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1.  Mechanisms of quinolone resistance in Escherichia coli: characterization of nfxB and cfxB, two mutant resistance loci decreasing norfloxacin accumulation. 
Two genetic loci selected for norfloxacin (nfxB) and ciprofloxacin (cfxB) resistance were characterized. Both mutations have previously been shown to confer pleiotropic resistance to quinolones, chloramphenicol, and tetracycline and to decrease expression of porin outer-membrane protein OmpF. nfxB was shown to map at about 19 min and thus to be genetically distinct from ompF (21 min), and cfxB was shown to be very closely linked to marA (34 min). cfxB was dominant over cfxB+ in merodiploids, in contrast to other quinolone resistance mutations. The two loci appear to interact functionally, because nfxB was not expressed in the presence of marA::Tn5. Both nfxB and cfxB decreased the expression of ompF up to 50-fold at the posttranscriptional level as determined in strains containing ompF-lacZ operon and protein fusions. Both mutations also decreased norfloxacin accumulation in intact cells. This decrease in accumulation was abolished by energy inhibitors and by removal of the outer membrane. These findings, in conjunction with those of Cohen et al. (S. P. Cohen, D. C. Hooper, J. S. Wolfson, K. S. Souza, L. M. McMurry, and S. B. Levy, Antimicrob. Agents Chemother. 32:1187-1191, 1988), suggest a model for quinolone resistance by decreased permeation in which decreased diffusion through porin channels in the outer membrane interacts with a saturable drug efflux system at the inner membrane.
PMCID: PMC171480  PMID: 2658782
2.  Relationship between intracellular concentration of S-adenosylhomocysteine and inhibition of vaccinia virus replication and inhibition of murine L-929 cell growth. 
9-(trans-2',trans-3'-Dihydroxycyclopent-4'-enyl)-adenine (compound 1) and -3-deazaadenine (compound 2), which are specific inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were reported earlier by our laboratory (M. Hasobe, J. G. McKee, D. R. Borcherding, and R. T. Borchardt, Antimicrob. Agents Chemother. 31:1849-1851, 1987) to have anti-vaccinia virus activity with reduced murine L-929 cell toxicity compared with the prototype compound neplanocin A. In this study, we showed that the antiviral and cytotoxic effects of compounds 1 and 2 can be related to intracellular concentrations of AdoHey, which are elevated in cells treated with these inhibitors of AdoHcy hydrolase. For example, concentrations of analogs 1 and 2 that produce 50% inhibition of vaccinia virus replication caused only slight elevations in intracellular levels of AdoHcy (from 50 [controls] to 100 to 125 [drug-treated cells] pmol/mg of protein) and elevations in the ratios of AdoHcy/S-adenosylmethionine (from 0.05 to 0.1 [controls] to 0.15 to 0.19 [drug-treated cells]). In contrast to the extreme susceptibility of virus replication to slight elevations in intracellular AdoHcy, cell viability was quite tolerant to higher levels of this metabolite. For example, concentrations of analogs 1 and 2 that produced 50% inhibition of L-929 cell replication caused significant increases in intracellular levels of AdoHcy (to 825 to 950 pmol/mg of protein) and elevations in AdoHcy/S-adenosylmethionine ratios (approximately 1.3). These data make it possible to assign a therapeutic index of 7 to 8 to these compounds on the basis of the comparison of intracellular levels of AdoHcy that caused 50% inhibition of vaccinia virus replication with those that caused 50% inhibition of L-929 cell replication.
PMCID: PMC284240  PMID: 2764532
4.  Widespread quinolone resistance among methicillin-resistant Staphylococcus aureus isolates in a general hospital. 
Ofloxacin and ciprofloxacin resistance (MIC, greater than 4 micrograms/ml) was encountered in 45 of 50 clinical isolates of methicillin-resistant Staphylococcus aureus. None of 20 methicillin-susceptible strains was resistant to the quinolones (P less than 10(-6). Quinolone-susceptible and -resistant isolates did not differ with respect to culture source or bacteriophage type. The future usefulness of quinolones for S. aureus infection may be limited.
PMCID: PMC172489  PMID: 2729953
5.  Comparative in vitro activities of ofloxacin, difloxacin, ciprofloxacin, and other selected antimicrobial agents against Brucella melitensis. 
The in vitro activities of three quinolones (ofloxacin, difloxacin, and ciprofloxacin) were compared with those of trimethoprim-sulfamethoxazole, streptomycin, tetracycline, and rifampin against 47 Brucella melitensis strains. Ofloxacin was the most active of the test antimicrobial agents. It inhibited 90% of B. melitensis strains at a concentration of 0.02 micrograms/ml.
PMCID: PMC172669  PMID: 2802568
6.  Influence of two quinolones, ofloxacin and pefloxacin, on human myelopoiesis in vitro. 
The influence of ofloxacin and pefloxacin on human myelopoiesis in vitro was investigated. Drug concentrations varied from 0.5 to 50 micrograms/ml, and the effect on granulomonocyte precursors was evaluated on cell cultures in agar. Our results indicate that ofloxacin and pefloxacin do not induce inhibition of myelopoiesis.
PMCID: PMC171436  PMID: 2712545
9.  Antimicrobial activity of Ro 23-9424, a novel ester-linked codrug of fleroxacin and desacetylcefotaxime. 
Ro 23-9424 is a novel ester-linked codrug of fleroxacin (Ro 23-6240; AM-833) and the cefotaxime metabolite desacetylcefotaxime. Its potency was determined against over 1,000 organisms and found to be intermediate between those of the two components. More than 99% of members of the family Enterobacteriaceae were inhibited by greater than or equal micrograms of Ro 23-9424 per ml; its MIC for 50% of strains tested ranged from greater than or equal to 0.06 to 1 micrograms/ml. Staphylococci, streptococci, Branhamella catarrhalis, Corynebacterium jeikeium, Bacillus spp., Haemophilus influenzae, Listeria monocytogenes, and the pathogenic Neisseria spp., including oxacillin-resistant Staphylococcus aureus, beta-lactamase-producing strains, and penicillin-resistant pneumococci, were also inhibited by Ro 23-9424. Pseudomonas aeruginosa, Enterococcus spp., and Bacteroides fragilis group isolates were more refractory to Ro 23-9424 (the MIC for 90% of strains tested was less than or equal to 32 micrograms/ml). Overall, Ro 23-9424 inhibited 97% of the aerobic strains, compared with 90% for ceftazidime and 92% for cefoperazone. Ro 23-9424 was bactericidal, was relatively stable to inoculum effects on MICs at 10(7) CFU/ml, and was determined to be highly active against organisms resistant to fluoroquinolones or ceftazidime. Preliminary quality control guidelines were determined, and a 30-micrograms disk concentration appears to be the most usable form.
PMCID: PMC284260  PMID: 2504106
10.  Efficacy of ciprofloxacin against Leptospira interrogans serogroup icterohaemorrhagiae. 
Ciprofloxacin activity against Leptospira interrogans serogroup icterohaemorrhagiae was studied in vitro and in an animal model. The MBC of ciprofloxacin was 0.6 microgram/ml. Three of three Syrian hamsters died 8 to 9 days after intraperitoneal challenge with 10(6) leptospires. In contrast, five of six animals given ciprofloxacin 3 or 5 days after challenge survived.
PMCID: PMC172537  PMID: 2751290
12.  Pseudomonas cepacia susceptibility to sulbactam. 
For 25 of 32 Pseudomonas cepacia isolates, predominantly from sputum of adult patients, agar dilution MICs of sulbactam were 2.5 micrograms/ml, and for only one was the MIC more than 80 micrograms/ml. Susceptibility was reliably predicted by response to a commercial sulbactam-ampicillin disk.
PMCID: PMC172485  PMID: 2729951
13.  Treatment failure of norfloxacin against Campylobacter pylori and chronic gastritis in patients with nonulcerative dyspepsia. 
Several reports have been published to show the in vitro susceptibility of Campylobacter pylori to different classes of antibiotics, including fluoroquinolones. The purpose of this study was to describe the clinical effect of norfloxacin on eradication of C. pylori in patients with gastritis. Endoscopy was performed in 38 patients with symptoms of nonulcerative dyspepsia. Of these, 20 patients had a C. pylori-positive culture. From this group, 17 patients were treated with norfloxacin for 1 month. After therapy, 15 patients still had positive cultures, and in 9 cases the strain was resistant to norfloxacin. These data, which confirm previous studies, support the concept that the in vitro activity of norfloxacin against C. pylori cannot be transposed to an in vivo effect.
PMCID: PMC171471  PMID: 2719469
14.  Reactivation of peptidoglycan synthesis in ether-permeabilized Escherichia coli after inhibition by beta-lactam antibiotics. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2101-2108.
The recovery of peptidoglycan-synthesizing activity after inhibition by beta-lactam antibiotics was investigated in ether-permeabilized cells of Escherichia coli B. Such cells synthesize sodium dodecyl sulfate-insoluble peptidoglycan when provided with UDP-linked precursors and Mg2+. The ability of beta-lactam antibiotics to inhibit the synthesis of peptidoglycan was correlated with their affinity for penicillin-binding proteins 1A and 1Bs. Penicillin-binding protein 1Bs is thought to be the major peptidoglycan synthetase in E. coli and is a major lethal target for beta-lactam antibiotics. Ether-treated bacteria were preincubated with concentrations of beta-lactams sufficient to completely inhibit peptidoglycan synthesis and then treated with beta-lactamases to inactivate free antibiotic prior to measurement of peptidoglycan synthesis. At 40 min after beta-lactamase treatment, the rate of peptidoglycan synthesis was about 74% of the control rate in cells pretreated with ampicillin, but only 15% of the control in cells pretreated with penicillin G or azlocillin. Reversal of inhibition by several other antibiotics fell between these extremes. When cross-linking of peptidoglycan was measured specifically, reversal of inhibition by ampicillin also occurred more readily than that by penicillin G. Reactivation of peptidoglycan synthesis was not due to de novo synthesis of penicillin-binding proteins since it occurred under conditions that did not allow incorporation of [14C]leucine. We conclude that there is considerable variation in the stability of the inactive acyl enzymes formed between various beta-lactams and penicillin-binding protein 1Bs, with those formed by penicillin G being relatively long-lived.
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PMCID: PMC172829  PMID: 2515794
15.  Binding and killing of bacteria by bismuth subsalicylate. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2075-2082.
Bismuth subsalicylate (BSS) is a compound without significant aqueous solubility that is widely used for the treatment of gastrointestinal disorders. BSS was able to bind bacteria of diverse species, and these bound bacteria were subsequently killed. A 4-log10 reduction of viable bacteria occurred within 4 h after a 10 mM aqueous suspension of BSS was inoculated with 2 x 10(6) Escherichia coli cells per ml. Binding and killing were dependent on the levels of inoculated bacteria, and significant binding but little killing of the exposed bacteria occurred at an inoculum level of 2 x 10(9) E. coli per ml. Intracellular ATP decreased rapidly after exposure of E. coli to 10 mM BSS and, after 30 min, was only 1% of the original level. Extracellular ATP increased after exposure to BSS, but the accumulation of extracellular ATP was not sufficient to account for the loss of intracellular ATP. The killing of bacteria exposed to BSS may have been due to cessation of ATP synthesis or a loss of membrane integrity. Bactericidal activity of BSS was also investigated in a simulated gastric juice at pH 3. Killing of E. coli at this pH was much more rapid than at pH 7 and was apparently due to salicylate released by the conversion of BSS to bismuth oxychloride. It is proposed that the binding and killing observed for BSS contribute to the efficacy of this compound against gastrointestinal infections such as traveler's diarrhea.
PMCID: PMC172824  PMID: 2694949
16.  Oral and parenteral therapy with saperconazole (R 66905) of invasive aspergillosis in normal and immunocompromised animals. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2063-2068.
Saperconazole (R 66905) is a broad-spectrum antifungal triazole with potent in vitro activity against Aspergillus spp. A total of 279 strains were tested in brain heart infusion broth. Development of the Aspergillus spp. was completely inhibited at 0.1 and 1 microgram of saperconazole per ml for 80.3 and 99.6% of the strains, respectively. Normal and immunocompromised guinea pigs were infected intravenously with Aspergillus fumigatus and treated orally, intravenously, or intraperitoneally with saperconazole or intraperitoneally with amphotericin B. Leukopenia, neutropenia, lymphocytosis, and monocytosis were obtained with mechlorethamine hydrochloride; leukopenia, neutrophilia, and lymphopenia were obtained with cyclophosphamide. Saperconazole was dissolved for oral treatment in polyethylene glycol and for parenteral treatment in cyclodextrins. Amphotericin B was given parenterally as Fungizone (E.R. Squibb & Sons). Treatment was given once daily for 14 days. An early starting treatment was efficacious, but the activity of saperconazole was maintained even when the onset of the treatment was delayed to the moribund state. The activity of saperconazole was not altered in immunocompromised animals. Saperconazole was clearly superior to amphotericin B and free of side effects. The oral and parenteral formulations of saperconazole were equipotent. The systemic activity of saperconazole in guinea pigs was confirmed in invasive aspergillosis in pigeons.
PMCID: PMC172822  PMID: 2619273
18.  Multiplicity of TEM-derived beta-lactamases from Klebsiella pneumoniae strains isolated at the same hospital and relationships between the responsible plasmids. 
Antimicrobial Agents and Chemotherapy  1989;33(11):1915-1920.
Five plasmid-mediated beta-lactamases conferring high-level resistance to ceftazidime were isolated from Klebsiella pneumoniae strains in the same hospital. These enzymes had isoelectric points ranging from 5.3 to 6.5 (CAZ-1, 5.55; CAZ-2, 6.0; CAZ-3, 5.3; CAZ-6, 6.5; and CAZ-7, 6.3). All isolates and their Escherichia coli transconjugants were highly resistant to amoxicillin (MICs, greater than 4,096 micrograms/ml), piperacillin (64 to 256 micrograms/ml), cephalothin (32 to 256 micrograms/ml), and ceftazidime (32 to 512 micrograms/ml) but remained moderately susceptible to cefotaxime (0.5 to 8 micrograms/ml). Only CAZ-6- and CAZ-7-producing strains were highly resistant to aztreonam (64 to 128 micrograms/ml). All the isolates remained susceptible to moxalactam and imipenem. The reduced activity of piperacillin, cefotaxime, ceftazidime, or aztreonam was restored by 2 micrograms of clavulanate, sulbactam, tazobactam, or brobactam per ml for E. coli producing CAZ-2, CAZ-3, and CAZ-7. Sulbactam had a lower protective effect than other inhibitors for E. coli harboring CAZ-1 and especially CAZ-6. Except for CAZ-1, which was mediated by a 150-kilobase (kb) plasmid (pCFF14), the other ceftazidimases were mediated by plasmids of 85 kb with EcoRI digestion patterns similar to that of pCFF04 encoding CTX-1 beta-lactamase. A TEM probe hybridized with a 19-kb EcoRI fragment of all these closely related plasmids.
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PMCID: PMC172787  PMID: 2558614
20.  Guidelines for Reports of Clinical Studies 
Antimicrobial Agents and Chemotherapy  1989;33(11):1829-1830.
PMCID: PMC172771  PMID: 16557677
21.  Role of autolysins in the activities of imipenem and CGP 31608, a novel penem, against slowly growing bacteria. 
Antimicrobial Agents and Chemotherapy  1989;33(10):1819-1821.
The carbapenem imipenem and the penem CGP 31608 demonstrated unusually good bactericidal activity against slowly growing bacteria. In contrast to that of penicillin, the rate of killing was independent of growth rate. In logarithmically growing cells, a decrease in growth rate was paralleled by a decrease in the relative activity of only one of four autolysins measured (membrane-bound endopeptidase), suggesting that autolysis induced by penicillin G may be rate limited by this enzyme. Imipenem, on the other hand, appeared to trigger different autolysins in Escherichia coli, as evidenced by differences in the structure of peptidoglycan after imipenem- versus penicillin-induced autolysis.
PMCID: PMC172763  PMID: 2574024
22.  Treatment of experimental disseminated candidiasis with cilofungin. 
Antimicrobial Agents and Chemotherapy  1989;33(10):1811-1812.
The efficacy of cilofungin treatment of experimental disseminated candidiasis in rabbits was examined. Cilofungin treatment reduced yeast counts, especially in the kidney, with activity comparable to that of amphotericin B. The peak level of cilofungin in serum was measured at 5 min after administration of a single dose, with no drug detectable after 90 min.
PMCID: PMC172760  PMID: 2589848
23.  Ex vivo study of serum bactericidal titers and killing rates of daptomycin (LY146032) combined or not combined with amikacin compared with those of vancomycin. 
Antimicrobial Agents and Chemotherapy  1989;33(10):1783-1790.
Twelve volunteers, in two groups of six, received daptomycin at a dose of 1 or 2 mg/kg. In addition, they received in a randomly allocated order amikacin (500 mg), daptomycin-amikacin, and vancomycin (500 mg). Thirty-five clinical isolates, including Staphylococcus aureus, S. epidermidis, Corynebacterium sp. group JK, and Enterococcus faecalis, were tested in vitro for the measure of the serum bactericidal titers and killing rates. The mean peak concentrations of daptomycin in serum 1 h after the administration of 1 and 2 mg/kg were 11 and 20 micrograms/ml, respectively. At 24 h after the administration of 2 mg/kg, the mean level in serum was 1.9 micrograms/ml, which is higher than the MICs for susceptible pathogens. Daptomycin and amikacin provided identical concentrations in serum whether given alone or in combination. Among the six regimens tested, those including daptomycin provided the highest and the most prolonged serum bactericidal titers against S. aureus, S. epidermidis, and E. faecalis. The killing rates measured by the killing curves were correlated with the concentration/MIC and concentration/MBC ratios of daptomycin for all strains tested. Significant killing occurred once the concentration of daptomycin in the serum 4- to 6-fold the MIC or 1- to 1.2-fold the MBC. The combination of daptomycin and amikacin had no effect on either the serum bactericidal titers or the rates of killing. Only vancomycin provided significant killing of the strains of Corynebacterium sp. group JK.
PMCID: PMC172755  PMID: 2556079
24.  Synergistic therapy by acyclovir and A1110U for mice orofacially infected with herpes simplex viruses. 
Antimicrobial Agents and Chemotherapy  1989;33(10):1691-1696.
Clinical effects of the administration of a combination of acyclovir (ACV) and compound A1110U (a 2-acetylpyridine thiocarbonothiohydrazone inactivator of herpes simplex virus [HSV] ribonucleotide reductase) on the development of herpetic skin lesions were studied in athymic and hairless mice infected intracutaneously with different HSV type 1 (HSV-1) strains. ACV was administered topically (5%) or orally (5 mg/ml), while A1110U was applied topically (3%). In all but one experiment, the effect of combination therapy was greater than that calculated for the sum of the individual drug effects in limiting the development of herpetic skin lesions in mice. In several experiments, combination therapy totally eliminated all signs of infection. This synergistic chemotherapeutic efficacy was evident in infections caused by ACV-susceptible as well as several ACV-resistant HSV-1 strains. These results indicate that this combination therapy may provide a significant improvement in clinical responses over single-agent topical therapy.
PMCID: PMC172739  PMID: 2556074
25.  Rapid nucleic acid assay for detection of bacteria with tetM-mediated tetracycline resistance. 
Antimicrobial Agents and Chemotherapy  1989;33(10):1813-1815.
A novel nucleic acid assay has been developed to screen bacterial populations for the presence of the tetM structural gene. The method involves the specific hybridization of several synthetic oligonucleotides to the gene in a crude bacterial lysate solution. As few as 1.5 x 10(4) CFU can be detected with the assay.
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PMCID: PMC172761  PMID: 2511803

Results 1-25 (462)