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1.  Paradoxical activity of beta-lactam antibiotics against Proteus vulgaris in experimental infection in mice. 
In previous papers (Y. Ikeda and T. Nishino, Antimicrob. Agents Chemother. 32:1073-1077, 1988; Y. Ikeda, T. Nishino, and T. Tanino, Antimicrob. Agents Chemother. 31:865-869, 1987), we reported that many of the 7-aminothiazolyl cephalosporins, such as cefmenoxime, showed paradoxically reduced activity against Proteus vulgaris at higher concentrations, whereas these paradoxical effects were not observed for other types of cephalosporins, such as cefbuperazone and cefoperazone. In this study, we compare the therapeutic effect of cefmenoxime with that of cefbuperazone and explore the in vivo paradoxical effect of cefmenoxime by using an experimental infection model in mice. In an intraperitoneal infection with P. vulgaris 11, the survival rate with cefmenoxime was increased to 43% at 3.13 mg/kg but was lower at higher doses. On the other hand, cefbuperazone did not show such a paradoxical therapeutic effect. In mice infected with P. vulgaris 11, cefmenoxime levels in both serum and peritoneal washings were rapidly reduced and beta-lactamase activities in the peritoneal cavity were increased at higher cefmenoxime doses. These findings suggested that high levels of cefmenoxime at the infection site induced increased production of beta-lactamase, which then rapidly inactivated the antibiotic. We conclude that the paradoxical therapeutic effect of cefmenoxime against P. vulgaris occurs by the same mechanisms as the in vitro effect and that the high beta-lactamase inducibility and low beta-lactamase stability may account for the paradoxical therapeutic effect of cefmenoxime against P. vulgaris.
PMCID: PMC171526  PMID: 2183712
2.  Ultrastructural alterations induced by two ergosterol biosynthesis inhibitors, ketoconazole and terbinafine, on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2097-2105.
We report the ultrastructural alterations induced during the proliferative stages of Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease, by two ergosterol biosynthesis inhibitors, ketoconazole and terbinafine, which had previously been shown to be potent growth inhibitors whose effects are potentiated when used in combination (J. A. Urbina, K. Lazardi, T. Aguirre, M. M. Piras, and R. Piras, Antimicrob. Agents Chemother. 32:1237-1242, 1988). Epimastigotes treated with a low concentration of ketoconazole (1 microM), which blocks ergosterol biosynthesis at the level of C-14 demethylation of lanosterol and induces cell lysis coincident with total ergosterol depletion, showed gross alterations of the kinetoplast-mitochondrion complex, which swelled and lost the organization of its inner membrane and the electron-dense bodies of its matrix. Thus, coincident with the beginning of cell lysis, the kinetoplast-mitochondrion complex occupied greater than 80% of the cell volume, while other subcellular structures such as the nucleus and subpellicular microtubules were not affected. Terbinafine, which blocks ergosterol synthesis in these cells at the level of squalene synthetase and thus leads to almost immediate arrest of growth at concentrations greater than 1 microM, produced proliferation of glycosomelike bodies, binucleated cells (arrest at cytokinesis), and eventually massive vacuolization. When the drugs were combined, the predominant effect was mitochondrial swelling, which was more drastic and took place earlier than that observed in cells treated with ketoconazole alone. In amastigotes proliferating in Vero cells, ketoconazole at the concentration required to eradicate the parasites (10 nM) produced mitochondrial swelling, the appearance of autophagic vacuoles containing partially degraded subcellular material, and finally a general breakdown of the subcellular structures. Terbinafine at 3 microM induced more limited ultrastructural damage to the amastigotes consistent with increased vacuolization of the cells and the appearance of occasional autophagic vacuoles. When the drugs were used in combination, just 1 nM was required for the total eradication of parasites, the ultrastructural effects were more extensive, and cell disintegration occurred earlier than when any of the drugs was used alone at a much higher concentration. No effect of the drugs on the ultrastructure of the host cells were observed at any of the concentrations tested.
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PMCID: PMC172006  PMID: 2073100
3.  Role of an energy-dependent efflux pump in plasmid pNE24-mediated resistance to 14- and 15-membered macrolides in Staphylococcus epidermidis. 
Antimicrobial Agents and Chemotherapy  1990;34(10):1973-1980.
We have elucidated a new mechanism for bacterial resistance to the 14-membered macrolides oleandomycin and erythromycin and the 15-membered macrolide azithromycin. Plasmid pNE24, previously isolated from a clinical specimen of Staphylococcus epidermidis, was characterized as causing resistance to 14-membered but not 16-membered macrolides by a mechanism suggested to involve reduced antibiotic permeation of bacterial cells (B. C. Lampson, W. von David, and J. T. Parisi, Antimicrob. Agents Chemother. 30:653-658, 1986). Our recent investigations have demonstrated that S. epidermidis 958-2 containing plasmid pNE24 also contains an energy-dependent macrolide efflux pump which maintains intracellular antibiotic concentrations below those required for binding to ribosomes. Thus, when strain 958-2 was pretreated with the inhibitor carbonyl cyanide m-chlorophenylhydrazone (CCCP), macrolide accumulated at the same rate and to the same extent as in CCCP-treated or untreated control cells lacking plasmid pNE24 (strain 958-1). In contrast, macrolide did not accumulate in energy-competent strain 958-2 but did accumulate to levels equal to those of ribosomes immediately following CCCP addition. Furthermore, intracellular macrolide was excreted and bacteria resumed growth when CCCP but not macrolide was removed from the growth medium. As expected, the 16-membered macrolide niddamycin accumulated to the same level in energy-competent strains 958-1 and 958-2 at the same rapid rate. Macrolide incubated with lysates prepared from both strains or recovered from cells of strain 958-2 was unmodified and bound to ribosomes from strains 958-1 and 958-2 with identical affinities and kinetics, thus precluding a role for ribosome or drug alteration in the resistance mechanism. We conclude that the presence of plasmid pNE24 results in specific energy-dependent efflux of 14- and 15-membered macrolides.
PMCID: PMC171974  PMID: 1963291
13.  In vitro susceptibility of Mycobacterium avium complex to the new fluoroquinolone sparfloxacin (CI-978; AT-4140) and comparison with ciprofloxacin. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2442-2444.
We tested the activity of the new fluoroquinolone sparfloxacin (CI-978; AT 4140) against 30 strains of Mycobacterium avium complex (MAC) isolated from patients with acquired immune deficiency syndrome. MICs of sparfloxacin (range, less than or equal to 0.06 to 4 micrograms/ml) were lower than MICs of ciprofloxacin for all 30 strains, and MBCs for acid-fast bacteria were lower for 28 of the 30 strains. In synergism experiments using 10 strains of MAC, fractional inhibitory concentration indices revealed that the combination of sparfloxacin plus ethambutol was synergistic against 9 strains, and the three-drug combination of sparfloxacin plus ethambutol plus rifampin was synergistic against all strains. In the absence of ethambutol, the combination of sparfloxacin plus rifampin appeared to be antagonistic against three of the MAC strains.
PMCID: PMC172081  PMID: 2088204
14.  Penicillinase production and in vitro susceptibilities of Staphylococcus lugdunensis. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2434-2435.
Of 59 clinical isolates of Staphylococcus lugdunensis, 76% were beta-lactamase negative, with penicillin G MICs of less than or equal to 0.13 microgram/ml, and 24% were beta-lactamase positive, with penicillin MICs of greater than or equal to 0.5 microgram/ml. Bimodal distributions were observed also with ampicillin, ampicillin-sulbactam, and amoxicillin-clavulanate. All strains were susceptible to oxacillin, cephalothin, gentamicin, rifampin, and vancomycin; 98% were erythromycin susceptible.
PMCID: PMC172078  PMID: 2088201
15.  Effect of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil against herpes simplex virus type 1 infection in immunosuppressed mice. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2431-2433.
1-beta-D-Arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) reduced the mortality rates of (i) 7-week-old, cyclophosphamide-treated, immunosuppressed mice (CYP mice) intraperitoneally infected with a moderately virulent strain of herpes simplex virus type 1 and (ii) 4-week-old CYP mice infected with a less virulent strain at doses of 20 and 50 mg/kg of body weight twice daily and 5 mg/kg, respectively. The degree of efficacy of BV-araU was equivalent to that of acyclovir in 4-week-old CYP mice infected with the less virulent strain. BV-araU (20 mg/kg) suppressed viral growth in various organs of CYP mice.
PMCID: PMC172077  PMID: 1965108
16.  Induction of the Citrobacter freundii group I beta-lactamase in Escherichia coli is not dependent on entry of beta-lactam into the cytoplasm. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2429-2430.
Induction of the cloned ampC Citrobacter freundii beta-lactamase in Escherichia coli by 6-aminopenicillanic acid was prevented by periplasmic TEM beta-lactamase in the same cell. In contrast, cytoplasmic TEM beta-lactamase did not prevent induction. This result implies that entry of the beta-lactam into the cytoplasm is not necessary for induction of ampC.
PMCID: PMC172076  PMID: 2088200
17.  Activity of cefixime against Helicobacter pylori and affinities for the penicillin-binding proteins. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2426-2428.
Cefixime induced the formation of rounded cells from the spiral bacillary form of Helicobacter pylori at the MIC or less. Three main penicillin-binding proteins, called A, B and C, were separated from H. pylori. Cefixime had the strongest affinity to penicillin-binding protein B. The binding of cefixime to this protein may induce the formation of rounded H. pylori cells.
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PMCID: PMC172075  PMID: 2088199
18.  Potentiation by salicylate and salicyl alcohol of cadmium toxicity and accumulation in Escherichia coli. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2402-2406.
The toxicity of Cd2+ in Escherichia coli K-12 was potentiated by salicylate and several related compounds. The efficiency of plating on Luria broth plates was reduced by more than 10(5)-fold when 10 mM salicylate and 200 microM CdCl2 were present simultaneously but was unaffected when either compound was present by itself. Synergistic effects were found at pH 7.4 with certain other weak acids (acetyl salicylate [aspirin], benzoate, and cinnamate) and with a nonacidic salicylate analog, salicyl alcohol, but not with acetate or p-hydroxy benzoate. Thus, the synergism with Cd2+ is determined by the structure of the compounds and not merely by their acidity. The kinetics of 109Cd2+ uptake by cells grown and assayed in broth indicated the presence of two uptake systems with Kms of 1 and 52 microM Cd2+ and Vmaxs of 0.059 and 1.5 mumol of Cd2+ per min per g of cells, respectively. The kinetics of uptake for cells grown and assayed with 20 mM salicyl alcohol showed 2.5-fold increases in the Vmaxs of both systems but no change in the Kms. Salicylate-grown cells also exhibited increased rates of 109Cd2+ uptake by both systems. Thus, enhanced uptake of Cd2+ may be responsible for the potentiation of Cd2+ toxicity by salicylate and salicyl alcohol.
PMCID: PMC172069  PMID: 2088194
19.  Intraprostatic distribution of lomefloxacin following multiple-dose administration. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2398-2401.
The ability of lomefloxacin to penetrate and distribute within the human prostate was assessed in 20 patients undergoing elective prostate surgery (18 transurethral prostatic resections and 2 prostatectomies). Subjects were middle-aged to elderly (mean age +/- standard deviation, 69.8 +/- 8.2 years) with normal hepatic function and with creatinine clearances ranging from 35.8 to 141 ml/min/1.73 m2. Lomefloxacin was administered in 400-mg doses orally every 24 h. Its disposition was characterized following the third dose by obtaining multiple serum samples and intraoperative paired central zone and peripheral zone prostate tissue samples. Lomefloxacin concentrations were determined by a validated high-performance liquid chromatography method with fluorescence detection. Concentrations in serum during the perioperative period declined from 3.1 +/- 1.0 mg/liter (mean +/- standard deviation) at 1 h postdose to 2.3 +/- 0.7 mg/liter at 6 h postdose. The time of tissue extraction ranged from 0.1 to 7.1 h postdose. Intraoperative serum lomefloxacin concentrations ranged from 0.5 to 4.8 (median, 2.4) mg/liter, while prostate tissue concentrations ranged from 1.1 to 10.1 (median, 5.4) mg/kg of tissue for the central zone and 0.9 to 6.5 (median, 5.2) mg/kg for the peripheral zone. Intraindividual paired prostate concentrations (central zone versus peripheral zone) were not statistically different. The partition coefficient (ratio of concentration in prostate to concentration in serum) for the central zone was 2.2 +/- 0.6 (range, 1.2 to 3.1), and for the peripheral zone it was 2.1 +/- 0.7 (range, 1.2 to 4.2). Lomefloxacin exhibited good penetration into the human prostate with homogeneous intraprostatic distribution following multiple-dose administration.
PMCID: PMC172068  PMID: 2088193
20.  Treatment of bone, joint, and vascular-access-associated gram-positive bacterial infections with teicoplanin. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2392-2397.
Teicoplanin, a glycopeptide antibiotic, was evaluated for safety and efficacy in the treatment of vascular-access-associated bacteremias and of bone and joint infections due to susceptible gram-positive organisms. Of 35 patients enrolled, 26 had osteomyelitis, 8 had vascular-access-associated bacteremias, and 1 had a joint infection. A total of 38 gram-positive isolates were identified: 23 Staphylococcus aureus and 6 coagulase-negative staphylococcus and 9 streptococcus isolates. After at least 6 months of follow-up, 17 patients were evaluable for efficacy: 10 of 14 (71%) with osteomyelitis and 3 of 3 with vascular-access-associated bacteremias had full resolution of their infections. Inadequate debridement, the presence of metal, and inadequate dosing were likely causes of two failures and two relapses in patients with osteomyelitis. For all but two organisms, teicoplanin MICs were less than or equal to 2 micrograms/ml. Patients who responded had median peak and trough serum bactericidal levels at serum dilutions of 1:64 and 1:16; trough levels of teicoplanin in serum were greater than 30 micrograms/ml. Patients did not respond as expected to daily doses of 4 mg/kg of body weight, which consequently were increased to greater than or equal to 15 mg/kg. Audiology testing of 20 patients found 2 with a mild loss of high-frequency hearing; 1 patient complained of tinnitus. Patients tolerated peak levels in serum as high as 127 micrograms/ml and trough levels of 49 micrograms/ml. However, 5 of 18 patients (28%) whose daily dose was greater than or equal to 12 mg/kg developed drug fever and rash and had teicoplanin discontinued. Further study of the antibiotic at such higher doses is needed.
PMCID: PMC172067  PMID: 2150908
21.  Intraoperative concentrations of ofloxacin in serum, bile fluid, and gallbladder wall tissue. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2354-2357.
To evaluate concentrations of ofloxacin in serum, bile fluid, and gallbladder wall tissue after intravenous administration, patients greater than or equal to 16 years old diagnosed with acute cholecystitis were randomly assigned to receive ofloxacin (400 mg) intravenously every 12 h or ceftazidime (2 g) intravenously every 8 h. Doses of each regimen were given preoperatively. Serum, bile fluid, and gallbladder wall tissue samples of consecutive patients in the ofloxacin group were obtained intraoperatively. The samples were frozen at -70 degrees C until analyzed by high-pressure liquid chromatography. Twenty-three patients (6 males and 17 females) were evaluated. The mean (+/- the standard deviation) ofloxacin concentrations in serum, bile fluid, and gallbladder wall tissue were 2.9 +/- 2.4 and 6.0 +/- 7.9 micrograms/ml and 3.1 +/- 2.9 micrograms/g, respectively. The mean number of doses each patient received before surgery was 5.3 +/- 3.0, and the mean delta time (time elapsed between last antibiotic administration and when intraoperative samples were obtained) was 9.6 +/- 7.5 h. The mean tissue-to-serum ratio was 1.2 +/- 0.5, and the mean bile-to-serum ratio was 2.3 +/- 1.4. The mean serum ofloxacin concentrations were not statistically different from the concentrations in bile (P = 0.1) and tissue (P = 0.7) at the mean delta time. The study revealed that concentrations of ofloxacin in serum, bile fluid, and gallbladder tissue after intravenous dosing were adequate against susceptible organisms found in the biliary tract.
PMCID: PMC172060  PMID: 2088189
22.  Comparative efficacy of daptomycin, vancomycin, and cloxacillin for the treatment of Staphylococcus aureus endocarditis in rats and role of test conditions in this determination. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2348-2353.
The in vivo efficacy of daptomycin, a new cell wall-active anti-gram-positive-bacterial agent, was compared to those of cloxacillin and vancomycin in a rat model of Staphylococcus aureus endocarditis. Both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains were used. When therapy was initiated early (8 h) after infection, at the time when valvular bacterial counts were relatively low (approximately 10(6) CFU/g of vegetation), 3 days of therapy was found to be effective against the MSSA strains whatever the antibiotic regimen. In contrast, when the onset of therapy was delayed up to 15 h after infection, so that higher bacterial counts could develop on the valves (approximately 10(9) CFU/g of vegetation), a longer period of treatment (6 days) was required to cure infection. Under these conditions after 3 days of therapy, daptomycin was more effective than cloxacillin and vancomycin against the MSSA strains. Similarly, daptomycin showed a greater activity than vancomycin against the MRSA strain after 3 days of treatment, but after 6 days both antibiotics were equally effective. Decreasing doses of daptomycin showed decreasing activity: 10 mg/kg of body weight every 12 h (q12h) was better than 5 mg/kg q12h, whereas 5 mg/kg q24h (providing drug levels in blood detectable only during the first 12 h) failed to cure infection. In vitro, daptomycin was highly bactericidal at high concentrations (25 and 60 micrograms/ml, corresponding to peak levels in serum after doses of 5 and 10 mg/kg, respectively) and bacteriostatic at lower concentrations (0.5 to 2.5 micrograms/ml, corresponding to trough levels in serum). In conclusion, against low-bacterial-count S. aureus endocarditis, daptomycin showed an efficacy similar to those of vancomycin and cloxacillin. Against high-bacterial-count S. aureus endocarditis, daptomycin showed a higher bactericidal activity than cloxacillin (against the MSSA strains) and vancomycin (against both the MSSA and MRSA strains).
PMCID: PMC172059  PMID: 1965105
23.  Human safety and pharmacokinetics of a single intramuscular dose of a novel spectinomycin analog, trospectomycin (U-63,366F). 
Antimicrobial Agents and Chemotherapy  1990;34(12):2342-2347.
In this study, local and systemic tolerance and pharmacokinetics of trospectomycin sulfate in human beings were evaluated for the first time. Trospectomycin sulfate (U-63,366F; trospectomycin) or sterile saline was administered to 96 healthy male volunteers in doses ranging from 0.25 ml (75 mg) to 3.3 ml (1,000 mg) in a single intramuscular injection in a double-blind, randomized design. Volunteers were screened to establish baseline vital signs and laboratory test values. Pain and tenderness at the injection site, which occurred at doses of 450 mg and above, were the most common side effects; they were mild in severity and transient. Adverse drug experiences reported by subjects included nausea, dizziness, light-headedness, diaphoresis, costal pain, and perioral numbness. The perioral numbness (paresthesia) experienced at doses of 750, 900, and 1,000 mg was probably drug related. No Clostridium difficile toxin was detected in fecal samples. Pharmacokinetic calculations based on data obtained by high-performance liquid chromatography showed that after a 1,000-mg intramuscular dose of trospectomycin (3.3 ml), the serum mean half-life was 1.85 h (1.70 to 2.02 h), mean area under the serum concentration-time curve was 140.2 micrograms.h/ml and was linear with dose, mean peak concentration was 28.3 micrograms/ml (20.4 to 34.7 micrograms/ml), mean time to maximum concentration was 71 min (30 to 120 min), and the elimination rate constant was 0.307 h-1. The elimination rate constant and half-life did not vary with dose. Little trospectomycin was detected in 2-day fecal collections. A few randomly occurring abnormal clinical laboratory test values and vital signs were observed. For the trospectomycin-treated group, creatinine phosphokinase increased substantially for 24 h after injection and then decrease through day 5, while serum glutamic oxalacetic transaminase and lactate dehydrogenase increased slightly.
PMCID: PMC172058  PMID: 2150907
24.  Novel bacteriological assay for detection of potential antiviral agents. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2337-2341.
A prototype assay for the initial screening of potential antiviral agents that uses bacterial growth on selective media is described. The human immunodeficiency virus (HIV) protease recognition sequence was inserted into the tetracycline resistance (Tet) protein encoded by plasmid pBR322 of Escherichia coli. Expression of both the HIV protease and the modified Tet protein prevented growth in the presence of tetracycline. However, inhibition of the HIV protease restored tetracycline resistance. Thus, potential HIV protease inhibitors can be identified by their ability to confer tetracycline resistance to this bacterial strain. The assay is simple, rapid, and inexpensive, and this concept can be applied to the search for inhibitors of other viral proteases.
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PMCID: PMC172057  PMID: 2088188
25.  Correlation of quinolone MIC and inhibition of DNA, RNA, and protein synthesis and induction of the SOS response in Escherichia coli. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2331-2336.
The effects of nalidixic acid and four fluoroquinolones on DNA, RNA, and protein synthesis in the presence and absence of 20 mg of chloramphenicol per liter were examined by comparing the killing kinetics, MIC, morphological response, and maximum concentration to induce recA in Escherichia coli. All agents demonstrated paradoxical killing kinetics, in that above an optimum concentration the rate of bactericidal action was slower. Filamentation of E. coli AB1157 was observed with all quinolones up to the optimum bactericidal concentration. Addition of chloramphenicol reduced the bactericidal activity, inhibited filamentation, and abolished recA induction, but it had no effect on DNA synthesis inhibition by any of the agents. Excellent correlation was obtained between the concentration required to inhibit DNA synthesis by 50%, the MIC, the maximum concentration to induce recA, and the optimum bactericidal concentration. Evidence from this study and previously published data suggest that the primary mechanism of action of quinolones is independent of the SOS response and does not require active protein synthesis; however, induction of recA and SOS responses is consequential and enhances cell death.
PMCID: PMC172056  PMID: 1708224

Results 1-25 (530)