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1.  In Vitro Resistance to Thrombin-Induced Platelet Microbicidal Protein among Clinical Bacteremic Isolates of Staphylococcus aureus Correlates with an Endovascular Infectious Source 
Antimicrobial Agents and Chemotherapy  1998;42(12):3169-3172.
Platelet microbicidal proteins (PMPs), small cationic peptides released at sites of endovascular damage, kill common bloodstream pathogens in vitro. Our group previously showed that in vitro resistance of clinical staphylococcal and viridans group streptococcal bacteremic strains to PMPs correlated with the diagnosis of infective endocarditis (IE) (Wu et al., Antimicrob. Agents Chemother. 38:729–732, 1994). However, that study was limited by (i) the small number of Staphylococcus aureus isolates from IE patients, (ii) the retrospective nature of the case definitions, and (iii) the diverse geographic sources of strains. The present study evaluated the in vitro PMP susceptibility phenotype of a large number of staphylococcemic isolates (n = 60), collected at a single medical center and categorized by defined and validated clinical criteria. A significantly higher proportion of staphylococcemic strains from patients with IE was PMP resistant in vitro than the proportion of strains from patients with soft tissue sepsis (83% and 33%, respectively; P < 0.01). Moreover, the levels of PMP resistance (mean percent survival of strains after 2-h exposure to PMP in vitro) were significantly higher for isolates from patients with IE and with vascular catheter sepsis than for strains from patients with abscess sepsis (P < 0.005 and P < 0.01, respectively). These data further support the concept that bloodstream pathogens that exhibit innate or acquired PMP resistance have a survival advantage with respect to either the induction or progression of endovascular infections.
PMCID: PMC106018  PMID: 9835510
2.  Gonococcal Resistance to β-Lactams and Tetracycline Involves Mutation in Loop 3 of the Porin Encoded at the penB Locus 
Antimicrobial Agents and Chemotherapy  1998;42(11):2799-2803.
penB is a chromosomal mutation that confers resistance to β-lactams and tetracyclines and reduced susceptibility to quinolones in Neisseria gonorrhoeae. It is linked to the porin gene (por) and requires the increased expression of an efflux pump due to mtr. Transformation of a susceptible gonococcus (strain H1) with chromosomal DNA from strain FA140 (penA mtr penB; porin serovar IB1) and conjugal transfer of a β-lactamase-expressing plasmid was used to produce isogenic strains for determination of equilibrium periplasmic penicillin concentrations by the method of Zimmermann and Rosselet (W. Zimmermann and A. Rosselet, Antimicrob. Agents Chemother. 12:368–372, 1977). In transformants with the Mtr and PenB phenotypes, equilibrium concentrations of penicillin were reduced. DNA sequence analysis of por from isogenic penB and penB+ transformants revealed 14 sequence differences; nine of these differences resulted in amino acid changes. Three amino acid changes were found in the putative gonococcal equivalent of the pore-constricting loop 3 of Escherichia coli OmpF. Two of these changes (Gly-101–Ala-102→Asp-Asp) result in an increased negative charge at this position in por loop 3. PCR products comprising the complete por gene from strain FA140 were transformed into strain H1-2 (penA mtr; porin serovar IB-3), with the resulting transformants having the antibiotic susceptibility phenotype associated with penB. penB-like mutations were found in loop 3 of clinical isolates of gonococci with chromosomally mediated resistance to penicillin. We conclude that penB is a mutation in loop 3 of por that reduces porin permeability to hydrophilic antibiotics and plays an important role in the development of chromosomally mediated resistance to penicillin and tetracycline in gonococci.
PMCID: PMC105946  PMID: 9797206
3.  Molecular Characterization of OXA-20, a Novel Class D β-Lactamase, and Its Integron from Pseudomonas aeruginosa 
The Pseudomonas aeruginosa Mus clinical isolate produces OXA-18, a pI 5.5 class D extended-spectrum β-lactamase totally inhibited by clavulanic acid (L. N. Philippon, T. Naas, A.-T. Bouthors, V. Barakett, and P. Nordmann, Antimicrob. Agents Chemother. 41:2188–2195, 1997). A second β-lactamase was cloned, and the recombinant Escherichia coli clone pPL10 expressed a pI 7.4 β-lactamase which conferred high levels of amoxicillin and ticarcillin resistance and which was partially inhibited by clavulanic acid. The 2.5-kb insert from pPL10 was sequenced, and a 266-amino-acid protein (OXA-20) was deduced; this protein has low amino acid identity with most of the class D β-lactamases except OXA-2, OXA-15, and OXA-3 (75% amino acid identity with each). OXA-20 is a restricted-spectrum oxacillinase and is unusually inhibited by clavulanic acid. OXA-20 is a peculiar β-lactamase because its translation initiates with a TTG (leucine) codon, which is rarely used as a translational origin in bacteria. Exploration of the genetic environment of oxa20 revealed the presence of the following integron features: (i) a second antibiotic resistance gene, aacA4; (ii) an intI1 gene; and (iii) two 59-base elements, each associated with either oxa20 or aacA4. This integron is peculiar because it lacks the 3′ conserved region, and therefore is not a sul1-associated integron like most of them, and because its 3′ end is located within tnpR, a gene involved in the transposition of Tn5393, a gram-negative transposon. P. aeruginosa Mus produces two novel and unrelated oxacillinases, OXA-18 and OXA-20, both of which are inhibited by clavulanic acid.
PMCID: PMC105865  PMID: 9687410
4.  Amino Acid Substitutions in the Cytochrome P-450 Lanosterol 14α-Demethylase (CYP51A1) from Azole-Resistant Candida albicans Clinical Isolates Contribute to Resistance to Azole Antifungal Agents 
The cytochrome P-450 lanosterol 14α-demethylase (CYP51A1) of yeasts is involved in an important step in the biosynthesis of ergosterol. Since CYP51A1 is the target of azole antifungal agents, this enzyme is potentially prone to alterations leading to resistance to these agents. Among them, a decrease in the affinity of CYP51A1 for these agents is possible. We showed in a group of Candida albicans isolates from AIDS patients that multidrug efflux transporters were playing an important role in the resistance of C. albicans to azole antifungal agents, but without excluding the involvement of other factors (D. Sanglard, K. Kuchler, F. Ischer, J.-L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother. 39:2378–2386, 1995). We therefore analyzed in closer detail changes in the affinity of CYP51A1 for azole antifungal agents. A strategy consisting of functional expression in Saccharomyces cerevisiae of the C. albicans CYP51A1 genes of sequential clinical isolates from patients was designed. This selection, which was coupled with a test of susceptibility to the azole derivatives fluconazole, ketoconazole, and itraconazole, enabled the detection of mutations in different cloned CYP51A1 genes, whose products are potentially affected in their affinity for azole derivatives. This selection enabled the detection of five different mutations in the cloned CYP51A1 genes which correlated with the occurrence of azole resistance in clinical C. albicans isolates. These mutations were as follows: replacement of the glycine at position 129 with alanine (G129A), Y132H, S405F, G464S, and R467K. While the S405F mutation was found as a single amino acid substitution in a CYP51A1 gene from an azole-resistant yeast, other mutations were found simultaneously in individual CYP51A1 genes, i.e., R467K with G464S, S405F with Y132H, G129A with G464S, and R467K with G464S and Y132H. Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives. We speculate that these specific mutations could combine with the effect of multidrug efflux transporters in the clinical isolates and contribute to different patterns and stepwise increases in resistance to azole derivatives.
PMCID: PMC105395  PMID: 9527767
10.  Comparative Efficacy of Trovafloxacin in Experimental Endocarditis Caused by Ciprofloxacin-Sensitive, Methicillin-Resistant Staphylococcus aureus 
Antimicrobial Agents and Chemotherapy  1998;42(12):3325-3327.
The new fluoroquinolone trovafloxacin was tested against a ciprofloxacin-sensitive, methicillin-resistant Staphylococcus aureus strain in the rabbit model of endocarditis. Trovafloxacin was more effective than vancomycin (CFU/g of vegetation, 2.65 ± 1.87 versus 4.54 ± 2.80 [mean ± standard deviation]; P < 0.05) or ampicillin-sulbactam plus rifampin (4.9 ± 1.1 CFU/g). The addition of ampicillin-sulbactam to trovafloxacin tended to reduce titers further.
PMCID: PMC106048  PMID: 9835540
11.  In Vitro Activities of Membrane-Active Peptides against Gram-Positive and Gram-Negative Aerobic Bacteria 
Antimicrobial Agents and Chemotherapy  1998;42(12):3320-3324.
Four peptides, cecropin P1, magainin II, indolicidin, and ranalexin, were evaluated against 202 clinical isolates of gram-positive and gram-negative aerobic bacteria by a microbroth dilution method. The gram-negative isolates were more susceptible to cecropin P1. Ranalexin was the most active compound against the gram-positive strains. The bactericidal activity of each peptide was equivalent to, or 1 dilution above, the MIC. In conclusion, the four peptides exhibited different in vitro activities and rapid time-dependent killing.
PMCID: PMC106047  PMID: 9835539
12.  Examination of Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Mutants with Low-Level Fluoroquinolone Resistance 
Antimicrobial Agents and Chemotherapy  1998;42(12):3317-3319.
For Staphylococcus aureus, stepwise mutations result in high-level quinolone resistance. Methicillin-resistant and -susceptible quinolone-resistant, first-step mutants generated in vitro were obtained and found to be no different than those recovered from murine abscesses. Approximately 10% of all first-step mutants were resistant to ethidium bromide, and selected strains had mutations that mapped to flqB. NorA-mediated resistance among first-step mutants may be more prevalent than previously reported.
PMCID: PMC106046  PMID: 9835538
13.  Macrolide Susceptibility and β-Lactamase Production among Haemophilus influenzae Isolates in the United States, 1996–1997 
Antimicrobial Agents and Chemotherapy  1998;42(12):3313-3314.
In 1996 and 1997, 68 hospital laboratories throughout the United States determined the β-lactamase production and susceptibility to macrolides of 1,998 isolates of Haemophilus influenzae obtained from patients with community-acquired respiratory tract infections. The MICs at which 90% of the isolates are inhibited of azithromycin, erythromycin, and clarithromycin were 4, 8, and 16 μg/ml, respectively. By National Committee for Clinical Laboratory Standards interpretive criteria, 99 and 78% of the isolates were susceptible to azithromycin and clarithromycin, respectively. The prevalence of β-lactamase production was 32%.
PMCID: PMC106044  PMID: 9835536
14.  Immunomodulating Effects of HMR 3004 on Pulmonary Inflammation Caused by Heat-Killed Streptococcus pneumoniae in Mice 
Antimicrobial Agents and Chemotherapy  1998;42(12):3309-3312.
We investigated the influence of HMR 3004, a new ketolide antibiotic, on the pulmonary inflammation induced by heat-killed fluorescein isothiocyanate-labeled Streptococcus pneumoniae. HMR 3004 downregulated (P < 0.05) the pneumococcus-induced release of interleukin-6 (IL-6), IL-1β, and nitric oxide in bronchoalveolar lavage fluid. The drug limited (P < 0.05) neutrophil recruitment to lung tissues and alveoli but did not interfere with phagocytosis. HMR 3004 totally abrogated lung edema. By reducing inflammation in addition to possessing antimicrobial properties, HMR 3004 may participate in improving the outcome of bacterial pneumonia.
PMCID: PMC106043  PMID: 9835535
15.  Efficacies of Cefepime, Ceftazidime, and Imipenem Alone or in Combination with Amikacin in Rats with Experimental Pneumonia Due to Ceftazidime-Susceptible or -Resistant Enterobacter cloacae Strains 
Antimicrobial Agents and Chemotherapy  1998;42(12):3304-3308.
The antibacterial activities of human regimens of cefepime, ceftazidime, and imipenem alone or in combination with amikacin against an isogenic pair of Enterobacter cloacae strains (wild type and its corresponding derepressed cephalosporinase mutant) were compared by using our nonlethal model of pneumonia with 180 immunocompetent rats. Compared with untreated animals, all β-lactam-treated rats, except those inoculated with the mutant isolate and receiving ceftazidime, had significantly lower bacterial counts in their lungs 60 h after the onset of therapy. Although the combination of a β-lactam and amikacin was more bactericidal than each corresponding antimicrobial agent alone, true synergy was noted only with cefepime and imipenem against the constitutive derepressed strain.
PMCID: PMC106042  PMID: 9835534
16.  In Vitro Susceptibilities of the Microsporidia Encephalitozoon cuniculi, Encephalitozoon hellem, and Encephalitozoon intestinalis to Albendazole and Its Sulfoxide and Sulfone Metabolites 
Antimicrobial Agents and Chemotherapy  1998;42(12):3301-3303.
In vitro comparisons demonstrated that the efficacy of albendazole, albendazole-sulfoxide, and albendazole-sulfone against pathogenic Encephalitozoon species was proportional to the degree of oxidation at a concentration of >10−3 μg/ml. Furthermore, at a concentration of <10−2 μg/ml, benzimidazoles were more effective against Encephalitozoon cuniculi and Encephalitozoon hellem than against Encephalitozoon intestinalis.
PMCID: PMC106041  PMID: 9835533
17.  An ampD Gene in Pseudomonas aeruginosa Encodes a Negative Regulator of AmpC β-Lactamase Expression 
Antimicrobial Agents and Chemotherapy  1998;42(12):3296-3300.
The ampD and ampE genes of Pseudomonas aeruginosa PAO1 were cloned and characterized. These genes are transcribed in the same orientation and form an operon. The deduced polypeptide of P. aeruginosa ampD exhibited more than 60% similarity to the AmpD proteins of enterobacteria and Haemophilus influenzae. The ampD product transcomplemented Escherichia coli ampD mutants to wild-type β-lactamase expression.
PMCID: PMC106040  PMID: 9835532
18.  Alteration in the GyrA Subunit of DNA Gyrase and the ParC Subunit of DNA Topoisomerase IV in Quinolone-Resistant Clinical Isolates of Staphylococcus epidermidis 
Antimicrobial Agents and Chemotherapy  1998;42(12):3293-3295.
We examined 22 clinical isolates of Staphylococcus epidermidis to analyze the association of alterations in GyrA and ParC with fluoroquinolone resistance. The simultaneous presence of GyrA and ParC alterations was associated with a high level of fluoroquinolone resistance in the clinical isolates of S. epidermidis.
PMCID: PMC106039  PMID: 9835531
19.  In Vitro Activities of Ketolide HMR 3647, Macrolides, and Clindamycin against Coryneform Bacteria 
Antimicrobial Agents and Chemotherapy  1998;42(12):3290-3292.
The in vitro activity of ketolide HMR 3647 against coryneform bacteria isolated from clinical samples was evaluated. Except against Corynebacterium jeikeium and C. urealyticum, HMR 3647 showed high activity against Corynebacterium spp., being more active than 14- and 16-membered macrolides, azithromycin, or clindamycin. HMR 3647 also had high in vitro activity against Brevibacterium spp. and Listeria monocytogenes.
PMCID: PMC106038  PMID: 9835530
20.  The Antiherpesvirus Activity of H2G [(R)-9-[4-Hydroxy-2-(Hydroxymethyl)Butyl]Guanine] Is Markedly Enhanced by the Novel Immunosuppressive Agent Mycophenolate Mofetil 
Antimicrobial Agents and Chemotherapy  1998;42(12):3285-3289.
Mycophenolate mofetil (MMF) has been approved as an immunosuppressive agent in kidney transplant recipients and may thus be used concomitantly with antiherpetic agents, which are used for the treatment of intercurrent herpesvirus infections. We have recently demonstrated that MMF and its parent compound mycophenolic acid (MPA), which is a potent inhibitor of IMP dehydrogenase, potentiate the antiherpesvirus activity of acyclovir, ganciclovir, and penciclovir. We have now evaluated the antiviral efficacy of the combination of MPA and the novel antiherpesvirus agent H2G [(R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine]. When combined with H2G, MPA (at concentrations ranging from 0.25 to 10 μg/ml, which are readily attainable in human plasma) markedly potentiated the antiviral efficacy of H2G against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), as reflected by a 10- to 150-fold decrease in the 50% effective concentration. Moreover, the activity of H2G against a thymidine kinase-deficient strain of HSV-1 (TK− HSV-1) was increased more than 2,500-fold when combined with MPA. MPA by itself had little or no effect on the replication of these viruses. Similar observations were made for varicella-zoster virus. Also, ribavirin (another inhibitor of IMP dehydrogenase) caused a marked enhancement of the activity of H2G against HSV-1 (10-fold), HSV-2 (10-fold), and TK− HSV-1 (>185-fold). Exogenously added guanosine reversed the potentiating effects of MPA on the antiviral activity of H2G, indicating that this potentiating effect resulted from a depletion of the endogenous dGTP pools, thus favoring the inhibitory action of the H2G triphosphate on the viral DNA polymerase.
PMCID: PMC106037  PMID: 9835529
21.  Joint Tolerance to β-Lactam and Fluoroquinolone Antibiotics in Escherichia coli Results from Overexpression of hipA 
Antimicrobial Agents and Chemotherapy  1998;42(12):3282-3284.
The basis of joint tolerance to β-lactam and fluoroquinolone antibiotics in Escherichia coli mediated by hipA was examined. An antibiotic tolerance phenotype was produced by overexpression of hipA under conditions that did not affect the growth rate of the organism. Overexpressing hipA probably decreases the period in which bacteria are susceptible to the antibiotics by temporarily affecting some aspect of chromosome replication or cell division.
PMCID: PMC106036  PMID: 9835528
22.  In Vitro Activity of the New Ketolide HMR3647 in Comparison with Those of Macrolides and Pristinamycins against Enterococcus spp. 
Antimicrobial Agents and Chemotherapy  1998;42(12):3279-3281.
Ninety-four erythromycin-susceptible and 107 erythromycin-resistant enterococcal strains (MIC of ≥512 μg/ml) were inhibited by the ketolide HMR3647 at MICs of ≤0.007 to 0.06 and 0.03 to 8 μg/ml, respectively. Eighteen vanA-positive isolates and 29 high-level-penicillin-resistant isolates, all of them erythromycin resistant, were inhibited by HMR3647 at an MIC range of 0.015 to 4 μg/ml. The new ketolide has excellent activity against Enterococcus species.
PMCID: PMC106035  PMID: 9835527
23.  Rapid Emergence of High-Level Resistance to Quinolones in Campylobacter jejuni Associated with Mutational Changes in gyrA and parC 
Antimicrobial Agents and Chemotherapy  1998;42(12):3276-3278.
Quinolone resistance in clinical isolates of Campylobacter jejuni in Sweden increased more than 20-fold at the beginning of the 1990s. Resistance to 125 μg of ciprofloxacin per ml in clinical isolates was associated with chromosomal mutations in C. jejuni leading to a Thr-86-Ile substitution in the gyrA product and a Arg-139-Gln substitution in the parC product.
PMCID: PMC106034  PMID: 9835526
24.  No Interaction between Ciprofloxacin and an Oral Contraceptive 
Antimicrobial Agents and Chemotherapy  1998;42(12):3266-3268.
Several antibiotics have been reported to lessen the ovarian suppression produced by oral contraceptive agents, as a result of drug interactions. The present investigation was designed to study the likelihood of the occurrence of any such interaction between the fluoroquinolone antibiotic ciprofloxacin (Ciproxin) at a dosage of 500 mg twice a day and the “low-dose” oral contraceptive Marvelon (30 μg of ethinyl estradiol [EE] plus 150 μg of desogestrel). Twenty-four healthy female volunteers were studied in a double-blind, placebo-controlled, randomized crossover trial. There were no significant differences between measurements of the area under the concentration-time curve of EE up to 24 h after oral contraceptive intake during placebo and ciprofloxacin administration on days 11 and 16 of the cycles, indicating the absence of pharmacokinetic interaction. Similarly, no clinically significant differences in the levels of sex hormone binding globulin were found between the placebo and ciprofloxacin cycles, indicating no major variation in EE levels during ciprofloxacin and placebo treatment. Ten subjects in each of the placebo and ciprofloxacin groups had early-follicular-phase levels of 17-β estradiol (<184 ng/liter) at one or more points during their cycles, but none had values above the early-follicular-phase range, indicating no significant ovarian activity. In addition, all subjects had progesterone levels of <2 ng/ml, indicating the absence of ovulation. Only two subjects, who received the placebo, had evidence of sustained follicular growth to a potentially ovulatory follicle (∼18 mm). We conclude that ciprofloxacin does not interfere with the ovarian suppression produced by the low-dose oral contraceptive Marvelon.
PMCID: PMC106032  PMID: 9835524
25.  An Escherichia coli Expression Assay and Screen for Human Immunodeficiency Virus Protease Variants with Decreased Susceptibility to Indinavir 
Antimicrobial Agents and Chemotherapy  1998;42(12):3256-3265.
We have developed a recombinant Escherichia coli screening system for the rapid detection and identification of amino acid substitutions in the human immunodeficiency virus (HIV) protease associated with decreased susceptibility to the protease inhibitor indinavir (MK-639; Merck & Co.). The assay depends upon the correct processing of a segment of the HIV-1 HXB2 gag-pol polyprotein followed by detection of HIV reverse transcriptase activity by a highly sensitive, colorimetric enzyme-linked immunosorbent assay. The highly sensitive system detects the contributions of single substitutions such as I84V, L90M, and L63P. The combination of single substitutions further decreases the sensitivity to indinavir. We constructed a library of HIV protease variant genes containing dispersed mutations and, using the E. coli recombinant system, screened for mutants with decreased indinavir sensitivity. The discovered HIV protease variants contain amino acid substitutions commonly associated with indinavir resistance in clinical isolates, including the substitutions L90M, L63P, I64V, V82A, L24I, and I54T. One substitution, W6R, is also frequently found by the screen and has not been reported elsewhere. Of a total of 12,000 isolates that were screened, 12 protease variants with decreased sensitivity to indinavir were found. The L63P substitution, which is also associated with indinavir resistance, increases the stability of the isolated protease relative to that of the native HXB2 protease. The rapidity, sensitivity, and accuracy of this screen also make it useful for screening for novel inhibitors. We have found the approach described here to be useful for the detection of amino acid substitutions in HIV protease that have been associated with drug resistance as well as for the screening of novel compounds for inhibitory activity.
PMCID: PMC106031  PMID: 9835523

Results 1-25 (665)