 strains of Legionella pneumophila (21 of human and 39 of environmental origin) . MIC50, MIC90, and MBC values were determined by a microdilution method . Inhibitory and bactericidal activity against human and environmental isolates were similar except for rifampicin, which was 100-fold less active for human strains than for environmental strains, particularly in terms of bactericidal activity . Nevertheless, in general, rifampicin was found to be the most active drug . Among the macrolides tested, clarithromycin showed the greatest activity in MIC assays and erythromycin was the least bactericidal . Azithromycin showed higher MICs and MBCs than the two macrolides, and doxycycline was the least active . The most important factors influencing in-vivo activity of antibiotics are discussed . Even if the in-vitro results cannot be fully extrapolated to activity in vivo, these results indicate the susceptibility of L . pneumophila strains in Italy as a basis for treatment of atypical pneumonia that may be due to Legionella spp.

Med Sci Law, 1994 Apr, 34(2), 106 - 10
Isolation of an unknown compound, from both blood of Bhopal aerosol disaster victims and residue of tank E-610 of Union Carbide India Limited--chemical characterization of the structure; Chandra H et al.; A total of more than 28 chemical entities/reaction products in the form of gases, vapour and particulate matter were reported from the tank E-610 of methyl isocyanate (MIC) storage tank of Union Carbide India Limited on the night of 2/3 December 1984 in Bhopal . In earlier studies, methyl isocyanate and its trimer, with a few other compounds, were reported in the human victims preserved in deep freeze . Randomly selected samples were analysed by gas chromatograph coupled with mass spectrometer (ITD-800, Finnigan MAT, UK) . Four of the cases showed the peaks and fragmentation pattern identified with one of the unidentified compound of molecular weight 269 amu in the Tank Residue, which constituted about 0.2 area per cent on GC-ITD . After isolation by column chromatography and being exposed to characterization, it was identified as a Spiro compound . It was possibly formed by the polymerization of five molecules of methyl isocyanate.

Genetika, 1994 Apr, 30(4), 445 - 51
{Plasmid genes participating in the synthesis of microcin C51}; Basiuk EI et al.; Microcin C51 is an antibiotic with a wide application range produced by Escherichia coli cells . Using insertions of transposon Tn5 a set of mutations was induced in the recombinant plasmid pAST, which determines synthesis of microcin C51 . The mutations were physically mapped . Complementation analysis was performed for insertions and deletions in the Mic+ plasmids pAST and pUHAB that lead to the absence of microcin or immunity to it . The analysis showed that at least three plasmid genes take part in microcin production and two genes determine immunity of producer cells to microcin . Functioning of the ompR gene product was necessary for synthesis of microcin C51.

Antimicrob Agents Chemother, 1994 Apr, 38(4), 805 - 11
The rpoB gene of Mycobacterium tuberculosis; Miller LP et al.; A portion of the Mycobacterium tuberculosis gene encoding the beta subunit of RNA polymerase (rpoB) was amplified by PCR using degenerate oligonucleotides and used as a hybridization probe to isolate plasmid clones carrying the entire rpoB gene of M . tuberculosis H37Rv, a virulent, rifampin-susceptible strain . Sequence analysis of a 5,084-bp SacI genomic DNA fragment revealed a 3,534-bp open reading frame encoding an 1,178-amino-acid protein with 57% identity with the Escherichia coli beta subunit . This SacI fragment also carried a portion of the rpoC gene located 43 bp downstream from the 3' end of the rpoB open reading frame; this organization is similar to that of the rpoBC operon of E . coli . The M . tuberculosis rpoB gene was cloned into the shuttle plasmid pMV261 and electroporated into the LR223 strain of Mycobacterium smegmatis, which is highly resistant to rifampin (MIC > 200 micrograms/ml) . The resulting transformants were relatively rifampin susceptible (MIC = 50 micrograms/ml) . Using PCR mutagenesis techniques, we introduced a specific rpoB point mutation (associated with clinical strains of rifampin-resistant M . tuberculosis) into the cloned M . tuberculosis rpoB gene and expressed this altered gene in the LR222 strain of M . smegmatis, which is susceptible to rifampin (MIC = 25 micrograms/ml) . The resulting transformants were rifampin resistant (MIC = 200 micrograms/ml) . The mutagenesis and expression strategy of the cloned M . tuberculosis rpoB gene that we have employed in this study will allow us to determine the rpoB mutations that are responsible for rifampin resistance in M . tuberculosis.

Antimicrob Agents Chemother, 1994 Apr, 38(4), 773 - 80
Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations; Takiff HE et al.; The emergence of multidrug-resistant strains of Mycobacterium tuberculosis has resulted in increased interest in the fluoroquinolones (FQs) as antituberculosis agents . To investigate the frequency and mechanisms of FQ resistance in M . tuberculosis, we cloned and sequenced the wild-type gyrA and gyrB genes, which encode the A and B subunits of the DNA gyrase, respectively; DNA gyrase is the main target of the FQs . On the basis of the sequence information, we performed DNA amplification for sequencing and single-strand conformation polymorphism analysis to examine the presumed quinolone resistance regions of gyrA and gyrB from reference strains (n = 4) and clinical isolates (n = 55) . Mutations in codons of gyrA analogous to those described in other FQ-resistant bacteria were identified in all isolates (n = 14) for which the ciprofloxacin MIC was > 2 micrograms/ml . In addition, we selected ciprofloxacin-resistant mutants of Mycobacterium bovis BCG and M . tuberculosis Erdman and H37ra . Spontaneously resistant mutants developed at a frequency of 1 in 10(7) to 10(8) at ciprofloxacin concentrations of 2 micrograms/ml, but no primary resistant colonies were selected at higher ciprofloxacin concentrations . Replating of those first-step mutants selected for mutants with high levels of resistance which harbored gyrA mutations similar to those found among clinical FQ-resistant isolates . The gyrA and gyrB sequence information will facilitate analysis of the mechanisms of resistance to drugs which target the gyrase and the implementation of rapid strategies for the estimation of FQ susceptibility in clinical M . tuberculosis isolates.

J Clin Microbiol, 1994 Apr, 32(4), 1104 - 6
Preliminary interpretive susceptibility testing criteria for FK-037 with 30-microgram disks; Jones RN; FK-037, a new parenteral cephalosporin, was tested against 483 organisms from clinical infections to establish preliminary susceptibility testing criteria with 30-micrograms disks . The proposed breakpoint zone diameters were > or = 17 mm (MIC correlate, < or = 8 micrograms/ml) for the susceptible category and < or = 13 mm (MIC correlate, > or = 32 micrograms/ml) for the resistant category . These interpretive guidelines produced no very major (false-susceptible) errors, 2.9% major (false-resistant) errors, and 6.2% minor errors for a total absolute agreement between methods of 90.9%.

Appl Environ Microbiol, 1994 Apr, 60(4), 1101 - 5
Evaluation of some essential oils for their toxicity against fungi causing deterioration of stored food commodities; Mishra AK et al.; During screening of essential oils for their antifungal activities against Aspergillus flavus, the essential oil of Cymbopogon citratus was found to exhibit fungitoxicity . The MIC of the oil was found to be 1,000 ppm, at which it showed its fungistatic nature, wide fungitoxic spectrum, nonphytotoxic nature, and superiority over synthetic fungicides, i.e., Agrosan G . N., Thiride, Ceresan, Dithane M-45, Agrozim, Bavistin, Emison, Thiovit, wettable sulfur, and copper oxychloride . The fungitoxic potency of the oil remained unaltered for 7 months of storage and upon introduction of high doses of inoculum of the test fungus . It was thermostable in nature with treatment at 5 to 100 degrees C . These findings thus indicate the possibility of exploitation of the essential oil of C . citratus as an effective inhibitor of storage fungi.

Indian J Pathol Microbiol, 1994 Apr, 37(2), 179 - 83
S . typhi with transferable chloramphenicol resistance isolated in Chandigarh during 1983-87; Kapil A et al.; Plasmid mediated chloramphenicol resistance in S . Typhi has been reported since the outbreak in Kerala in 1972 from India . 876 strains of S . typhi isolated at Chandigarh during Jan 1983 to July 1987 were investigated for the incidence of chloramphenicol resistance . In 1983 34% of the total isolated were resistant to chloramphenicol, in 1984 24%, during 1985 5% & while in 1986 2% of the strains showed chloramphenicol resistance . The resistant strain showed chloramphenicol resistance . The resistant strains had an minimum inhibitory concentration of 64-128 ug/ml for chloramphenicol . All the resistant strains showed multiple drug resistance with the resistance pattern CSSuT . Of these 50 strains were studied for their mechanism of resistance by conjugation experiments which showed that CSSUT pattern could be transferred to E . coli J-53 and E . coli J-62 in primary and secondary transfer experiments indicating that the resistance was carried on a transferable plasmid.

Eur J Ophthalmol, 1994 Apr-Jun, 4(2), 115 - 7
Human vitreous penetration of imipenem; Adenis JP et al.; The purpose of this study was to determine imipenem concentrations in vitreous humor of non-infected human eyes . Ten patients undergoing vitrectomy were infused with a single dose of either 0.5g (5 patients) or 1g (5 patients) of imipenem . Vitreous humor was withdrawn 2 or 4 hours after the end of the infusion . Results differed in relation to the dose . After 0.5g, vitreous levels were stable (approximately 0.20 mg/l), but after 1g they were significantly higher (approximately 2 mg/l) . These levels were above the minimum inhibitory concentration of imipenem for 90% (MIC 90) of the main species responsible for endophthalmitis.

J Clin Invest, 1994 Apr, 93(4), 1670 - 6
Treatment with oral clotrimazole blocks Ca(2+)-activated K+ transport and reverses erythrocyte dehydration in transgenic SAD mice . A model for therapy of sickle cell disease; De Franceschi L et al.; Prevention of red cell K+ and water loss is a therapeutic strategy for sickle cell disease . We have investigated in vitro and in vivo the effects of clotrimazole (CLT) and miconazole (MIC) on transgenic mice red cells expressing hemoglobin SAD . CLT blocked the Gardos channel (ID50 75 +/- 22 nM; n = 3) and the A23187-induced dehydration of Hbbs/Hbbthal SAD 1 mouse erythrocytes in vitro . Oral treatment with CLT (160 mg/kg per d) and MIC (100 mg/kg per d) inhibited the Gardos channel in both SAD 1 and control (Hbbs/Hbbthal) mice . In the SAD 1 mice only, cell K+ content increased, and mean corpuscular hemoglobin concentration and cell density decreased . After 7 d of treatment, the hematocrit of SAD 1, CLT-treated animals also increased . All changes were fully reversible . Long-term treatments of SAD 1 mice with oral CLT (80 mg/kg per d for 28 d) lead to sustained increases in cell K+ content and hematocrit and sustained decreases in mean corpuscular hemoglobin concentration and cell density, with no changes in animals treated with vehicle alone . Thus, CLT and MIC can reverse dehydration and K+ loss of SAD 1 mouse erythrocytes in vitro and in vivo, further supporting the potential utility of these drugs in the treatment of sickle cell anemia.

Biochem Pharmacol, 1994 Mar 29, 47(7), 1197 - 206
Selective and irreversible inhibition of glutathione reductase in vitro by carbamate thioester conjugates of methyl isocyanate; Jochheim CM et al.; Exposure of yeast glutathione reductase (GR) in vitro to S-(N-methylcarbamoyl)glutathione (SMG) and S-(N-methylcarbamoyl)cysteine (SMC), two carbamoylating metabolites of methylisocyanate (MIC), led to a time-dependent, irreversible loss of enzyme activity (50-90%) over a period of 3 hr . The extent of inhibition was dependent upon the concentration of these carbamate thioester conjugates (0.1 to 1.0 mM) and on the presence of NADPH (100 microM) . Omission of NADPH markedly attenuated the inhibitory effects of both SMG and SMC, while oxidized glutathione (GSSG), the natural substrate of the enzyme, protected against the inhibition . Parallel experiments with the antineoplastic drug N,N'-bis-(2-chloroethyl)-N-nitrosourea (BCNU), a carbamoylating agent which is known to inhibit GR selectively, gave results that were similar to those obtained with the above conjugates . When analogs of SMG and SMC labeled with 14C in the carbamoyl group were incubated with GR, radioactivity became bound covalently to the enzyme . These findings, together with the results of kinetic experiments on the release of GSH from SMG and cysteine from SMC, suggested that while both conjugates inhibit GR by carbamoylation of an active-site thiol(s), SMG exhibits a greater affinity for the active site than SMC . In contrast to the studies with GR, SMG and SMC failed to inhibit either glutathione-S-transferase (GST) or glutathione peroxidase (GPO) enzymes in vitro . It is concluded, therefore, that these conjugates most likely inhibit GR by carbamoylating free thiol groups in the active site of this enzyme, which are absent (or inaccessible) at the active-site of GST and GPO.

Chest, 1994 Mar, 105(3), 667 - 72
Eucapnic voluntary hyperventilation as a bronchoprovocation technique . Comparison with methacholine inhalation in asthmatics; Roach JM et al.; Methacholine inhalation challenge (MIC) is probably the most widely used and best standardized test for nonspecific bronchoprovocation challenge (BPC) . There has been increasing interest in developing "physical" stimuli such as eucapnic voluntary hyperventilation (EVH) with dry gas to assess airway hyperreactivity (AHR), because of inherent problems with using a pharmacologic agent in epidemiologic surveys . To our knowledge, no studies exist that compare MIC with EVH in known asthmatics . We conducted a prospective, randomized, crossover trial with a group of subjects (n = 16) who met the American Thoracic Society definition of asthma with these objectives: (1) to compare the sensitivity of EVH with MIC; (2) to compare the quantitative response of one test with the response to the other challenge; and (3) to correlate the response of both tests with symptoms, serum IgE levels, and serum eosinophil counts . We found that (1) EVH was positive in 75 percent of cases and MIC was positive in 81 percent of cases; one subject reacted to EVH but not to MIC and vice-versa . (2) The quantitative response to one test correlated with the response to the other test (r = -0.60, p = 0.01) . (3) There was a correlation between severity of asthma symptoms and the response to EVH (r = 0.62; p = 0.01), but not to MIC . (4) Response to MIC (log PD20), but not EVH, correlated with serum IgE level (r = -0.53, p = 0.04) . We suggest that EVH may be used for the initial assessment of AHR in the evaluation of asthma . Eucapnic voluntary hyperventilation is a sensitive measure of AHR and it correlates well with symptoms . Furthermore, though these points were not addressed in our study, it is more physiologic than MIC, and it is easy and less expensive to perform.

Infection, 1994 Mar-Apr, 22(2), 152 - 5
Penetration of ampicillin and sulbactam into human costal cartilage; Meier H et al.; The question of whether ampicillin and sulbactam are able to penetrate sufficiently into costal cartilage tissue was investigated in 21 children undergoing surgery for funnel chest malformations . The concentrations of both compounds were determined in the core and mantle pieces of samples taken 45 min or 120 min after infusion of ampicillin/sulbactam (33.3/16.7 mg/kg bodyweight) preoperatively for antibiotic prophylaxis . Ampicillin was determined by bioassay and sulbactam was determined by gas-chromatography/mass spectrometry . Mean concentrations of ampicillin were 23.3 mg/kg and 10.4 mg/kg at 45 min and at 27.4 mg/kg and 7.8 mg/kg 120 min in the mantle and core piece, respectively . Mean concentrations of sulbactam were at the same time 21.3 mg/kg and 9.7 mg/kg and 17.5 mg/kg and 11.9 mg/kg, respectively . These values indicate that both compounds achieve high concentrations even in bradytrophic tissue such as cartilage . The concentrations exceed the MIC values of important bacterial pathogens involved in postoperative wound infections . Therefore ampicillin protected by sulbactam appears to be a well-suited agent for perioperative prophylaxis in thoracic surgery.

Clin Exp Dermatol, 1994 Mar, 19(2), 121 - 6
Levels of terbinafine in plasma, stratum corneum, dermis-epidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once daily for 7 and 14 days; Faergemann J et al.; In earlier skin pharmacokinetic studies we have shown that terbinafine is rapidly delivered to the stratum corneum, nails and hair both through sebum and by direct diffusion through dermis-epidermis . In the present study the skin pharmacokinetic profile of terbinafine was studied in two groups of eight human male volunteers during and after 250 mg orally once daily for 7 and 14 days . In the 7-day study high terbinafine levels were found in sebum (19.0 micrograms/g) and stratum corneum (2.5 micrograms/g), and a concentration in stratum corneum above the minimal inhibitory concentration for most dermatophytes was still found 48 days after the last day of medication . Terbinafine was found in peripheral nail clippings after 7 days of medication and the concentration was, in the 7-day study, 0.5 microgram/g 1 day after stopping medication; it was still 0.2 microgram/g 90 days after stopping treatment . The results in the 14-day study were in parallel with, but higher than, in the 7-day study . The elimination of terbinafine from several compartments is biphasic, with a faster initial elimination followed by a slower secondary elimination . For nails, the elimination is slower compared with the other compartments . The results indicate that terbinafine may be effective in short-term treatment of several dermatophytoses . The concentration of 0.2 microgram/g of terbinafine found in nails 90 days after stopping medication, following 7 days of treatment, indicates that the duration of therapy, even in tinea ungium, may be shorter than is currently the case.

Vet Parasitol, 1994 Mar, 52(1-2), 37 - 46
Drug sensitivity of Chinese Trypanosoma evansi and Trypanosoma equiperdum isolates; Brun R et al.; The drug sensitivities of eleven Trypanosoma evansi isolates from China were examined using two different in vitro assays, a 3H-hypoxanthine incorporation assay and a long incubation low inoculation test (LILIT) . Better discrimination of the drug susceptibility of the strains was observed with the LILIT . The drug responses of all the isolates to the arsenical melarsoprol were very similar . In contrast, for suramin, minimal inhibitory concentrations (MIC) varied within a 27-fold range and for diminazene within a 55-fold range . Comparison of MIC values with expected drug levels in the host as well as in vivo experiments with selected isolates and drugs indicated that all the isolates examined would be sensitive to melarsoprol, diminazene and suramin under in vivo conditions . For isometamidium, the difference in MIC values between the most and the least sensitive isolate was 724-fold . Neither of two isolates tested in mice--the most resistant and the second most sensitive--was cured with the highest acceptable dose of 10 mg kg-1 isometamidium chloride . Comparison of our results with blood levels of drug to be expected in cattle support the assumption that the Chinese T . evansi isolates have more or less innate resistance to isometamidium under in vivo conditions . One Trypanosoma equiperdum isolate was tested in the 3H-hypoxanthine incorporation assay . The results indicated that this isolate was highly sensitive to melarsoprol, isometamidium and suramin; with regard to diminazene, T . equiperdum was not as sensitive as the most sensitive T . evansi strains.

Methods Find Exp Clin Pharmacol, 1994 Mar, 16(2), 79 - 84
Uptake and killing of Candida by human peritoneal macrophages and amphotericin B; Linde HJ et al.; The effects of amphotericin B at subinhibitory and inhibitory concentrations on ingestion and intracellular killing of C . albicans ATCC 10,231 and C . tropicalis ATCC 13,803 by human peritoneal macrophages in vitro was investigated . Peritoneal macrophages were harvested from overnight peritoneal dialysate of 26 patients undergoing regular continuous ambulatory peritoneal dialysis (CAPD) using a new simple isolation technique . Macrophages were suspended with Candida (1:2-3) together with pooled human serum and with or without amphotericin B at various concentrations . Vital staining with acridine orange at a very low concentration using the metachromatic property of the dye allowed simultaneous assessment of ingestion and intracellular viability of the yeasts . Counts of Candida in 100 macrophages were performed at 1, 2, 3, 4, 6 and 24 h under a fluorescence microscope at 1000x and the ratios of living to dead intracellular Candida were calculated . Amphotericin B was added at concentrations of 0.1, 1 and 10 times the MIC . Ingestion was rapid and complete, while intracellular killing ranged from 4-69% for C . albicans and from 9-48% for C . tropicalis . Amphotericin B at 1 MIC enhanced the killing of C . tropicalis (factor 1.32) but reduced killing of C . albicans (factor 0.6) after 6 h.

J Parasitol, 1994 Feb, 80(1), 158 - 60
Prolonged exposure of Plasmodium falciparum to ciprofloxacin increases anti-malarial activity; Yeo AE et al.; The minimum inhibitory concentration (MIC) of ciprofloxacin was determined for 2 isolates of Plasmodium falciparum at 48, 96, and 144 hr . The MIC decreased from mean values of 28.1 micrograms/ml for the FC isolate and 27.2 micrograms/ml for the K1 isolate at 48 hr to 2.8 micrograms/ml and 4.4 micrograms/ml, respectively, at 96 hr . Concentrations of 0.1-1.0 micrograms/ml were effective in suppressing parasite growth over 144 hr of incubation . These findings indicate that the multiplication of malaria parasites can be inhibited by clinically achievable concentrations of ciprofloxacin provided that exposure to the drug is prolonged over several asexual erythrocytic cycles . They also raise the possibility that this antibiotic could be used eventually, in combination with a rapidly acting but noncurative drug regimen, to treat patients with refractory falciparum infections.

Acta Trop, 1994 Feb, 56(1), 51 - 4
The in vitro antimalarial activity of chloramphenicol against Plasmodium falciparum; Yeo AE et al.; The minimum inhibitory concentrations, MIC, of chloramphenicol were determined for two isolates of Plasmodium falciparum at 48, 96 and 144 h . The MIC decreased from values greater than 100 micrograms/ml at 48 h to 10.7-12.5 micrograms/ml at 96 h . During 144 h of incubation, concentrations of 0.8-1.6 micrograms/ml were effective in suppressing parasite growth . These results indicate that the multiplication of malaria parasites can be inhibited by clinically achievable concentrations of chloramphenicol provided that exposure to the drug is prolonged over several asexual life cycles . They suggest that undiagnosed falciparum infections may be cured when patients with fever of doubtful origin are treated with 10 to 14 day courses of chloramphenicol . They also raise the possibility that this antibiotic may eventually be used, in combination with a rapidly acting but non-curative drug regimen, to treat patients with falciparum infections in whom the use of tetracyclines is contraindicated, e.g., young children.

Antimicrob Agents Chemother, 1994 Feb, 38(2), 381 - 4
Identification of mutations in 23S rRNA gene of clarithromycin-resistant Mycobacterium intracellulare; Meier A et al.; Clarithromycin is a potent macrolide that has been used for treating infections with nontuberculous mycobacteria . Pairs of susceptible and resistant Mycobacterium intracellulare strains were obtained from patients with chronic pulmonary M . intracellulare infections undergoing monotherapy with clarithromycin . Nucleotide sequence comparisons of the peptidyltransferase region in 23S rRNAs from parental and resistant strains revealed that in three of six resistant strains, for which the MIC was > 32 micrograms/ml, a single base was mutated (Escherichia coli equivalent, A-2058-->G, C, or U) . As the modification of adenine 2058 by dimethylation is a frequent cause of macrolide resistance in a variety of different bacteria, we suggest that mutation of A-2058 confers acquired resistance to clarithromycin in M . intracellulare.

J Antimicrob Chemother, 1994 Feb, 33(2), 289 - 97
The concentrations of clarithromycin and its 14-hydroxy metabolite in sputum of patients with bronchiectasis following single dose oral administration; Tsang KW et al.; Clarithromycin and its metabolite, 14-hydroxy-clarithromycin are active against a wide range of respiratory pathogens . Antibiotics generally penetrate poorly into respiratory secretions which may therefore continue to harbour bacteria following bronchial infection . We have studied sputum and serum concentrations of clarithromycin and 14-hydroxy-clarithromycin in eight patients with idiopathic bronchiectasis without infective exacerbations (five male, three female; mean age 53.3 years) . Oral single dose administration of 250 or 500 mg clarithromycin, separated by at least 6 days, was given to each patient . Serum and sputum samples were collected (the latter by physiotherapy at 0, 1, 2, 4, 8, 24 and 0, 4, 8 and 24 h respectively after administration of each dose . Serum sol phase was obtained by high speed centrifugation and concentrations of clarithromycin and 14-hydroxy-clarithromycin were determined by high performance liquid chromatography . Serum Cmax for clarithromycin and 14-hydroxy-clarithromycin were 1.20 mg/L (3 h) and 0.37 mg/L (3.1 h) for clarithromycin (250 mg)) and were 2.78 mg/L (2.5 h) and 0.68 mg/L (2.6 h) for clarithromycin (500 mg) respectively . Sputum Cmax for clarithromycin and 14-hydroxy-clarithromycin were 0.52 mg/L (5 h) and 0.30 mg/L (5.5 h) for clarithromycin (250 mg) and were 1.59 mg/L (5 h) and 0.47 mg/L (5.5 h) for clarithromycin (500 mg) respectively . The sputum/serum percentage ratios at Cmax (sputum) for clarithromycin and 14-hydroxy-clarithromycin were 74.3% and 113.9% (250 mg) and 94.7% and 99.9% (500 mg) respectively . We conclude that oral administration of clarithromycin to patients with bronchiectasis results in rapid penetration into respiratory mucus with persistent drug concentrations that exceed its MIC for many respiratory pathogens.

J Antimicrob Chemother, 1994 Feb, 33(2), 273 - 9
Bioavailability and chemotherapeutic activity of clofazimine against Mycobacterium avium complex infections in beige mice following a single implant of a biodegradable polymer; Kailasam S et al.; We have studied the bioavailability of clofazimine following administration of a single dose of the drug in the biodegradable polymer polylactic-co-glycolic acid (PLGA) . We compared the levels of clofazimine achieved in the liver with single implants with those obtained with daily oral treatment . Even though the levels achieved with implants were much lower than those obtained after daily oral treatment, they were higher than the MIC of clofazimine for Mycobacterium leprae, Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) . Experimental studies in beige mice after infection with MAC strain 101 showed similar reductions in cfu counts, after both single dose polymer and daily oral treatment . Macroscopically, hyperpigmentation giving an orange-yellow colour to all visceral organs, was seen in animals after daily oral treatment but not in those animals that received polymer implants.

J Antimicrob Chemother, 1994 Feb, 33(2), 215 - 22
Susceptibility of Moraxella catarrhalis isolates to beta-lactam antibiotics in relation to beta-lactamase pattern; Fung CP et al.; Moraxella catarrhalis isolates (n = 413) were collected from 20 clinical laboratories in England and Scotland in 1991 and were examined for beta-lactamase production by isoelectric focusing . beta-Lactamases were found in 375 isolates of which, 349 (93.1%) had BRO-1 enzyme and 26 (6.9%) had BRO-2 . Minor variation in electrofocusing pattern occurred within both enzyme types . Ampicillin MICs for BRO-1 producers were 25-fold higher than for non-producers, but those for BRO-2 producers were raised only four-fold . MICs of cefaclor, cefixime, loracarbef, co-amoxiclav and cefetamet generally were two- to four-fold higher for BRO-1 producers than for BRO-2 producers and enzyme non-producers . Similarly, the inhibition zones of discs containing cefaclor, cefixime, loracarbef or co-amoxiclav were smaller for BRO-1 producers than for non-producers . Amongst the compounds tested, cefetamet seemed the least affected by beta-lactamase production in both MIC and disc tests . Overall, these results indicate that BRO-1 enzyme predominates amongst M . catarrhalis isolates from the UK, as in other countries, and suggest that BRO-1 production gives slight protection against many of the newer oral beta-lactams as well as causing ampicillin resistance.

APMIS, 1994 Feb, 102(2), 94 - 102
Impact of the agar medium and disc type on disc diffusion susceptibility testing against teicoplanin and vancomycin; Jensen KT et al.; Susceptibility to teicoplanin and vancomycin was assessed by three disc types: two commercially available discs (NeoSensitabs and PDM disc (30 micrograms)) and one locally prepared 30 micrograms disc (SS disc) on four different medium types: Mueller-Hinton agar (MH medium), MH medium and PDM agar II supplemented with 5% horse blood (HMB medium and PDM medium, respectively), and Danish blood agar (DBA medium) . Two previously studied groups of Gram-positive bacteria were tested: group B (N = 75) comprised miscellaneous cocci, and group C (N = 59) mostly rods . With NeoSensitabs, mean zone diameters were larger than with PDM and SS discs on all medium types, and mean zone diameters were larger on DBA medium than on MHB and PDM medium with all disc types . The impact of the medium type on the zone diameter was evaluated for 121 strains growing on MHB medium, PDM medium, and DBA medium . Bacterial groups B and C each divided into three MIC groups were analysed separately . We compared mean zone diameters for each specific group with the average zone diameter, i.e . the mean value for all zone diameters obtained . The smallest deviations from the average zone diameters were observed on PDM medium for both teicoplanin and vancomycin . Thirty-seven percent of strains failed to grow on MH medium, but supplementation of MH medium with horse blood significantly reduced the zone diameter for group B strains both for teicoplanin and vancomycin . Poor predictability of MIC from the zone diameter was found especially for strains with MICs < or = 1 microgram/ml . The medium type hardly affected the results of regression analysis . In contrast, the medium type markedly affected the results of error-rate bounded analysis . No errors were recorded with the SS disc on MHB medium for either teicoplanin or vancomycin, but no strains with MICs of vancomycin within the intermediate group could be correctly classified on DBA medium.

Clin Infect Dis, 1994 Feb, 18(2), 188 - 93
Treatment failure with use of a third-generation cephalosporin for penicillin-resistant pneumococcal meningitis: case report and review; John CC; Recent reports have documented the increasing number of pneumococcal isolates that are relatively or completely resistant to penicillin and other antibiotics . This report documents a case in which third-generation cephalosporin failed in the treatment of pneumococcal meningitis and reviews the clinical and microbiological features of the seven similar cases reported to date . In all eight cases, the pneumococci were penicillin resistant . Taken together, these cases suggest that (1) children with intermediately penicillin-resistant pneumococcal meningitis (MIC, 0.1-1.0 micrograms/mL) who are treated with cefotaxime or ceftriaxone should be observed carefully for treatment failure and (2) children with highly penicillin-resistant pneumococcal meningitis (MIC, > or = 2.0 micrograms/mL) are best treated with vancomycin and rifampin until the MICs of cefotaxime and ceftriaxone for the pneumococcus are known.

Kansenshogaku Zasshi, 1994 Feb, 68(2), 201 - 8
{Susceptibility to macrolides against Mycoplasma pneumoniae isolated during 7 years}; Arai S et al.; The efficacies of macrolide antibiotics, rokitamycin, leukomycin, josamycin and erythromycin were investigated against 63 strains of M . pneumoniae included FH strain which were isolated from clinical specimens obtained in 1986-1987, 1991, 1992-1993 . Values of MICs and MBCs of these antibiotics were evaluated by two methods, broth dilution method and M . pneumoniae L cell infection system . In broth dilution method, MIC50 and MBC50 of rokitamycin were 0.0063-0.025 microgram/ml and 0.025-0.2 microgram/ml respectively . The ratios of MBC50/MIC50 were 1-32 . MIC50 of leukomycin, josamycin and erythromycin were 0.0063-0.05 micrograms/ml, 0.0025-0.05 microgram/ml, and 0.0125-0.05 microgram/ml respectively . MBC50 of these drugs were 0.0125-50 micrograms/ml, 25-50 micrograms/ml, and 25-50 micrograms/ml respectively . The ratios of MIC50/MBC50 were 2-800, 500-2000, 500-4000 . MIC50 of rokitamycin and leukomycin to the isolates during period from 1992-1993 were higher as compare to those of isolates during 1986 to 1991 . On the other hand, rokitamycin markedly reduced the numbers of CFU in the growth phase when added at the concentrations of 16 and 4 times the MIC, but the other macrolides were reduced slightly CFU at the concentrations of 4 times, the MIC . In L cell infectious system, MIC50 and MBC50 of rokitamycin were 0.005-0.0125 microgram/ml and 0.05-0.1 microgram/ml respectively . The ratios of MBC50/MIC50 were 1-2 Ratios of leukomycin, josamycin, and erythromycin were 0.05-0.1 microgram/ml, 0.05-0.2 microgram/ml and 0.050-0.1 microgram/ml respectively . The MBC50 of these drugs were 0.2-0.4 micrograms/ml, 0.8-1.6 microgram/ml, 0.8-1.6 microgram/ml . Ratios of MBC50/MIC50 were 2-8, 4-32, 8-32.(ABSTRACT TRUNCATED AT 250 WORDS)

Ceska Slov Farm, 1994 Feb, 43(1), 9 - 10
{Antibiotic activity of cortalcerone and its 7-diphenylhydrazone derivative}; Gabriel J et al.; The present paper investigates the antibiotic properties of the novel antifungal antibiotic agent cortalceron and its semisynthetic derivative cortalceron 7-diphenylhydrazone . The MIC values were assayed by the agar diffusion method . Cortalceron was found to weakly inhibit the growth of E . coli and B . subtilis . The growth of yeast was not influenced . On i.v . administration to mice {correction of rats}, the agent produced breathing disorders and convulsions which later disappeared . The diphenylhydrazine derivative of cortalceron inhibited the growth of most yeasts tested as well.

Sheng Li Xue Bao, 1994 Feb, 46(1), 44 - 51
{Transplacental neurotoxic effects of monosodium glutamate on structures and functions of specific brain areas of filial mice}; Gao J et al.; Monosodium glutamate (MSG) was shown to penetrate placental barrier and distribute almost evenly among embryonic tissues using 3H-Glu as a tracer . When a lower (1.0 mg/g) and a higher (2.5 mg/g) doses of MSG were alternatively injected to Kunming maternal mice in every other days from mating to deliveries, obvious injury occurred in the ability of memory retention and Y-maze discrimination learning of adult filial mice pregnantly treated with higher doses (2.5 mg/g) of MSG . Meanwhile, the neuronal damages were observed in not only arcuate nucleus but also ventromedial nucleus of hypothalamus . Characteristic cytopathological changes induced by MSG showed swollen cytoplasm, dark pyknotic nuclei and loss of neurons . The radioligand-bindings in both hippocampus and hypothalamus altered significantly after the pregnant treatment of MSG . Possible mechanisms underlying MSG excitotoxic phenomena studied in single neuron by use of Ca2+ sensitive indicator Fura-2 with Spex AR-CM-MIC Cation Measurement System, might be due to increases of intracellular free Ca2+ concentration induced by MSG exposure, which was related to both the influx of Ca2+ and the depletion of Ca2+ from the intracellular Ca2+ stores . These experimental findings indicated that MSG performed its transplacental neurotoxicity in a dose-dependent manner . The excessive activation of Glu receptors and the overloading of intracellular Ca2+ induced by MSG ultimately leading to neuronal death may result in the reduction of the capability of learning and memory in adult filial mice pregnantly treated with MSG.

Indian J Med Res, 1994 Feb, 99, 71 - 3
Antifungal activity of allylamine derivatives; Venugopal PV et al.; The antifungal activity of the two allylamine derivatives, naftifine and terbinafine was investigated against 25 clinical isolates of filamentous fungi by agar dilution method . The isolates included Aspergillus sp . (10), Penicillium sp . (3), Cladosporium sp . (3), Rhizopus sp . (3), Paecilomyces sp . (2), Syncephalastrum sp . (1), Pyrenochaeta romeroi (1), Piedraia hortae (1) and Mortierella sp . (1) . Terbinafine was found to be more active than naftifine, inhibiting 50 per cent (MIC 50) and 90 per cent (MIC 90) of the isolates of Aspergillus sp., at 0.1 and 0.5 microgram/ml respectively . The MIC 50s for the other isolates of hyalohyphomycetes, dematiaceous fungi and zygomycetes were 1, 5 and 100 micrograms/ml respectively . Naftifine inhibited 50 and 90 per cent of the Aspergillus sp., at 1 and 5 micrograms/ml, respectively . The MIC 50s for the other hyalohyphomycetes, dematiaceous fungi and zygomycetes were 5, 10 and 100 micrograms/ml respectively.

Farmaco, 1994 Feb, 49(2), 105 - 10
Quinolizidine derivatives with antitubercular activity; Vazzana I et al.; By reacting lupinylmagnesium chloride with suitable aromatic ketones, several lupinyldiarylcarbinols were obtained, whose dehydration gave the corresponding lupinylidenediarylmethanes . By reduction of three of these unsaturated compounds, the corresponding lupinyldiarylmethanes were also obtained . Direct condensation of lupinine with fluorene gave the 9-epi-lupinylfluorene . The quinolizidine derivatives obtained were tested against Mycobacterium tuberculosis H37RV . Nine compounds resulted endowed with good antitubercular activity with MIC < 8 micrograms/ml, while the remaining were only moderately active . Most interesting was the lupinylidene derivative 13 with MIC > 0.1 < 0.5 micrograms/ml.

J Appl Bacteriol, 1994 Feb, 76(2), 190 - 5
Effect of sub-MIC antibiotics on the cell surface and extracellular virulence determinants of Pseudomonas cepacia; McKenney D et al.; The effects of sub-MICs of ciprofloxacin and tobramycin on the cell surface characteristics and extracellular virulence factors of Pseudomonas cepacia were evaluated . Cells were grown in batch culture under iron-deficient and iron-replete conditions . At sub-MIC levels that did not affect bacterial growth cell surface hydrophobicity decreased under both iron-replete and iron-depleted conditions with ciprofloxacin, but increased with tobramycin under iron-sufficient conditions . Exopolysaccharide synthesis, lipase production and siderophore production were all significantly increased by the presence of ciprofloxacin under both growth conditions . Outer membrane protein and lipopolysaccharide profiles were not affected by exposure to the two antibiotics.

Am J Ophthalmol, 1994 Jan 15, 117(1), 87 - 9
Aqueous humor penetration of ofloxacin given by various routes; von Gunten S et al.; We studied the aqueous humor penetration of ofloxacin after topical, oral, and intravenous administration in 51 consecutive patients undergoing cataract surgery . Aqueous humor concentration (mean +/- SD) was 0.53 +/- 0.35 mg/l when ofloxacin 0.3% eyedrops were instilled topically six times, one drop every three hours, until 90 minutes preoperatively, and 0.63 +/- 0.29 mg/l (P = .45) when two additional instillations were made, one drop every 30 minutes, until 30 minutes before aqueous humor aspiration . Aqueous humor concentration two hours after a single 200-mg oral dose (0.38 +/- 0.15 mg/l) was significantly lower (P = .048) than that 12 hours after the same oral dose (0.58 +/- 0.24 mg/l) . Two hours following an intravenous infusion of 200 mg of ofloxacin, aqueous humor concentration was 0.33 +/- 0.19 mg/l . Our results suggest that therapeutic levels above the minimum inhibitory concentration for many bacteria cultured in endophthalmitis can be achieved in aqueous humor after either topical or oral administration, which indicates that this antibiotic passes easily through the corneal and the blood aqueous barriers.

Gut, 1994 Jan, 35(1), 51 - 4
Phenotypic and genotypic variation in Giardia lamblia isolates during chronic infection; Butcher PD et al.; Two Giardia isolates were axenised in vitro after recovery by duodenal aspiration from a man with hypo-gamma globulinaemia and chronic giardiasis, before and after three unsuccessful courses of metronidazole . In vitro drug sensitivity assays showed that the pretreatment isolate was sensitive to metronidazole with minimum inhibitory concentration (MIC) and dose that inhibited growth by 50% (ED50) values of 0.1 and 0.03 mumol/l, respectively . The post-treatment isolate was 20-fold more resistant (MIC and ED50 4.3 and 0.58 mumol/l, respectively) . Differences between these isolates were also found in the surface protein profiles after radioiodination, metabolic labelling patterns with 35S-methionine, malic enzyme isoenzyme patterns, and by DNA fingerprinting with a M-13 bacteriophage probe . The phenotypic and genotypic differences between the pretreatment and post-treatment isolates suggest that we have isolated two different strains from the same patient and that treatment with metronidazole resulted in selection of the more resistant strain.

Chemotherapy, 1994 Jan-Feb, 40(1), 37 - 41
The in vitro effects of ceftibuten on the host defense mechanism; Braga PC et al.; The in vitro effects of ceftibuten on human polymorphonuclear leukocyte (PMN) chemotaxis, phagocytosis and chemiluminescence were investigated . PMN from healthy adult donors were incubated for 1 h in medium alone or in medium containing increasing concentrations of ceftibuten (4, 8 and 40 times the MIC for Escherichia coli) . Up to 40 MIC ceftibuten did not significantly interfere with the function of PMN.

Leukemia, 1994 Jan, 8(1), 67 - 71
The prognostic significance of deletion of the long arm of chromosome 20 in myeloid disorders; Campbell LJ et al.; A review of patients with myeloid disorders presenting to a large cytogenetic referral centre over a ten year period was undertaken to assess the clinical relevance of the presence of del(20q) in their malignant karyotypes . Twenty-six patients were identified, four with myeloproliferative disorders (MPD), 15 with myelodysplastic syndromes (MDS) and seven with acute leukemia . The presence of del(20q) in four patients with MPD did not appear to adversely affect survival, with all patients alive 18 to 184 months post diagnosis . However, the 15 patients with MDS had a median survival of only 12 months . Seven of these patients developed acute leukemia including three of four patients with refractory anemia with ringed sideroblasts (RARS) . Of the seven patients with acute leukemia de novo and del(20q), six were treated with only two achieving complete remission . The median duration of survival for these seven patients was 5 months . These results, when compared with published survival data from the MIC Cooperative Group, indicated that del(20q) in MDS is associated with a high rate of transformation to acute leukemia and a poor prognosis . In de novo acute leukemia, del(20q) is associated with a poor response to treatment and reduced survival.

Scand J Infect Dis, 1994, 26(1), 67 - 75
Sensitivity of 880 blood culture isolates to 24 antibiotics; Walder M et al.; Blood culture isolates (n = 880) collected during 2.5 years (period I n = 515, July 1988 to December 1989; period II n = 365, January 1992 to December 1992) were analysed with the agar dilution method to ascertain their sensitivity to 24 antibiotics . The susceptibility of bacteria was classified according to MIC values and susceptibility grouping used in the SIR system (sensitive-S, intermediate-I, resistant-R) . Comparison of percentage S+I values for the 2 periods revealed no major development of resistance . Co-trimoxazole and some cephalosporins (cefpirom, cefepime and cefotaxime) were active (S+I) against 88-92% of the strains . Imipenem and the combination piperacillin-tazobaclam were active against 95% of the strains . A very large number of strains (98.2 to 98.6%) were inhibited (S+I) by the quinolones tested, ciprofloxacin and ofloxacin . Comparison of the present results with those of our 1980-81 study yielded no evidence of resistance development, except for an increase in betalactamase-producing S . aureus strains, from 67% to 85%.

Antimicrob Agents Chemother, 1994 Jan, 38(1), 144 - 6
Comparative activities of piperacillin and tazobactam against clinical isolates of Legionella spp; Collins LA et al.; We evaluated the in vitro activity of piperacillin alone or in combination with the beta-lactamase inhibitor tazobactam against clinical isolates of Legionella species . At an inoculum of approximately 10(4) CFU, tazobactam, piperacillin, and the 8:1 combination had equivalent activities against Legionella spp . At an approximately 10-fold higher inoculum, the following results were obtained, expressed as MICs for 50 and 90% of strains tested (MIC range): piperacillin, 4 and 16 (0.25 to 32) micrograms/ml; tazobactam, 0.5 and 1 (0.125 to 2) micrograms/ml; and piperacillin-tazobactam (expressed in terms of MIC of piperacillin) 0.5 and 1 (0.03 to 2) micrograms/ml . Tazobactam alone and the combination with piperacillin were more active than piperacillin alone at the higher inoculum.

Jpn J Antibiot, 1994 Jan, 47(1), 40 - 9
{Various factors influencing in vitro antifungal activities of omoconazole nitrate (OMZ), a new imidazole antimycotic}; Itoyama T et al.; Effects of various factors on in vitro antifungal activities of omoconazole nitrate (OMZ) were investigated with bifonazole (BFZ) as the reference drug using an agar dilution method and a broth dilution method . Composition of the culture medium significantly altered the activity as determined by minimum inhibitory concentration (MIC) of OMZ; OMZ exhibited a greater anti-Candida activity (smaller MIC values) on casitone agar (CA) than on Sabouraud dextrose agar (SDA) . Anti-Candida activity of OMZ was the highest in pH 5 medium, but it was lowered by an increase of inoculum size, a prolongation of the incubation period and the addition of calf serum to the medium . Anti-Trichophyton activity of OMZ was not influenced with these factors except for the addition of calf serum . The activity of OMZ was fungicidal against Candida at pH 5.0 and against Trichophyton at pH 5.0 and 6.6 . The geometric mean MIC of OMZ was lower than that of BFZ against C . albicans freshly-isolated on acid CA.

J Orthop Res, 1994 Jan, 12(1), 79 - 82
In vitro elution of ciprofloxacin from polymethylmethacrylate cement beads; DiMaio FR et al.; The use of antibiotic-impregnated polymethylmethacrylate (PMMA) cement beads for the local delivery of antibiotics in the treatment of chronic osteomyelitis has become a standard orthopaedic practice . The increasing resistance to antibiotics of organisms associated with orthopaedic infections has led to interest in the incorporation of more effective antibiotics into PMMA cement . Ciprofloxacin, a synthetic fluoroquinolone, is potent against a broad spectrum of bacteria associated with osteomyelitis . In this study, strands of ciprofloxacin-impregnated PMMA cement beads were prepared with 0.2, 0.5, or 1.0 g of ciprofloxacin per 40 g of PMMA . The elution concentration of ciprofloxacin was at least 1-2 mcg/ml for 7 days (0.2 g), 30 days (0.5 g), and 42 days (1.0 g) . This concentration is equivalent to the minimum inhibitory concentration for the common pathogens associated with osteomyelitis . Concurrent systemic and local ciprofloxacin therapy appears to be a method for the treatment of chronic osteomyelitis.

Clin Oncol (R Coll Radiol), 1994, 6(2), 91 - 5
A phase II study of mitomycin, ifosfamide and cisplatin in operable and inoperable squamous cell carcinoma of the oesophagus; Allen SM et al.; We have evaluated the effect of mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 (MIC) in two groups of patients with squamous or undifferentiated carcinoma of the oesophagus, as either preoperative or primary treatment . Response was assessed by barium swallow, CT scan, and measurement of metastases where present . Toxicity was acceptable and there were no chemotherapy related deaths . In the operated group, five of 23 patients (22%) showed a complete response (three confirmed histologically) and nine (39%) showed a partial response following two courses of MIC . Resection was completed in 21 patients, with three hospital deaths (14%) . Of the 18 patients who were discharged from hospital, eight have died at 4-24 months (median 13) from the start of treatment and 10 are alive at 5-35 months, with known recurrence in one . In the non-operated group, five of 20 patients (25%) showed a response, one complete, following one to four (mean 2.6) courses of MIC . Nineteen patients have died (at median 5 months), and one, who had a complete response, is alive and free from disease at 29 months . Neo-adjuvant therapy with MIC in squamous carcinoma of the oesophagus has shown encouraging early results, with acceptable toxicity.

Tumour Biol, 1994, 15(6), 354 - 60
Action of nitrogenated and sulfonylated inositol derivatives upon the proliferation in vitro of normal mouse cells and tumor mouse cells; Eijan AM et al.; Despite the major advances of cancer chemotherapy during the past 40 years, host toxicities and drug resistance justify the need to continue the search for new antineoplastic agents . In the present work, we have studied the effect of six synthetic drugs on the in vitro growth of two murine mammary adenocarcinomas (M3 and MM3), as well as on normal embryonic cells . AI, MIC and MPI are purines coupled to a sulfonylated inositol, while DIC and DEI have nitrogen mustard as substituent . Methylsulfonylmucoinositol was the common substituent . Our results indicated that only drugs substituted with nitrogen mustards had an antiproliferative effect . DEI was more effective on tumor cells than on normal cells.

Med Dosw Mikrobiol, 1994, 46(3), 181 - 94
{Effect of subinhibitory doses of some antibiotics on bacteria in vitro}; Denys A et al.; The study was aimed at observation of influence of subinhibitory doses of selected beta-lactam antibiotics (cefuroxime, ceftazidime, thienamycin) and of ciprofloxacin on morphology and physiology of S . aureus and E . coli . The bacteria were subjected to action of these antibiotics in various subinhibitory concentrations in fluid Mueller-Hinton medium at 37 degrees C for 18 hours, and morphological changes in bacterial cells were observed in light and electronic microscope . In case of E . coli changes appeared as presence of elongated forms, while S . aureus formed giant cells with changes in staining . It was found that intensity of these morphological changes was proportional to concentrations of antibiotics . For determination of influence of tested antibiotics on growth of bacteria they were cultured in the fluid Mueller-Hinton medium containing antibiotics in concentrations of 4, 1 1/4 MIC . The culture lasted for 6 hours, and number of bacterial cells in 1 ml of the medium was periodically determined . Distinct inhibition of growth of bacterial cells was proportional to the used concentrations of antibiotics . Described in this paper morphological changes of bacteria found confirmation in change of their physiology expressed as inhibition of bacterial cell growth.

Med Dosw Mikrobiol, 1994, 46(1-2), 91 - 4
{Septo-clean* new disinfecting agent and antiseptic}; Muszynski Z et al.; The study was aimed at evaluation of usefulness of Septo-Clean, which contain in 100 cm3 of distilled water 1 g of didecyl-dimethylammonium chloride and 70 cm3 of isopropyl alcohol . This preparation is prepared for quick disinfection of surfaces and antiseptic action on hand skin . Investigations were carried on test strains of S . aureus, E . coli, P . aeruginosa and C . albicans . It was demonstrated that MIC of Septo-Clean amount to 0.04% for S . aureus to 0.88% for P . aeruginosa . MBC 5 min values were respectively 0.19 and 1.05% . It was found that this preparation effectively lowers natural contamination with bacteria of hospital usable surfaces by 98%, exhibiting effectiveness similar to preparations containing 2.5% of chlorhexidine in 70% ethanol or isopropanol.

Microbiol Immunol, 1994, 38(5), 399 - 402
In vitro antibiotic susceptibilities of Borrelia isolates from erythema migrans lesion of Lyme disease patients in Japan; Masuzawa T et al.; Antibiotic susceptibilities of twelve borrelial isolates from skin of patients with erythema migrans (EM) and ticks (Ixodes persulcatus and I . ovatus) in Japan were examined by in vitro microdilution MIC method and macrodilution MBC method . Nine EM isolates and 3 tick isolates were susceptible to amoxicillin, erythromycin, and minocycline . MICs for Japanese isolates were 0.038-0.30 microgram/ml, < 0.012 microgram/ml, and < 0.012-0.05 microgram/ml, respectively . MBCs were as follows: 0.038-0.88 microgram/ml, < 0.012-0.10 microgram/ml, and < 0.025-0.78 microgram/ml, respectively . These antibiotics could be recommended for treatment of patients in early stage of Lyme disease in Japan.

Chemotherapy, 1994, 40 Suppl 1, 3 - 7
Study of the distribution of oral ciprofloxacin into the mucosa of the middle ear and the cortical bone of the mastoid process; Massias L et al.; This multicentre study evaluates the distribution of ciprofloxacin into the tissue structures of the middle ear following multiple dosing of one 500 mg tablet every 12 h . The samples were taken perioperatively from adult patients due to undergo surgery for chronic otitis . Administration of ciprofloxacin was instigated 9 days prior to the operation . The samples were taken at different intervals after the last dose in order to evaluate variations in concentration with time . The average peak concentrations recorded and the time taken to reach these concentrations were as follows: middle ear mucosa (n = 16): 5.54 +/- 3.46 micrograms/g (3-4 h): cortical bone of the mastoid process (n = 21): 1.07 +/- 1.29 micrograms/g (4 h) . The measurements carried out 12 h after the last dose show that concentrations of ciprofloxacin in the middle ear mucosa were still at least as high as the minimum inhibitory concentration for this antibiotic for most of the pathogens implicated in acute exacerbations of chronic otitis . These results suggest that, administered as an oral dose of 500 mg every 12 h, ciprofloxacin may be an effective agent for the treatment of chronic suppurative otitis . These results now need to be backed up by clinical trials.

Scand J Infect Dis, 1994, 26(6), 659 - 66
Pneumococcal meningitis in adults; Kragsbjerg P et al.; A retrospective study was conducted to examine the clinical features and outcome of 31 adult pneumococcal meningitis patients during the years 1981-92 . The incidence was 1.0/100,000 adults/year . The case fatality rate was 16% (5/31), and in patients older than 70 years, 33% (3/9) . Sequelae were seen in 29% (7/24), mostly otoneurologic symptoms . In 27/28 bacterial isolates the serotypes found were included in the 23-valent unconjugated polysaccharide vaccine in current use . All 28 isolates were fully sensitive to penicillin . 49/51 non-meningitis blood isolates had MIC values < or = 0.06 mg/l, 2 isolates had MIC values of 0.125 mg/l and 0.25 mg/l, and 50/50 were serotypes included in the 23-valent vaccine . Pneumococcal meningitis is a disease causing considerable mortality and morbidity . The relatively low case fatality rate found in the present study may be due to the patients' good health prior to admission, rapid specific microbiological diagnosis, absence of penicillin-resistant pneumococci among the meningitis strains, and immediate institution of specific and supportive therapy.

Arch Toxicol, 1994, 69(1), 45 - 51
Comparative toxicity of methyl isocyanate and its hydrolytic derivatives in rats . II . Pulmonary histopathology in the subacute and chronic phases; Sriramachari S et al.; This paper describes the long-term (subacute and chronic) histopathological effects in the lungs of rats subjected to a single exposure to methyl isocyanate (MIC) by both the inhalation and subcutaneous (s.c.) routes as well as the role of methylamine (MA) and N,N'-dimethyl-urea (DMU), the hydrolytic derivatives of MIC in eliciting the observed changes . At the subacute phase, the intraalveolar and interstitial edema were prominent only in the inhalation group as against the more pronounced inflammatory response in the s.c . route . With the progress of time the evolution of lesions appeared to be similar, culminating in the development of significant interstitial pneumonitis and fibrosis . MA, one of the hydrolytic derivatives of MIC, also caused interstitial pneumonitis progressing to fibrosis, albeit to a lesser extent than MIC, indicating its contribution to the long-term pulmonary damage . The diffuse interstitial pulmonary fibrosis observed at 10 weeks after a single exposure to MIC by either route is of greater significance in the context of the occurrence of pulmonary fibrosis in the late autopsies of Bhopal gas victims and also clinical sequelae in some of the survivors.

Arch Toxicol, 1994, 69(1), 39 - 44
Comparative toxicity of methyl isocyanate and its hydrolytic derivatives in rats . I . Pulmonary histopathology in the acute phase; Jeevaratnam K et al.; The present study describes the acute histopathological changes induced by methyl isocyanate (MIC) in the lungs of rats at 24 h after a single exposure to varied concentrations/doses of MIC by inhalation and subcutaneous (s.c.) routes and also delineates the effects due to the hydrolytic derivatives of MIC, viz., methylamine (MA) and N,N'-dimethyl urea (DMU) . MIC, either inhaled or administered s.c., resulted in a wide range and extent of histopathological changes in the lungs, proportional to the exposure concentration/dose . The salient, effects of inhaled MIC are acute necrotizing bronchitis of the entire respiratory tract accompanied by varying degrees of confluent congestion, hyperemia and interstitial and intra-alveolar edema, while MIC administered s.c . led to prominent vascular endothelial damage, congestion and severe interstitial pneumonitis with apparently normal bronchial epithelium; and intra-alveolar edema only with the high dose . The only noteworthy lesion produced by MA and DMU (to some extent) was interstitial pneumonitis, suggesting their possible involvement in the subsequent inflammatory response of MIC . Except, for the endothelial changes, the overall spectrum of the histopathological lesions is quite comparable to those observed in the lungs of Bhopal victims during the acute phase.

Cesk Epidemiol Mikrobiol Imunol, 1993 Dec, 42(4), 172 - 6
{Use of diffusion methods in the determination of sensitivity of medically important micromycetes}; Pospisil J et al.; The authors evaluated the sensitivity of 35 strains of mycotic agents to eight antifungal preparations, using two methods: the diffuse disc test and the method of assessment of the MIC in a liquid medium . On comparison of results obtained by the two methods they reached the conclusion that the diffuse disc method makes possible only orientation as regards sensitivity and does not fully correlate with the results of MIC . Some strains with MIC values at the sensitivity level seemed resistant according to the disc test . From a total of seven agar media used for the disc test only two were suitable: the medium with casitone and Sabouraud's glucose agar . In particular on the former there were inhibition zones round the discs which were easiest to evaluate and which were constant at different incubation temperatures.

Nippon Rinsho, 1993 Dec, 51(12), 3261 - 6
{Activity of Lansoprazole (new proton pump inhibitor) against Helicobacter pylori and its therapeutic efficacy}; Tamura K et al.; Lansoprazole, one of PPIs, is a strong antacid and it cures stomach and duodenal ulcers at early stages as well as having antibiotic action towards HP . The in vitro MIC of the product is between 3.13 and 12.5 micrograms/ml and it was 12.5 micrograms/ml, which was the same as MIC of colloidal bismuth citrate, in our study . Sterilizing effect of Lansoprazole is reported to be the direct attack on HP bacteria from electron microscopic findings . Our study revealed that Lansoprazole would preserve the epithelial cells on the edge of a stomach ulcer and would protect PAS-positive substance within them . Lansoprazole is said to cure many H2-Blocker resistant ulcers and to suppress the rate of recurrence of stomach and duodenal ulcers . These effects are considered to be attributable to maintenance of mucous barrier and maintenance of cytoprotection of the gastric mucosa by Lansoprazole as well as its sterilizing action mainly on HP.

J Toxicol Environ Health, 1993 Dec, 40(4), 513 - 29
The Bhopal accident and methyl isocyanate toxicity; Varma DR et al.; The Bhopal accident, the world's worst industrial disaster, in which nearly 40 metric tons of methyl isocyanate (MIC) was released from the Union Carbide pesticide plant, occurred nearly 10 yr ago during the night of December 2 and 3, 1984 . Over 3000 people residing in areas adjacent to the plant died of pulmonary edema within 3 d of the accident . Follow-up studies revealed pulmonary, ophthalmic, reproductive, immunologic, neurological, and hematologic toxicity among the survivors . Despite high reactivity, MIC can traverse cell membranes and reach distant organs, perhaps as a reversible conjugate with glutathione, which may explain some of the systemic effects of MIC . MIC can be degraded as a result of pyrolysis and interaction with water, but none of the breakdown products can duplicate the toxicity observed in Bhopal and in animal models . MIC may be the most toxic of all isocyanates because of its very high vapor pressure relative to other isocyanates and because of its ability to exert toxic effects on numerous organ systems.

Mol Gen Genet, 1993 Dec, 241(5-6), 700 - 6
Cloning and mapping of the genetic determinants for microcin C51 production and immunity; Kurepina NE et al.; Microcin C51 is a small peptide antibiotic produced by Escherichia coli cells harbouring the 38 kb low copy number plasmid pC51, which codes for microcin production and immunity . The genetic determinants for microcin synthesis and immunity were cloned into the vectors pBR325, pUC19 and pACYC184 . Physical and phenotypic analysis of deletion derivatives and mutant plasmids bearing insertions of transposon Tn5 showed that a DNA fragment of about 5 kb is required for microcin C51 synthesis and expression of complete immunity to microcin . Partial immunity can be provided by a 2 kb DNA fragment . Mutant plasmids were tested for their ability to complement Mic- mutations . Results of these experiments indicate that at least three plasmid genes are required for microcin production . The host OmpR function is also necessary for microcin C51 synthesis.

J Neurochem, 1993 Dec, 61(6), 2155 - 63
Microglia-derived elastase produces a low-molecular-weight plasminogen that enhances neurite outgrowth in rat neocortical explant cultures; Nakajima K et al.; In the course of analysis of plasminogen in microglial conditioned medium (Mic-CM), novel low-molecular-weight (LMW) zymogen with a molecular mass of approximately 36 kDa was detected by casein-urokinase zymography . Because this form was produced when rat native plasminogen was incubated with Mic-CM, a specific protease in the Mic-CM was thought to be responsible for the production of LMW plasminogen . The production of LMW plasminogen was strongly inhibited by elastase inhibitors . Furthermore, elastase (pancreatic or leukocyte) was also found to produce LMW zymogen from native plasminogen . These results indicate that LMW plasminogen is produced through limited proteolysis by an elastase-like protease in Mic-CM . To determine the biochemical characteristics of LMW plasminogen, rat native plasminogen was cleaved by pancreatic elastase, and the fragments (LMW plasminogen and nonzymogen fragments) were purified by several kinds of column chromatography . Amino acid sequence analysis revealed that LMW plasminogen is a carboxy-terminal region that contains the fifth kringle domain and a protease active site, and the amino acid sequence is identical to that of LMW plasminogen produced by Mic-CM . On the other hand, the nonzymogen fragment was the amino-terminal region containing four kringle domains . The effects of native plasminogen and the fragments on neurite outgrowth of rat brain explant were examined . LMW plasminogen promoted neurite outgrowth as well as did native plasminogen, whereas nonzymogen fragments did not . These results suggest that LMW plasminogen, which is produced from native plasminogen by elastase, may be a physiologically active molecule that mediates the intercellular interaction between microglia and neurons.

J Infect Dis, 1993 Dec, 168(6), 1532 - 6
Invasive pneumococcal disease in central Oklahoma: emergence of high-level penicillin resistance and multiple antibiotic resistance . Pneumococcus Study Group; Haglund LA et al.; Relatively penicillin-resistant pneumococci have caused 10% of invasive pneumococcal disease in central Oklahoma during the last decade, but almost no high-level penicillin or other antibiotic resistance has been described . This study evaluated antibiotic susceptibility and serotype distribution in invasive pneumococcal disease in the Oklahoma City metropolitan area (1990 population 848,000) . A total of 144 cases of invasive infection was collected in 1 year (17 with meningitis, 120 with other bacteremic infections, and 7 with other invasive infections), for a rate of 16.9/100,000 (95% confidence interval {CI}, 14.0-19.5) . For the population aged > or = 60, invasive pneumococcal disease rates were higher among nursing home residents (352/100,000) than among nonresidents (25.6/100,000; relative risk, 13.7; 95% CI, 7.7-24.7) . Antibiotic-resistant organisms caused 19.4% of the cases: relative penicillin resistance, 7.6%; high-level penicillin resistance, 1.4% (2 cases), and 11% resistance to erythromycin, trimethoprim-sulfamethoxazole, or both, with 5% sharing both resistances plus a MIC of penicillin of 0.06 microgram/mL.

J Ethnopharmacol, 1993 Dec, 40(3), 207 - 13
Plants used in Guatemala for the treatment of dermatophytic infections . 2 . Evaluation of antifungal activity of seven American plants; Caceres A et al.; From 52 plants screened for antifungal activity, 26 (50%) were active against dermatophytes . This paper reports further evaluation of seven American plants against four pathogenic fungi (Aspergillus flavus, Epidermophyton floccosum, Microsporum gypseum and Trichophyton rubrum), the part showing most activity, the best solvent and, in three cases, the minimal inhibitory concentration (MIC) against the fungus in pure culture . Antifungal activity was confirmed in all of the plants, but not all parts; the most active parts were the bark and leaves . The most active species were Byrsonima crassifolia, Cassia grandis, Gliricidia sepium and Malpighia glabra . Diphysa robinioides, Rhizophora mangle and Cassia occidentalis were less active . The most susceptible fungi were E . floccosum and T . rubrum; A . flavus was not susceptible . Ethanol was usually the best solvent and the MIC of C . grandis, C . occidentalis and D . robinioides was 50 micrograms/ml.

J Antimicrob Chemother, 1993 Dec, 32(6), 831 - 6
In-vitro activity of the new triazole D0870 compared with amphotericin B and itraconazole against Aspergillus spp; Moore CB et al.; The in-vitro activity of D0870, a new triazole, was compared with amphotericin B (AMP B) and itraconazole (ITZ) against 40 Aspergillus isolates, which included 25 isolates of Aspergillus fumigatus, using a broth macro-dilution method at 37 degrees C . Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) (killing of > or = 98%) were measured . For 40 isolates, geometric mean (GM) MIC values and ranges were D0870 10.55 and 2-32, ITZ 2.26 and 0.5-64, AMP B 2.42 and 1-64 mg/L . Differences in susceptibilities between species were apparent with Aspergillus flavus (n = 5) being the most susceptible to D0870 (GM 2.64, range 2-8 mg/L) . MFC values were within one dilution of the MIC value for 90% of isolates (D0870 and ITZ) and 95% of isolates (AMP B) . In reproducibility studies, seven, eight and four of eight isolates retested gave MIC results within one dilution for D0870, AMP B, and ITZ, respectively . Therefore, in-vitro mould testing with D0870 is feasible and reproducible with clear MIC and MFC end-points . D0870 is active against most Aspergillus spp., but at higher concentrations than either ITZ or AMP B.

Antimicrob Agents Chemother, 1993 Dec, 37(12), 2762 - 5
Efficacy of intravenous itraconazole against experimental pulmonary aspergillosis; Miyazaki HM et al.; The efficacy of intravenous itraconazole solubilized in hydroxypropyl-beta-cyclodextrin was assessed in a rat model of Aspergillus fumigatus pneumonia . Immunosuppressed rats were infected by intratracheal inoculation of A . fumigatus conidia . Intravenous administration of various doses of itraconazole was started immediately after infection and continued once a day for 7 days . A 10-mg dose of intravenous itraconazole per kg was as effective on survival as 1 mg of amphotericin B per kg daily (a survival rate of 100% in 28 days), while treatment with 1 mg/kg did not increase the survival rate . The 50% lethal dose of intravenous itraconazole given to immunosuppressed and uninfected rats for 7 days was 24.5 mg/kg/day . A microbiological assay to estimate accumulation in tissue after five daily intravenous administrations of itraconazole at 10 mg/kg showed that itraconazole and its active metabolites were present in the lungs for at least 6 h, reaching the MIC as previously described (B . Dupont and E . Drouchet, Rev . Infect . Dis . 9(Suppl . 1):71-76, 1987; A . Espinel-Ingroff, S . Shadomy, and R . J . Gebhart, Antimicrob . Agents Chemother . 26:5-9, 1984) . Intravenous itraconazole was considered to be worth evaluating in clinical trials of aspergillosis.

Antimicrob Agents Chemother, 1993 Dec, 37(12), 2638 - 44
Morphological response of Bilophila wadsworthia to imipenem: correlation with properties of penicillin-binding proteins; Summanen P et al.; The penicillin-binding protein (PBP) patterns of six strains of Bilophila wadsworthia were investigated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and subsequent fluorography of membrane preparations labelled with {3H}benzylpenicillin . The PBP profiles among the strains were similar; generally, seven to nine PBP-reactive bands could be visualized; their molecular weights ranged from 31 to 137 kDa . The relative affinities of the PBPs of four strains of B . wadsworthia for imipenem were examined and correlated with the morphological responses of the cells to imipenem . Morphological changes were examined by light and electron microscopies . Light microscopy revealed that at low concentrations (less than the MIC), imipenem induced the formation of rounded and bulging cells; rarely, elongation without filamentation was observed . In the presence of imipenem at the MIC, spheroplast formation was observed . Scanning and transmission electron microscopies revealed round forms together with larger, multilobate cells in the presence of subinhibitory concentrations of imipenem, suggesting that new growth sites were initiated while cell division was inhibited . Peeling of the outer membrane was also seen . Spheroplasts were very large (up to 30 microns in diameter) and stable in aqueous solution . Inhibition of the PBPs could be seen in the presence of low imipenem concentrations.

Antimicrob Agents Chemother, 1993 Dec, 37(12), 2588 - 92
Limitations of plasmid complementation test for determination of quinolone resistance due to changes in the gyrase A protein and identification of conditional quinolone resistance locus; Soussy CJ et al.; Plasmid pJSW101 derived from pUC19 and carrying the wild-type gyrA gene was found to be unstable in HM72, a quinolone-resistant (QR) clinical isolate of Escherichia coli, and resulted in no change in quinolone MICs . MICs determined in the presence of ampicillin to ensure plasmid presence, however, resulted in complementation . HM72 was proved to have a gyrA mutation based on the DNA sequence of a 418-bp fragment of gyrA . DNA sequencing identified a common mutation encoding Leu-83 as the cause of QR . To identify loci other than gyrA and nfxB contributing to QR in KF111b, zgh-3075::Tn10 (67 min) in CAG12152 was transduced into KF111b . Sixteen percent of the transductants had a fourfold decrease in norfloxacin MIC, indicating the presence of a locus, nfxD, which contributes to QR . Outcross of nfxD from DH151 (gyrA nfxB nfxD zgh-3075::Tn10) resulted in 8% of the KF130 gyrA, 2% of the EN226-3 gyrA, and none of the KL16 (wild-type) transductants, with a four- to eightfold increase in norfloxacin MIC . In the presence of ampicillin, the resistance of a gyrA nfxD double mutant, DH161 nfxD gyrA (from EN226-3), was fully complemented by gyrA+ . Thus, gyrA+ plasmid complementation tests for QR may be falsely negative with plasmid instability, a difficulty which may be circumvented by maintenance of plasmid selection . In addition, if nfxD-like mutations occur in gyrA clinical isolates, a positive test may overestimate the level of resistance attributable to gyrA alone.

Antimicrob Agents Chemother, 1993 Dec, 37(12), 2678 - 83
Correlation of tobramycin-induced inhibition of protein synthesis with postantibiotic effect in Escherichia coli; Barmada S et al.; Scant data exist on intracellular events during aminoglycoside-induced postantibiotic effect (PAE) . We examined DNA, RNA, and protein syntheses after tobramycin exposure using {3H}thymidine, {14C}uracil, and {14C}alanine incorporation in a clinical Escherichia coli strain . Late-log-phase bacteria in oxygenated minimal salts medium at 37 degrees C were exposed to tobramycin (7.5 micrograms/ml) (twice the MIC) for 30 min . Tobramycin caused a kill of 2 log10 CFU/ml prior to drug removal by filtration and a 5-h PAE, measured by viable counts . Excess amounts of labelled precursors were added to tobramycin-exposed organisms during, immediately after, and at various intervals following exposure . In the presence of tobramycin, DNA, RNA, and protein syntheses were sequentially inhibited within 1 generation time . Following drug removal, both DNA and RNA syntheses promptly resumed, suggesting readily dissociable nonspecific binding to DNA and RNA . However, total protein synthesis did not resume until 4 h later . beta-Galactosidase activity, a measure of functional enzymatic protein synthesis, was also inhibited for 4 h after drug removal . Bacterium length, measured by confocal microscopy, increased during PAE . Two distinct populations eventually emerged: one that returned to control dimensions and one that remained excessively elongated by the end of PAE (2.5 microns versus 4.0 microns; P < 0.05) . We hypothesize that only viable cells return to the control morphology . Flow cytometry showed enhanced DNA complexity during PAE, consistent with either impaired cellular protein synthesis in viable cells or perturbations in dying cells . In summary, duration of PAE correlated with inhibition of total and functional protein synthesis but not DNA or RNA synthesis.

Acta Derm Venereol, 1993 Dec, 73(6), 416 - 8
Dermatophytes and keratin in patients with hereditary palmoplantar keratoderma . A mycological study; Gamborg Nielsen P et al.; Fourteen patients with hereditary palmoplantar keratoderma of the Unna Thost variety were included in the study . Dermatophytosis was found in 7 of the 14 patients . Six were affected with T . rubrum and one with T . mentagrophytes . The growth pattern of dermatophytes in keratin from the patients did not differ from that of normal control individuals . Keratin from patients with hereditary palmoplantar keratoderma was sterilized with ethylene gas and placed in the center of culture plates, previously broad inoculated with control dermatophytes or dermatophytes isolated from patients . An inhibition zone around the keratin was found in 42.9% of the control dermatophytes and in 83.4% of the patient cultures . The inhibition zone was only seen in cultures with T . rubrum and not in those with T . mentagrophytes . No significant difference in minimal inhibitory concentration values against ketoconazole between control dermatophytes and dermatophytes from patients was demonstrated.

Ugeskr Laeger, 1993 Nov 8, 155(45), 3665 - 70
{Pneumococcal bacteremia in Hvidovre Hospital 1986-1990}; Jensen C et al.; The study describes 156 consecutive cases of pneumococcal bacteraemia among patients admitted to Hvidovre Hospital during the five-year period 1986-1990 . Pneumococcal bacteraemia was most common in the age groups 0-4 and 50-99 years . The most common focus of infection was the lungs (84%) . 81% had preexisting diseases and the most common were: Immunosuppression due to drugs, alcoholism, cardiovascular disease, chronic obstructive lung disease, diabetes and myelomatosis . Patients over 65 years of age had a higher case fatality (35%) than younger (12%) . The overall case fatality rate was 24% . Twenty-three percent of cases were hospital-acquired, and associated with a case fatality of 37% . Pneumococcal bacteraemia was most common during the winter season and unrelated to influenza . Eighty-four percent of the examined isolates represented capsular types included in the 23-valent pneumococcal vaccine . Three percent of the tested strains were relatively resistant to penicillin (MIC > 0.1 microgram/ml) . Despite antibiotic treatment, the mortality from pneumococcal bacteraemia, particularly in elderly, remains high . With this in mind, one may consider offering pneumococcal vaccination to persons over 65 years of age with chronic predisposing diseases.

Head Neck, 1993 Nov-Dec, 15(6), 526 - 31
Bacteriologic profile of surgical infection after antibiotic prophylaxis; Clayman GL et al.; Wound infections resulting from contamination during major head and neck surgery continue to be a critical issue . In this study, specimens of pus or draining fluids from the wounds of 43 surgical patients who received perioperative administration of ampicillin/sulbactam or clindamycin were cultured for aerobic and anaerobic isolates to species level . Polymicrobial infections were identified in 13 of 43 patients (30%); 82% of isolates were aerobic organisms (45 of 55), and 18% were anaerobic or facultative species (10 of 55) . Nine of 43 patients (21%) showed no bacterial isolates from cultured material . Independent of the primary site of malignancy or antibiotics used, nine of 25 isolates (36%) obtained from patients who underwent concomitant dental extractions, but only one of 24 (4%) who did not, developed anaerobic infections, (p < 0.001) . The minimum inhibitory concentration of anaerobic isolates suggested sensitivity to the antibiotics used, and minimum bactericidal concentration data suggested that further postoperative doses may be required to adequately treat the heavily contaminated wounds . These data suggest that wound colonization following dental extraction procedures in clean contaminated head and neck surgery increases the risk of anaerobic infections . The use of a therapeutic dose and longer duration of perioperative antibiotics may be warranted.

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