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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
5.  In vitro activity of ciprofloxacin in combination with ceftazidime, aztreonam, and azlocillin against multiresistant isolates of Pseudomonas aeruginosa. 
The combinations of ciprofloxacin plus ceftazidime, ciprofloxacin plus aztreonam, and ciprofloxacin plus azlocillin were evaluated for the presence of synergy against multiresistant isolates of Pseudomonas aeruginosa. The frequency of synergy was dependent on antibiotic susceptibilities. If the organism was resistant to ciprofloxacin, synergy was observed in more than 50% of the isolates; however, if the organism was resistant to the beta-lactam (with the exception of ceftazidime), synergy was generally observed in less than 10% of the isolates. Antagonism was not observed with any of the combinations. These results may be helpful in making clinical decisions in treating P. aeruginosa infections.
PMCID: PMC171935  PMID: 2126693
7.  In Vitro Susceptibility of Campylobacter jejuni to Rokitamycin 
The susceptibilities of 100 clinical isolates of Campylobacter jejuni to rokitamycin, a new macrolide, and eight other oral antibiotics were tested by using a broth microdilution method. Rokitamycin demonstrated antibacterial activity that was higher than those of fosfomycin and the tetracyclines and comparable to those of erythromycin and clindamycin, whereas it was slightly less active than the quinolones.
PMCID: PMC175996  PMID: 2386373
8.  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
9.  Percentages and distributions of teicoplanin- and vancomycin-resistant strains among coagulase-negative staphylococci. 
The activities of teicoplanin and vancomycin against 362 coagulase-negative staphylococci were determined by an agar dilution method. At the 4- and 32-micrograms/ml breakpoint levels of the National Committee for Clinical Laboratory Standards, 23.2% of the strains were intermediate and 1.7% were resistant to teicoplanin, in contrast to less than 0.3% intermediate to vancomycin. Resistant strains belonged to the species Staphylococcus epidermidis (74%) and S. haemolyticus (19%).
PMCID: PMC171714  PMID: 2141780
10.  Penetration of clindamycin, cefoxitin, and metronidazole into pelvic peritoneal fluid of women undergoing diagnostic laparoscopy. 
A single dose of clindamycin, cefoxitin, or metronidazole was administered to each of 30 women. The mean concentration of cefoxitin in pelvic fluid at 1 h exceeded those of the other two drugs (P less than 0.007). Cefoxitin concentrations were inferior to those of the other drugs when compared with the published MIC for 90% of Bacteroides fragilis strains.
PMCID: PMC171594  PMID: 2139315
11.  Activities of pefloxacin and ciprofloxacin against experimental malaria in mice. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2327-2330.
We investigated the in vivo antimalarial activities of pefloxacin and ciprofloxacin in Swiss albino mice infected intravenously with 5 x 10(6) Plasmodium yoelii N67 parasites 1 h before treatment. Groups of 20 mice received a subcutaneous injection of 40, 80, or 160 mg of ciprofloxacin or pefloxacin per kg of body weight every 8 h for 3 days. Parasitologic activity was assessed on day 4, and survival was assessed on day 21. Control mice had a fulminant course with a parasitemia of 61.3% +/- 12.1% on day 4, and 90% of the mice were dead on day 21. The lower dosages of pefloxacin and ciprofloxacin (40 and 80 mg/kg) were not efficient. With 160 mg/kg, ciprofloxacin achieved an 85.8% reduction in parasitemia and 17 of 20 mice survived. Pefloxacin achieved a 92.8% reduction in parasitemia, and all mice survived. All treated, noninfected control mice survived. With ciprofloxacin, the antimalarial activity was similar with injections of 240 mg/kg every 12 h but was strongly diminished with injections of 160 mg/kg every 12 h. With pefloxacin, similar activities were observed with injections of 160 mg/kg every 8 h or injections of 160 or 240 mg/kg every 12 h. With both drugs, this activity was highly reduced when the treatment was delayed by 24 h. This underlines the need to provide treatment within the first hours after infection to achieve an optimal effect in this rapidly lethal experimental model of malaria. Pefloxacin and, to a lesser extent, ciprofloxacin are potent antimalarial drugs which might prove useful in the treatment of less rapidly aggressive human malaria.
PMCID: PMC172055  PMID: 1708223
12.  In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to seven fluoroquinolones. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2287-2288.
The in vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to seven fluoroquinolones were assessed by the agar dilution method. Ciprofloxacin and temafloxacin were the most active compounds (MIC for 90% of isolates tested [MIC90], 0.06 microgram/ml), while enoxacin and pefloxacin were the least active (MIC90, 0.5 microgram/ml). Fleroxacin, lomefloxacin, and ofloxacin showed intermediate activities (MIC90s, 0.125 to 0.25 microgram/ml). These results suggest a possible role for the fluoroquinolones in the treatment of pertussis, at least in adult patients.
PMCID: PMC172042  PMID: 2073123
13.  Comparison of oral fluconazole and clotrimazole troches as treatment for oral candidiasis in patients infected with human immunodeficiency virus. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2267-2268.
Thirty-nine adult patients with human immunodeficiency virus infection and oral candidiasis were randomly assigned to receive either one fluconazole capsule (100 mg) or five clotrimazole troches (10 mg each) daily for 14 days. Among 36 evaluable patients, clinical resolution rates were 100 and 65%, respectively (P = 0.018). Mycological eradication rates were 75 and 20%, respectively (P = 0.004). Fluconazole-treated patients were more likely to remain disease free during follow-up than those treated with clotrimazole (P = 0.014 at 2 weeks). Prolonged clinical responses correlated with mycological eradication at the end of therapy (P = 0.043).
PMCID: PMC172036  PMID: 2073120
14.  Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2217-2222.
Intracellular tubercle bacilli (TB) reside in vacuoles in infected human macrophages (MPs). The relative impotency of streptomycin against TB in MPs and the contrary greatly increased potency of pyrazinamide (PZA) have been attributed to the fact that these vacuoles are phagolysosomes and, therefore, acidic. Chloroquine (CQ) is a lysomotropic base which can be used to raise phagolysosomal pH. Consequently, it was tested for its ability to increase the anti-TB effectiveness of streptomycin and decrease that of PZA in cultured human MPs. MPs infected with virulent Erdman strain TB were incubated in medium with various combinations of the drugs. Samples were taken at 0, 4, and 7 days and lysed for CFU counts of viable TB on nutrient agar. As expected, CQ increased the effectiveness of SM, but unexpectedly, it did not decrease that of PZA. CQ alone was found to be able to inhibit intracellular TB. Because of this, it was also tested with isoniazid, 1,25(OH)2-vitamin D3, and 25-OH-vitamin D3. It significantly enhanced the anti-TB protectiveness of both isoniazid and 25-OH-vitamin D3. Some combinations of CQ and the various drugs tested were able to kill intracellular TB. These results suggest that CQ may be useful in the treatment of tuberculosis.
PMCID: PMC172025  PMID: 2127346
15.  Antimicrobial resistance among respiratory isolates of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in the United States. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2075-2080.
A national surveillance study was conducted to determine trends in antimicrobial resistance patterns among three common causes of community-acquired respiratory tract infections. Fifteen participating U.S. medical centers submitted clinically significant isolates of Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and Streptococcus pneumoniae to two central laboratories for testing with a group of 12 antimicrobial agents. The majority of isolates were recovered from adult males greater than 50 years old. Overall, 84.1% of 378 M. catarrhalis and 16.5% of 564 H. influenzae (29.5% of type b strains; 15.0% of non-type b strains) produced beta-lactamase and were thus resistant to penicillin, ampicillin, and amoxicillin. Resistance in H. influenzae to other agents was 2.1% to tetracycline, 0.7% to trimethoprim-sulfamethoxazole, 1.1% to cefaclor, and 0.2% to cefuroxime and amoxicillin-clavulanate, while the M. catarrhalis isolates yielded very low MICs of these latter drugs. As demonstrated in prior studies, erythromycin showed little activity against H. influenzae. Of 487 S. pneumoniae isolates, 1 (0.2%) was penicillin resistant, while 3.8% were relatively resistant to penicillin, 4.5% were resistant to trimethoprim-sulfamethoxazole, 2.3% were resistant to tetracycline, 1.2% were resistant to chloramphenicol, and 0.2% were resistant to erythromycin. Overall, the lowest resistance rates for these common bacterial respiratory pathogens were noted with amoxicillin-clavulanate, cefuroxime, and cefaclor.
PMCID: PMC172002  PMID: 2127342
16.  Comparative in vitro activities of amoxicillin-clavulanic acid, cefuroxime, cephalexin, and cephalothin against trimethoprim-resistant Escherichia coli isolated from stools of children attending day-care centers. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2047-2049.
A high prevalence of fecal colonization with trimethoprim-resistant Escherichia coli was found in diapered children attending day-care centers in Houston, Tex. In the present study, 100 isolates of E. coli resistant to multiple antibiotics, including trimethoprim (100%), sulfisoxazole (100%), streptomycin (94%), and ampicillin (87%), were obtained over a 5-month period from stool samples of diapered children attending four day-care centers and tested for their susceptibilities to amoxicillin-clavulanic acid, cefuroxime, cephalexin, and cephalothin. The MICs for 50 and 90% of strains tested were 16 and 32 micrograms/ml, respectively, for amoxicillin-clavulanic acid, 4 and 16 micrograms/ml, respectively, for cefuroxime, 4 and 64 micrograms/ml, respectively, for cephalexin, and 32 and greater than 64 micrograms/ml, respectively, for cephalothin. Although all three oral beta-lactams tested were generally active at concentrations likely to be achieved in urine, cefuroxime and cephalexin were more potent and are thus more likely to be inhibitory at the concentrations needed for systemic infections.
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PMCID: PMC171996  PMID: 2073095
17.  In vitro activity of LY264826, a new glycopeptide antibiotic, against gram-positive bacteria isolated from patients with cancer. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2137-2141.
The in vitro activity of LY264826, a novel glycopeptide antibiotic produced by Amycolatopsis orientalis, was compared with those of vancomycin, teicoplanin, and oxacillin against 311 gram-positive clinical isolates from patients with cancer, LY264826 had lower MICs for 90% of isolates (MIC90) than vancomycin for all species tested. It was active against oxacillin-resistant isolates including Staphylococcus aureus (MIC90, 0.5 micrograms/ml), Staphylococcus haemolyticus (MIC90, 2.0 micrograms/ml), Enterococcus spp. (MIC90, 0.5 micrograms/ml), Bacillus cereus (MIC90, 0.25 micrograms/ml), and Corynebacterium jeikeium (MIC90, 0.12 micrograms/ml). For S. aureus, including oxacillin-resistant isolates, the MICs of LY264826 were similar to those of teicoplanin. For coagulase-negative staphylococci, however, LY264826 had MICs that were 4- to 32-fold lower than those of teicoplanin. Against most streptococcal species the activities of LY264826 and teicoplanin were similar. Bactericidal activity against Staphylococcus spp. and most Streptococcus pyogenes isolates was less than or equal to 1 dilution of the MIC. One isolate of S. pyogenes and all Enterococcus faecalis strains tested were tolerant of LY264826, with MBCs greater than or equal to 32-fold greater than the MICs. The addition of 50% human serum resulted in a significant increase in activity only against Staphylococcus epidermidis. Variations in pH from 6.4 to 8.4 and in inoculum from 10(3) to 10(7) CFU/ml did not significantly affect the activity of LY264826.
PMCID: PMC172013  PMID: 2149921
18.  In vitro activity of tosufloxacin, a new quinolone, against respiratory pathogens derived from cystic fibrosis sputum. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2223-2227.
By using broth microdilution methods, the in vitro activity of tosufloxacin (A-64730), a new quinolone, was compared with those of other agents, including five quinolones, against geographically diverse cystic fibrosis sputum isolates obtained from 26 cystic fibrosis centers in the United States. These included Pseudomonas aeruginosa, conventional as well as especially resistant (ceftazidime, aztreonam, gentamicin, and/or tobramycin) isolates: Escherichia coli; Pseudomonas cepacia; Staphylococcus aureus; and Haemophilus influenzae. Tosufloxacin MICs for 50 and 90% of isolates of standard P. aeruginosa were 0.5 and 2.0 mg/liter, for resistant P. aeruginosa they were 4.0 and greater than 16.0 mg/liter, for E. coli they were less than or equal to 0.016 mg/liter, for P. cepacia they were 4.0 and 8.0 mg/liter, for S. aureus they were 0.063 and 0.063 mg/liter, and for H. influenzae they were less than or equal to 0.016 and 0.032 mg/liter, respectively. Tosufloxacin activities against standard and resistant strains of P. aeruginosa were similar to those of comparative quinolones. Against E. coli, tosufloxacin activity was similar to those of other quinolones. Against S. aureus, tosufloxacin activity was similar to those of trimethoprim-sulfamethoxazole and cephalexin, but tosufloxacin was more active than other agents. Against H. influenzae, tosufloxacin activity was similar to those of other quinolones. There was minor diminution of activity at pH 8.2 but major diminution of activity at pH 5.2 and at inoculum sizes of greater than or equal to 10(7) CFU/ml. Activity was unaffected by sputum but was enhanced by serum and by the omission of cation supplementation. Tosufloxacin has consistent activity against common cystic fibrosis pathogens. Its high degree of activity against S. aureus with activity maintained against P. aeruginosa and other gram-negative bacteria of interest suggests that further in vitro studies and assessment of activity in in vivo models of cystic fibrosis pulmonary infections are warranted.
PMCID: PMC172026  PMID: 2073112
19.  Pharmacokinetics of cefepime in patients with respiratory tract infections. 
Antimicrobial Agents and Chemotherapy  1990;34(10):1885-1888.
The steady-state pharmacokinetics of cefepime were evaluated in 10 middle-aged and elderly patients with acute lower respiratory tract infections who were receiving 1 g intravenously every 12 h. One preinfusion and 15 postinfusion serum samples and total urine output were collected over one dosing interval between days 3 and 8 of therapy. Cefepime concentrations in serum over time exhibited a multicompartmental profile. Peak and trough concentrations in serum determined by a validated high-performance liquid chromatography method were 71.2 +/- 17.2 (mean +/- standard deviation) and 6.0 +/- 4.9 mg/liter, respectively. The steady-state volume of distribution was 0.22 +/- 0.05 liter/kg. Elimination half-lives ranged from 1.93 to 6.04 h (3.92 +/- 1.28 h), and total body clearances ranged from 36.9 to 102 ml/min per 1.73 m2 (73.0 +/- 19.7 ml/min per 1.73 m2). The disposition of cefepime at steady state in patients was comparable to previous observations in healthy elderly volunteers. The predictive performance of regression equations derived from single-dose studies in volunteers relating creatinine clearance with total body and renal clearances of cefepime exhibited slight biases (mean predictive errors, -9.7 and 2.1 ml/min per 1.73 m2, respectively) and similar precisions. Predicted and observed total body clearances (63.3 +/- 25.1 versus 73.0 +/- 19.7 ml/min per 1.73 m2, respectively) and renal clearances (51.3 +/- 24.4 versus 49.3 +/- 19.6 ml/min per 1.73 m2, respectively) were not significantly different. The pharmacokinetics of cefepime in infected patients appeared to be unaltered by illness, and the steady-state disposition of cefepime was predictable from data derived from single-dose studies in volunteers.
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PMCID: PMC171959  PMID: 2291655
20.  Aminoglycoside acetyltransferase 3-IV (aacC4) and hygromycin B 4-I phosphotransferase (hphB) in bacteria isolated from human and animal sources. 
Antimicrobial Agents and Chemotherapy  1990;34(10):1915-1920.
Members of the family Enterobacteriaceae harboring an enzyme of the aminoglycoside acetyltransferase 3 class (AAC-3-IV) (apramycin and gentamicin resistance) and hygromycin B phosphotransferase 4 (HPH-4-I) (hygromycin B resistance) have been isolated from human clinical sources in Europe. A cluster of genes containing IS140, aacC4, and hphB was found in these strains. We demonstrate by Southern hybridization that this cluster is identical to the operon found in animals that also contains insertion sequences belonging to the ISO family. This provides another example of presumptive transfer of antibiotic resistance genes between bacteria of animal and human origin.
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PMCID: PMC171964  PMID: 1963287
21.  Pharmacokinetics of Ro 23-9424, a dual-action cephalosporin, in animals. 
Antimicrobial Agents and Chemotherapy  1990;34(10):1895-1900.
Ro 23-9424 is a dual-action cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and fleroxacin esterified at the 3' position. The new compound has broad and potent antibacterial activity in vitro and in vivo, reflecting contributions from both the beta-lactam moiety and the quinolone moiety. In animals, the ester bond potentially could be hydrolyzed enzymatically or nonenzymatically, to yield the active metabolites desacetylcefotaxime and fleroxacin. The extent to which Ro 23-9424 acts in vivo as a true dual-action cephalosporin, or acts as a combination of active metabolites, is therefore a function of its pharmacokinetic properties. To investigate these properties, Ro 23-9424 was administered as a single intravenous dose of 20 mg/kg of body weight to mice, rats, dogs, and baboons. Timed plasma samples were assayed by an ion-paired high-pressure liquid chromatography method that allowed detection of both intact Ro 23-9424 and fleroxacin. The pharmacokinetic parameters of Ro 23-9424 were similar to published results for cefotaxime, while concentrations of fleroxacin in plasma were low and fairly constant (about 1 to 3 micrograms/ml) in all species, suggesting that excretion of the intact molecule is a major route of elimination for Ro 23-9424, as it is for cefotaxime. For technical reasons, urinary recovery of Ro 23-9424 was not quantitated, but intact Ro 23-9424 was found in high concentrations (greater than 400 micrograms/ml) in mouse urine aspirated directly from the bladder. In all species, low concentrations of free fleroxacin in plasma persisted after the elimination of Ro 23-9424 was complete, but fleroxacin did not accumulate unduly in a 14-day multiple-dose experiment in baboons. Thus, it seems likely that the activity seen in vivo is primarily due to intact Ro 23-9424, although the low levels of free fleroxacin may also have some therapeutic significance.
PMCID: PMC171961  PMID: 2127171
22.  Assessment of effects of protein binding on daptomycin and vancomycin killing of Staphylococcus aureus by using an in vitro pharmacodynamic model. 
Antimicrobial Agents and Chemotherapy  1990;34(10):1925-1931.
Initial clinical trials with daptomycin (2 mg/kg per day) were prematurely suspended because of unexplained treatment failures in patients with bacteremia who were treated with daptomycin, despite in vitro data indicating that the gram-positive cocci causing the infection were susceptible to daptomycin. One explanation for these clinical failures may relate to the relatively high degree of daptomycin protein binding (94%). To evaluate the impact of protein on daptomycin activity, a two-chamber in vitro pharmacodynamic model was used to study and compare the interaction between Staphylococcus aureus (clinical isolate) and either daptomycin or vancomycin, each in the presence and absence of physiologic human albumin concentrations. Low-dose (2 mg/kg) daptomycin, high-dose (6 mg/kg) daptomycin, and 10 mg of vancomycin per kg beta-phase elimination serum-concentration-versus-time curves were simulated by using this in vitro pharmacodynamic model. The bacterial kill rates by all three regimens were decreased in the presence of albumin (P less than 0.0002). The average times required for a 99% kill of the initial S. aureus inocula (approximately 5 x 10(7) CFU/ml) without albumin were 0.81 (low-dose daptomycin), 0.33 (high-dose daptomycin), and 6.18 (vancomycin) h. The average times required for a 99% kill of S. aureus with albumin were 7.66 (low-dose daptomycin), 0.95 (high-dose daptomycin), and 10.52 (vancomycin) h. These data demonstrate that, depending on the concentration of daptomycin, the presence of albumin can profoundly diminish the bactericidal activity of daptomycin.
PMCID: PMC171966  PMID: 1963288
23.  Antistaphylococcal activities of sparfloxacin (CI-978; AT-4140), ofloxacin, and ciprofloxacin. 
The activity of sparfloxacin (CI-978; AT-4140) was compared with those of ofloxacin and ciprofloxacin against clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis. All 10 ciprofloxacin-resistant staphylococci had reduced susceptibility to sparfloxacin and ofloxacin. Against 105 ciprofloxacin-susceptible strains of S. aureus, the sparfloxacin MIC for 90% of strains tested was at least fourfold lower than those of ciprofloxacin and ofloxacin, while against 104 ciprofloxacin-susceptible strains of S. epidermidis, the MIC of sparfloxacin for 90% of strains tested was twofold lower than that of ciprofloxacin and fourfold lower than that of ofloxacin. MBCs of sparfloxacin were less than or equal to 4 x MICs. The effects of inoculum size and pH variations, as well as the presence of serum, on the MICs of sparfloxacin were minimal. Subinhibitory concentrations of sparfloxacin did reduce adherence of S. epidermidis.
PMCID: PMC171945  PMID: 2285304
24.  Effect of food on absorption of lomefloxacin. 
Twelve subjects participated in an open-label, single-dose, balanced three-way crossover study in which the absorptions of lomefloxacin were compared following (i) an overnight fast, (ii) a carbohydrate meal, and (iii) a high-fat meal. The time to peak concentration of lomefloxacin was delayed, but peak concentration in plasma and amount of drug absorbed were unchanged following both meals.
PMCID: PMC171929  PMID: 2285293
25.  Erythromycin and azithromycin transport into Haemophilus influenzae ATCC 19418 under conditions of depressed proton motive force (delta mu H). 
The effect of collapsing the electrochemical proton gradient (delta mu H) on [3H]erythromycin and [14C]azithromycin transport in Haemophilus influenzae ATCC 19418 was studied. The proton gradient and membrane potential were determined from the distribution of [2-14C]dimethadione and rubidium-86, respectively. delta mu H was reduced from 124 to 3 mV in EDTA-valinomycin-treated cells at 22 degrees C with 150 mM KCl and 0.1 mM carbonyl cyanide m-chlorophenylhydrazone. During the collapse of delta mu H, macrolide uptake increased. Erythromycin efflux studies strongly suggested that this increase was not due to an energy-dependent efflux pump but was likely due to increased outer membrane permeability. These data indicated that macrolide entry was not a delta mu H-driven active transport process but rather a passive diffusion process.
PMCID: PMC171926  PMID: 2178338

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