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1.  Accumulation of 3-Ketosteroids Induced by Itraconazole in Azole-Resistant Clinical Candida albicans Isolates 
Antimicrobial Agents and Chemotherapy  1999;43(11):2663-2670.
The effects of itraconazole on ergosterol biosynthesis were investigated in a series of 16 matched clinical Candida albicans isolates which had been previously analyzed for mechanisms of resistance to azoles (D. Sanglard, K. Kuchler, F. Ischer, J. L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother., 39:2378–2386, 1995). Under control conditions, all isolates contained ergosterol as the predominant sterol, except two strains (C48 and C56). In isolates C48 and C56, both less susceptible to azoles than their parent, C43, substantial concentrations (20 to 30%) of 14α-methyl-ergosta-8,24(28)-diene-3β,6α-diol (3,6-diol) were found. Itraconazole treatment of C43 resulted in a dose-dependent inhibition of ergosterol biosynthesis (50% inhibitory concentration, 2 nM) and accumulation of 3,6-diol (up to 60% of the total sterols) together with eburicol, lanosterol, obtusifoliol, 14α-methyl-ergosta-5,7,22,24(28)-tetraene-3βol, and 14α-methyl-fecosterol. In strains C48 and C56, no further increase of 3,6-diol was observed after exposure to itraconazole. Ergosterol synthesis was less sensitive to itraconazole inhibition, as was expected for these azole-resistant isolates which overexpress ATP-binding cassette transporter genes CDR1 and CDR2. In addition to 3,6-diol, substantial amounts of obtusifolione were found after exposure to itraconazole. This toxic 3-ketosteroid was demonstrated previously to accumulate after itraconazole treatment in Cryptococcus neoformans and Histoplasma capsulatum but has not been reported in Candida isolates. Accumulation of obtusifolione correlated with nearly complete growth inhibition in these azole-resistant strains compared to that found in the susceptible parent strain, although the onset of growth inhibition only occurred at higher concentrations of itraconazole. ERG25 and ERG26 are the only genes assigned to the 4-demethylation process, of which the 3-ketoreductase is part. To verify whether mutations in these ERG25 genes contributed to obtusifolione accumulation, their nucleotide sequences were determined in all three related isolates. No mutations in ERG25 alleles of isolates C48 and C56 were found, suggesting that this gene is not involved in obtusifolione accumulation. The molecular basis for the accumulation of this sterol in these two strains remains to be established.
PMCID: PMC89540  PMID: 10543744
2.  In Vivo Efficacies of Combinations of β-Lactams, β-Lactamase Inhibitors, and Rifampin against Acinetobacter baumannii in a Mouse Pneumonia Model 
The effects of various regimens containing combinations of β-lactams, β-lactam inhibitor(s), and rifampin were assessed in a recently described mouse model of Acinetobacter baumannii pneumonia (M. L. Joly-Guillou, M. Wolff, J. J. Pocidalo, F. Walker, and C. Carbon, Antimicrob. Agents Chemother. 41:345–351, 1997). Two aspects of the therapeutic response were studied: the kinetics of the bactericidal effect (treatment was initiated 3 h after intratracheal inoculation, and bacterial counts were determined over a 24-h period) and survival (treatment was initiated 8 h after inoculation, and the cumulative mortality rate was assessed on day 5). Two clinical strains were used: a cephalosporinase-producing strain (SAN-94040) and a multiresistant strain (RCH-69). For SAN-94040 and RCH-69, MICs and MBCs (milligrams per liter) were as follows: ticarcillin, 32, 64, 256, and >256, respectively; ticarcillin-clavulanate, 32, 64, and 512, and >512, respectively; imipenem, 0.5, 0.5, 8, and 32, respectively; sulbactam, 0.5, 0.5, 8, and 8, respectively; and rifampin, 8, 8, 4, and 4, respectively. Against SAN-94040, four regimens, i.e., imipenem, sulbactam, imipenem-rifampin, and ticarcillin-clavulanate (at a 25/1 ratio)-sulbactam produced a true bactericidal effect (≥3-log10 reduction of CFU/g of lung). The best survival rate (i.e., 93%) was obtained with the combination of ticarcillin-clavulanate-sulbactam, and regimens containing rifampin provided a survival rate of ≥65%. Against RCH-69, only regimens containing rifampin and the combination of imipenem-sulbactam had a true bactericidal effect. The best survival rates (≥80%) were obtained with regimens containing rifampin and sulbactam. These results suggest that nonclassical combinations of β-lactams, β-lactamase inhibitors, and rifampin should be considered for the treatment of nosocomial pneumonia due to A. baumannii.
PMCID: PMC89287  PMID: 10348761
3.  Mechanism of the Intracellular Killing and Modulation of Antibiotic Susceptibility of Listeria monocytogenes in THP-1 Macrophages Activated by Gamma Interferon 
Listeria monocytogenes, a facultative intracellular pathogen, readily enters cells and multiplies in the cytosol after escaping from phagosomal vacuoles. Macrophages exposed to gamma interferon, one of the main cellular host defenses against Listeria, become nonpermissive for bacterial growth while containing Listeria in the phagosomes. Using the human myelomonocytic cell line THP-1, we show that the combination of l-monomethyl arginine and catalase restores bacterial growth without affecting the phagosomal containment of Listeria. A previous report (B. Scorneaux, Y. Ouadrhiri, G. Anzalone, and P. M. Tulkens, Antimicrob. Agents Chemother. 40:1225–1230, 1996) showed that intracellular Listeria was almost equally sensitive to ampicillin, azithromycin, and sparfloxacin in control cells but became insensitive to ampicillin and more sensitive to azithromycin and sparfloxacin in gamma interferon-treated cells. We show here that these modulations of antibiotic activity are largely counteracted by l-monomethyl arginine and catalase. In parallel, we show that gamma interferon enhances the cellular accumulation of azithromycin and sparfloxacin, an effect which is not reversed by addition of l-monomethyl arginine and catalase and which therefore cannot account for the increased activity of these antibiotics in gamma interferon-treated cells. We conclude that (i) the control exerted by gamma interferon on intracellular multiplication of Listeria in THP-1 macrophages is dependent on the production of nitric oxide and hydrogen peroxide; (ii) intracellular Listeria may become insensitive to ampicillin in macrophages exposed to gamma interferon because the increase in reactive oxygen and nitrogen intermediates already controls bacterial growth; and (iii) azithromycin and still more sparfloxacin cooperate efficiently with gamma interferon, one of the main cellular host defenses in Listeria infection.
PMCID: PMC89140  PMID: 10223943
4.  Type II Topoisomerase Mutations in Ciprofloxacin-Resistant Strains of Pseudomonas aeruginosa 
We determined the sequences of the quinolone resistance-determining regions of gyrA, gyrB, and parC genes for 30 clinical strains of Pseudomonas aeruginosa resistant to ciprofloxacin that were previously complemented by wild-type gyrA and gyrB plasmid-borne alleles and studied for their coresistance to imipenem (E. Cambau, E. Perani, C. Dib, C. Petinon, J. Trias, and V. Jarlier, Antimicrob. Agents Chemother. 39:2248–2252, 1995). In the present study, we found mutations in type II topoisomerase genes for all strains. Twenty-eight strains had a missense mutation in gyrA (codon 83 or 87). Ten of them had an additional mutation in parC (codon 80 or 84), including a novel mutation of Ser-80 to Trp, but all were fully complemented by a plasmid-borne wild-type gyrA allele. The remaining two strains harbored the first gyrB mutation described in P. aeruginosa, leading to the substitution of phenylalanine for serine 464. The strains which had two mutations in type II topoisomerase genes (i.e., gyrA and parC) were significantly more resistant to fluoroquinolones than those with a single mutation in gyrA or gyrB (geometric mean MICs of ciprofloxacin, 39.4 versus 10.9 μg/ml, P < 0.01; geometric mean MICs of sparfloxacin, 64.0 versus 22.6, P < 0.01). No mutant with a parC mutation alone was observed, which favors DNA gyrase being the primary target for fluoroquinolones. These results demonstrate that gyrA mutations are the major mechanism of resistance to fluoroquinolones for clinical strains of P. aeruginosa and that additional mutations in parC lead to a higher level of quinolone resistance.
PMCID: PMC89021  PMID: 9869566
5.  Close Association between Clearance of Recombinant Human Granulocyte Colony-Stimulating Factor (G-CSF) and G-CSF Receptor on Neutrophils in Cancer Patients 
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is used to counter chemotherapy-induced neutropenia. Our previous study showed an inverse correlation between serum rhG-CSF levels and the number of circulating neutrophils in cancer patients (H. Takatani, H. Soda, M. Fukuda, M. Watanabe, A. Kinoshita, T. Nakamura, and M. Oka, Antimicrob. Agents Chemother. 40:988–991, 1996). The aim of this study was to clarify the relationship between rhG-CSF clearance and G-CSF receptors on circulating neutrophils. In five cancer patients receiving chemotherapy, a bolus dose of rhG-CSF (5 μg/kg) was injected intravenously during defined phases of posttreatment neutropenia and neutrophilia. Serum rhG-CSF levels were measured by a chemiluminescence enzyme immunoassay and analyzed by moment analysis. G-CSF receptors on neutrophils were detected by flow cytometry with biotinylated rhG-CSF. rhG-CSF clearance was significantly higher at neutrophilia than at neutropenia (1,497 ± 132 versus 995 ± 266 ml/h; P < 0.01). The percentage of G-CSF receptor-positive neutrophils, reflecting the number of G-CSF receptors per cell, was low at neutropenia without rhG-CSF therapy (44.5% ± 22.1%) and high at neutrophilia with rhG-CSF therapy (73.0% ± 11.4%; P < 0.01). rhG-CSF clearance closely correlated with the percentage of G-CSF receptor-positive neutrophils (r2 = 0.91; P < 0.0001) and neutrophil count (r2 = 0.72; P < 0.005). Our results indicate that, in cancer patients receiving chemotherapy, rhG-CSF increases the number of G-CSF receptors per cell as well as circulating neutrophil counts, resulting in modulation of its own clearance.
PMCID: PMC89014  PMID: 9869559
11.  In Vitro Activities of Ketolide HMR3647, Macrolides, and Other Antibiotics against Lactobacillus, Leuconostoc, and Pediococcus Isolates 
Antimicrobial Agents and Chemotherapy  1999;43(12):3039-3041.
Testing of susceptibility to 13 antibiotics was performed with 90 isolates of Lactobacillus, Leuconostoc, and Pediococcus. MICs at which 90% of the isolates tested were inhibited by HMR3647, erythromycin, and ciprofloxacin were 0.015, 0.125 and 32 μg/ml, respectively. The penicillin MIC was ≥16 μg/ml against 26.2% of the studied Lactobacillus sp. isolates and 50% of Lactobacillus plantarum. HMR3647 showed excellent activity against these genera.
PMCID: PMC89613  PMID: 10582908
12.  Novel Streptomycin and Spectinomycin Resistance Gene as a Gene Cassette within a Class 1 Integron Isolated from Escherichia coli 
Antimicrobial Agents and Chemotherapy  1999;43(12):3036-3038.
The aadA genes, encoding resistance to streptomycin and spectinomycin, have been found as gene cassettes in different gram-negative and gram-positive bacterial species. The present study has revealed the sequence of a new gene, aadA5, integrated as a gene cassette together with the trimethoprim resistance gene dfr7 in a class 1 integron. The integron was located on a plasmid and was identified in a pathogenic porcine Escherichia coli isolate.
PMCID: PMC89612  PMID: 10582907
13.  Beneficial Effect of Adjunctive Azithromycin in Treatment of Mucoid Pseudomonas aeruginosa Pneumonia in the Murine Model 
Antimicrobial Agents and Chemotherapy  1999;43(12):3033-3035.
While a time-kill methodology noted no appreciable improvement in bactericidal activity with the addition of azithromycin (AZM) to a ceftazidime (CAZ) regimen, data from the murine pneumonia model showed that the addition of AZM significantly improved survival compared to treatment with CAZ alone. These data suggest that AZM might be a useful adjunctive therapy in the management of pneumonia resulting from mucoid isolates of Pseudomonas aeruginosa.
PMCID: PMC89611  PMID: 10582906
14.  Comparative Bacteriostatic and Bactericidal Activities of Cefodizime against Borrelia burgdorferi Sensu Lato 
Antimicrobial Agents and Chemotherapy  1999;43(12):3030-3032.
The MIC and MSC (minimum spirocheticidal concentration) and killing rate for Borrelia burgdorferi, the etiological agent of Lyme disease, were assessed for cefodizime in comparison with ceftriaxone, minocycline, azithromycin, roxithromycin, and ciprofloxacin. The range of cefodizime MICs was greater than those of azithromycin and roxithromycin but comparable to those of ceftriaxone and minocycline. The MSCs were 1 to 2 dilutions higher than the MICs of all of the tested compounds. The killing curves of cefodizime and ceftriaxone showed parallel courses. In conclusion, cefodizime exerted an activity comparable to that of ceftriaxone against B. burgdorferi.
PMCID: PMC89610  PMID: 10582905
15.  Population Pharmacokinetics of Lamivudine in Adult Human Immunodeficiency Virus-Infected Patients Enrolled in Two Phase III Clinical Trials 
Antimicrobial Agents and Chemotherapy  1999;43(12):3025-3029.
Lamivudine population pharmacokinetics were investigated by using nonlinear mixed-effect modelling (NONMEM) analysis of data from 394 human immunodeficiency virus (HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two large, phase III clinical efficacy-safety trials, NUCA3001 and NUCA3002. Analyses of 1,477 serum lamivudine concentration determinations showed that population estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of distribution (V/F; 128 liters) were similar to values previously reported for HIV-infected patients in phase I pharmacokinetic studies. Lamivudine CL/F was significantly influenced by the covariates creatinine clearance and weight and not affected by age, Centers for Disease Control and Prevention (CDC) classification, CD4+ cell count, HIV type 1 (HIV-1) RNA PCR, or gender and race when CL/F was corrected for differences in patient weight. The population estimate for lamivudine V/F was not significantly influenced by the covariates gender, race, age, weight, renal function, HIV-1 RNA PCR, or CDC classification and CD4+ cell count when creatinine clearance was included with CL/F in the model. Lamivudine disposition was significantly influenced by renal function. However, as only three patients had an estimated creatinine clearance of <60 ml/min, dosage adjustments for patients with impaired renal function should not be determined based on the population parameters derived in this analysis.
PMCID: PMC89609  PMID: 10582904
16.  Antimicrobial Resistance of Diarrheagenic Escherichia coli Isolated from Children under the Age of 5 Years from Ifakara, Tanzania 
Antimicrobial Agents and Chemotherapy  1999;43(12):3022-3024.
Diarrhea caused by multidrug-resistant bacteria is an important public health problem among children in developing countries. The prevalence and antimicrobial susceptibility of diarrheagenic Escherichia coli in 346 children under 5 years of age in Ifakara, Tanzania, were studied. Thirty-eight percent of the cases of diarrhea were due to multiresistant enterotoxigenic E. coli, enteroaggregative E. coli, or enteropathogenic E. coli. Strains of all three E. coli categories showed high-level resistance to ampicillin, tetracycline, co-trimoxazole, and chloramphenicol but were highly susceptible to quinolones. Guidelines for appropriate use of antibiotics in developing countries need updating.
PMCID: PMC89608  PMID: 10582903
17.  Genetic Characterization of Antimicrobial Resistance in Canadian Isolates of Salmonella Serovar Typhimurium DT104 
Antimicrobial Agents and Chemotherapy  1999;43(12):3018-3021.
PCR was used to identify antibiotic resistance determinants in 31 Canadian Salmonella serovar Typhimurium DT104 isolates. Genes encoding resistance to ampicillin (pse1 or blaP1), chloramphenicol (pasppflo-like), streptomycin-spectinomycin (aadA2), sulfonamide (sulI), and tetracycline [tet(G)] were mapped to a 13-kb region of DNA of one isolate. Two copies of sulI were identified and mapped to the 3′ end of either pse1 or aadA2 integrons. The two integrons were separated by the pasppflo-like gene and the tet(G) gene. The kanamycin resistance determinant (aphA-1) was present on a 2.0-MDa plasmid (five isolates) or on the chromosome (three isolates).
PMCID: PMC89607  PMID: 10582902
18.  Distribution of β-Lactamases in Actinomycetes 
Antimicrobial Agents and Chemotherapy  1999;43(12):3014-3017.
The distribution of β-lactamase activities in a collection of actinomycete strains was surveyed. Six of 127 strains were found to produce β-lactamase. This low frequency was in contrast to the case with Streptomyces species. The producing strains were not related phylogenetically. MICs of benzylpenicillin did not correlate with β-lactamase production.
PMCID: PMC89606  PMID: 10582901
19.  Characterization of a Mycobacterium smegmatis Mutant Lacking Penicillin Binding Protein 1 
Antimicrobial Agents and Chemotherapy  1999;43(12):3011-3013.
The ponA gene of Mycobacterium smegmatis encodes a 95-kDa penicillin binding protein, PBP1, that is similar to PBP1s of Mycobacterium tuberculosis and Mycobacterium leprae. Transposon disruption of ponA in M. smegmatis resulted in a PBP1-deficient mutant that was sensitive to β-lactam antibiotics, was more permeable to glycine, and grew slowly in liquid culture.
PMCID: PMC89605  PMID: 10582900
20.  High-Level Aminoglycoside Resistance in the Beta-Hemolytic Group G Streptococcus Isolate BM2721 
Antimicrobial Agents and Chemotherapy  1999;43(12):3008-3010.
The beta-hemolytic group G Streptococcus clinical isolate BM2721 was resistant to high levels of aminoglycosides by synthesis of AAC(6′)-APH(2"), APH(3′)-III, and ANT(6) modifying enzymes. The corresponding genes were found to be adjacent as the result of a recombination event between Tn4001 and Tn5405, two transposons originating in staphylococci.
PMCID: PMC89604  PMID: 10582899
21.  Oral Bioavailability and Pharmacokinetics of Trovafloxacin in Patients with AIDS 
Antimicrobial Agents and Chemotherapy  1999;43(12):3005-3007.
Trovafloxacin pharmacokinetics were evaluated in 12 subjects with AIDS. By using a randomized design, single 200-mg doses of oral trovafloxacin and intravenous alatrofloxacin were administered. The mean absolute bioavailability was 91%. The pharmacokinetics of trovafloxacin when administered orally as the active form or intravenously as the prodrug (alatrofloxacin) are not altered in subjects with AIDS compared to those in healthy adults.
PMCID: PMC89603  PMID: 10582898
22.  Activity of Gemifloxacin against Penicillin- and Ciprofloxacin-Resistant Streptococcus pneumoniae Displaying Topoisomerase- and Efflux-Mediated Resistance Mechanisms 
Antimicrobial Agents and Chemotherapy  1999;43(12):2998-3000.
Nine penicillin-resistant Streptococcus pneumoniae clinical isolates from Northern Ireland, resistant to ciprofloxacin (MICs, 2 to 64 μg/ml) through topoisomerase- and/or reserpine-sensitive efflux mechanisms, were highly susceptible to gemifloxacin (MICs, 0.03 to 0.12 μg/ml). Two strains (requiring a ciprofloxacin MIC of 64 μg/ml) carried known quinolone resistance mutations in parC, parE, and gyrB, resulting in S79F, D435V, and E474K changes, respectively. Thus, gemifloxacin is active against clinical strains exhibiting altered topoisomerase and efflux phenotypes.
PMCID: PMC89601  PMID: 10582896
23.  In Vitro Activities of SCH27899 Alone and in Combination with 17 Other Antimicrobial Agents 
Antimicrobial Agents and Chemotherapy  1999;43(12):2996-2997.
SCH27899, an everninomicin antibiotic, was tested for its in vitro activity against 718 bacterial isolates representing 27 species. The Enterobacteriaceae and nonenteric gram-negative bacilli were resistant to ≥8.0 μg/ml, but all others were inhibited by ≤1.0 μg/ml. When tested in combination with 17 other antimicrobial agents against 110 strains, SCH27899 demonstrated no significant antagonism or synergy. Consequently, combination therapy is not contraindicated.
PMCID: PMC89600  PMID: 10582895
24.  Antibiotic-Induced Cell Wall Fragments of Staphylococcus aureus Increase Endothelial Chemokine Secretion and Adhesiveness for Granulocytes 
Antimicrobial Agents and Chemotherapy  1999;43(12):2984-2989.
Antibiotics release inflammatory fragments, such as lipoteichoic acid (LTA) and peptidoglycan (PG), from the cell wall of Staphylococcus aureus. In this study, we exposed S. aureus cultures to a number of β-lactam antibiotics (imipenem, flucloxacillin, and cefamandole) and protein synthesis-inhibiting antibiotics (erythromycin, clindamycin, and gentamicin) and investigated whether supernatants of these cultures differ in their capacity to stimulate endothelial cells (EC). After 24 h of incubation, endothelial adhesiveness for leukocytes, surface expression of various adhesion molecules, and secretion of the chemokines interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) were measured. Supernatants of β-lactam-exposed cultures (designated β-lactam supernatants) enhanced the adhesiveness of EC for granulocytes, whereas those of protein synthesis-inhibiting antibiotic-exposed cultures (designated protein synthesis-inhibitor supernatants) did not. This hyperadhesiveness coincided with a higher intercellular adhesion molecule-1 expression on the surface of the stimulated EC. In addition, EC stimulated with β-lactam supernatants secreted significantly higher concentrations of the chemokines IL-8 and MCP-1 than those stimulated with protein synthesis-inhibitor supernatants. The finding that the concentrations of LTA and PG in β-lactam supernatants were much higher than those in protein synthesis-inhibitor supernatants suggests that the observed differences in stimulatory effect between these supernatants are a result of differences in the release of cell wall fragments, although the presence of other stimulatory factors in the supernatants cannot be excluded. In conclusion, our results argue for a release of LTA and PG from S. aureus after exposure to β-lactam antibiotics that enhances the development of a systemic inflammatory response by stimulating EC such that adhesiveness for granulocytes is increased and large amounts of IL-8 and MCP-1 are secreted.
PMCID: PMC89598  PMID: 10582893
25.  Characterization of a Pseudomonas aeruginosa Efflux Pump Contributing to Aminoglycoside Impermeability 
Antimicrobial Agents and Chemotherapy  1999;43(12):2975-2983.
Pseudomonas aeruginosa can employ many distinct mechanisms of resistance to aminoglycoside antibiotics; however, in cystic fibrosis patients, more than 90% of aminoglycoside-resistant P. aeruginosa isolates are of the impermeability phenotype. The precise molecular mechanisms that produce aminoglycoside impermeability-type resistance are yet to be elucidated. A subtractive hybridization technique was used to reveal gene expression differences between PAO1 and isogenic, spontaneous aminoglycoside-resistant mutants of the impermeability phenotype. Among the many genes found to be up-regulated in these laboratory mutants were the amrAB genes encoding a recently discovered efflux system. The amrAB genes appear to be the same as the recently described mexXY genes; however, the resistance profile that we see in P. aeruginosa is very different from that described for Escherichia coli with mexXY. Direct evidence for AmrAB involvement in aminoglycoside resistance was provided by the deletion of amrB in the PAO1-derived laboratory mutant, which resulted in the restoration of aminoglycoside sensitivity to a level nearly identical to that of the parent strain. Furthermore, transcription of the amrAB genes was shown to be up-regulated in P. aeruginosa clinical isolates displaying the impermeability phenotype compared to a genotypically matched sensitive clinical isolate from the same patient. This suggests the possibility that AmrAB-mediated efflux is a clinically relevant mechanism of aminoglycoside resistance. Although it is unlikely that hyperexpression of AmrAB is the sole mechanism conferring the impermeability phenotype, we believe that the Amr efflux system can contribute to a complex interaction of molecular events resulting in the aminoglycoside impermeability-type resistance phenotype.
PMCID: PMC89597  PMID: 10582892

Results 1-25 (608)