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1.  A study to determine the pharmacokinetics and inflammatory fluid penetration of two doses of a solid formulation of the hexetil prodrug of a trinem, sanfetrinem (GV 104326). 
The trinem sanfetrinem (GV 104326) was administered as the oral hexetil prodrug GV 118819X in two dose levels to six healthy volunteers. A single dose equivalent to 125 mg of sanfetrinem was administered, followed 6 weeks later by a single dose equivalent to 500 mg of sanfetrinem. The concentrations of the drug in plasma, cantharidin-induced inflammatory fluid, and urine were measured with a microbiological assay. The stability of sanfetrinem was studied in serum and inflammatory fluid. The mean peak concentrations in plasma of 0.77 and 2.47 microg/ml were attained at 1.1 and 2.0 h after the 125- and 500-mg doses, respectively. Mean peak concentrations in inflammatory exudate of 0.26 and 0.86 microg/ml were attained at 2.80 and 2.67 h after the 125- and 500-mg doses, respectively. The mean terminal elimination half-lives in plasma were 1.33 and 1.97 h for the 125- and 500-mg doses, respectively. The half-lives in the inflammatory fluid were 1.66 and 1.74 h for the 125- and 500-mg doses, respectively. The overall penetration of the drug into the inflammatory fluid was 51.4 and 47.0% for the 125- and 500-mg doses, respectively. Mean urine recovery was greater following 500 mg (24.15%) than after 125 mg (18.4%) of sanfetrinem. Sanfetrinem was relatively unstable in the inflammatory exudate in vitro (half-life, 5.5 h), and this could explain the poor penetration of the drug in the inflammatory exudate observed in this study.
PMCID: PMC164000  PMID: 9257756
2.  Pharmacodynamic properties of BAY 12-8039 on gram-positive and gram-negative organisms as demonstrated by studies of time-kill kinetics and postantibiotic effect. 
Time-kill kinetics of BAY 12-8039 were studied at two inocula against three strains each of Bacteroides fragilis, Escherichia coli, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pyogenes. The postantibiotic effects of BAY 12-8039 were studied on three strains each of E. coli, S. aureus, H. influenzae, Streptococcus pyogenes, and Streptococcus pneumoniae. The pharmacodynamic data demonstrated that BAY 12-8039 has marked activity against gram-positive and gram-negative organisms (under both anaerobic and aerobic conditions) and anaerobes. BAY 12-8039 also exhibited a postantibiotic effect of >1 h for all strains except one E. coli strain.
PMCID: PMC163919  PMID: 9174203
3.  In vitro activity of BAY 12-8039, a new fluoroquinolone. 
The in vitro activity of BAY 12-8039, a new fluoroquinolone, was studied in comparison with those of ciprofloxacin, trovafloxacin (CP 99,219), cefpodoxime, and amoxicillin-clavulanate against gram-negative, gram-positive, and anaerobic bacteria. Its activity against mycobacteria and chlamydia was also investigated. BAY 12-8039 was active against members of the family Enterobacteriaceae (MIC at which 90% of strains tested were inhibited [MIC90S] < or = 1 microgram/ml, except for Serratia spp. MIC90 2 microgram/ml), Neisseria spp. (MIC90S, 0.015 microgram/ml), Haemophilus influenzae (MIC90, 0.03 microgram/ml), and Moraxella catarrhalis (MIC90, 0.12 micrgram/ml), and these results were comparable to those obtained for ciprofloxacin and trovafloxacin. Against Pseudomonas aeruginosa, the quinolones were more active than the beta-lactam agents but BAY 12-8039 was less active than ciprofloxacin. Strains of Stenotrophomonas maltophilia were fourfold more susceptible to BAY 12-8039 and trovafloxacin (MIC90S, 2 micrograms/ml) than to ciprofloxacin. BAY 12-8039 was as active as trovafloxacin but more active than ciprofloxacin against Streptococcus pneumoniae (MIC90, 0.25 microgram/ml) and methicillin-susceptible Staphylococcus auerus (MIC90S, 0.12 micrograms/ml). The activity of BAY 12-8039 against methicillin-resistant S. aureus (MIC90, 2 micrograms/ml) was lower than that against methicillin-susceptible strains. BAY 12-8039 was active against anaerobes (MIC90S < or = 2 micrograms/ml), being three- to fourfold more active against Bacteroides fragilis, Prevotella spp., and Clostridium difficile than was ciprofloxacin. Against Mycobacterium tuberculosis, BAY 12-8039 exhibited activity comparable to that of rifampin (MICs < or = 0.5 micrograms/ml). Against Chlamydia trachomatis and Chlamydia pneumoniae BAY 12-8039 was more active (MICs < or = 0.12 microgram/ml) than either ciprofloxacin or erythromycin and exhibited a greater lethal effect than either to these two agents. The protein binding of BAY 12-8039 was determined at 1 and 5 micrograms/ml as 30 and 26.4%, respectively. The presence of human serum (at 20 or 70%) had no marked effect on the in vitro activity of BAY 12-8039.
PMCID: PMC163668  PMID: 8980763
4.  In vitro activity of the tricyclic beta-lactam GV104326. 
GV104326 is a novel tricyclic beta-lactam (a trinem or, formerly, tribactam). The in vitro activity of GV104326 was compared with those of cefuroxime, cefixime, amoxicillin, amoxicillin-clavulanic acid, cefpirome, and ciprofloxacin. GV104326 had in vitro activity generally similar to that of cefixime against members of the family Enterobacteriaceae (MIC at which 90% of the isolates are inhibited [MIC90], < or = 2 micrograms/ml), with cefuroxime and amoxicillin-clavulanic acid being 8- to 32-fold less active and with cefpirome being 4- to 8-fold more active against members of this family. The trinem had no activity against Pseudomonas aeruginosa or Stenotrophomonas maltophilia (MIC90, > 128 micrograms/ml) but was the most active agent against Acinetobacter calcoaceticus. GV104326 was particularly active against gram-positive cocci. Ninety percent of methicillin-susceptible Staphylococcus aureus strains were susceptible to 0.03 microgram of GV104326 per ml, making it the most active agent studied. Enterococci and Lancefield group A and B streptococci were generally equally or somewhat more susceptible to GV104326 than they were to amoxicillin. Streptococcus pneumoniae strains were highly susceptible to GV104326, and those strains which showed decreased susceptibility to penicillin were generally twofold more susceptible to the trinem than to amoxicillin. Haemophilus influenzae and Moraxella catarrhalis were highly susceptible to GV104326 (MIC90s, 0.12 and 0.03 microgram/ml, respectively). The anaerobes Clostridium perfringens, Bacteroides fragilis, and Peptostreptococcus spp. were more susceptible to the trinems (formerly tribactams) than to the other agents studied.
PMCID: PMC163300  PMID: 8723475
5.  Pharmacokinetics and penetration into inflammatory fluid of trovafloxacin (CP-99,219). 
A single 200-mg oral dose of trovafloxacin (CP-99,219) was given to each of eight healthy male volunteers, and the concentrations of the drug were measured in plasma, cantharides-induced inflammatory fluid, and urine over the subsequent 36 h. The mean maximum concentration observed in plasma was 2.9 micrograms/ml at a mean time of 0.75 h postdose. The mean maximum concentration observed in inflammatory fluid was 1.2 micrograms/ml at 4.0 h postdose. The mean elimination half-life in plasma was 7.8 h. The overall penetration into inflammatory fluid was 64%, as assessed by determining the ratio of the area under the concentration-time curves. Recovery of the dose in urine within the first 36 h postdose was 5.0% of the administered dose. Our results indicate that trovafloxacin, at a dosage of 200 mg once or twice daily, should be adequate for the treatment of systemic infections caused by most common bacterial pathogens.
PMCID: PMC163054  PMID: 8787877
6.  Open-label crossover study to determine pharmacokinetics and penetration of two dose regimens of levofloxacin into inflammatory fluid. 
Antimicrobial Agents and Chemotherapy  1995;39(12):2749-2751.
Two levofloxacin administration regimens were used for six healthy male volunteers. They received either 500 mg of levofloxacin orally every 12 h for five doses or 500 mg every 24 h for three doses, and then 6 weeks later they received the other course. The concentrations of the drug in plasma, cantharidin-induced inflammatory fluid, and urine were measured with a microbiological assay following administration of the final dose. Mean peak concentrations in plasma of 9.3 and 6.6 micrograms/ml were attained 1.1 and 1.2 h after the 12- and 24-h regimens, respectively. Mean peak concentrations is inflammatory fluid of 6.8 and 4.3 micrograms/ml were attained at 2.3 and 3.7 h, respectively. The average steady-state concentrations were 5.0 and 2.2 micrograms/ml in plasma and 4.7 and 2.3 micrograms/ml in inflammatory fluid, respectively. The mean terminal elimination half-lives for plasma were 7.9 and 8.0 h for the two regimens, respectively, and the same values were noted for inflammatory fluid. The overall penetration into inflammatory fluid ranged from 88 to 101% with the 12-h regimen and 83 to 112% with the 24-h regimen. Mean urinary recoveries were 87 and 86% over the corresponding interval of the 12- and 24-h regimens, respectively. These results suggest that administration of levofloxacin once and twice daily should be efficacious for infections caused by the majority of pathogens.
PMCID: PMC163023  PMID: 8593013
7.  Pharmacokinetics and tissue penetration of the new fluoroquinolone grepafloxacin. 
A single 400-mg oral dose of grepafloxacin (OPC-17116) was given to each of six healthy male volunteers, and the concentrations of the drug in plasma, cantharides-induced inflammatory fluid, and urine were measured over the subsequent 12 h. The mean peak concentration in plasma of 1.5 micrograms/ml was attained at a mean time of 2.0 h postdose. The mean peak concentration in inflammatory fluid of 1.1 micrograms/ml was attained at a mean time of 4.8 h postdose. The mean elimination half-life in plasma was 5.2 h, and that in inflammatory fluid was 12.7 h. The overall penetration into inflammatory fluid was 180.6% (or 133% if one aberrant result from one volunteer is excluded). Recovery of the drug in urine during the first 24 h postdose was 8.3% of the administered dose. Our results indicate that a once- or twice-daily dosage of grepafloxacin should be adequate to treat systemic infections caused by most bacterial pathogens.
PMCID: PMC162569  PMID: 7726523
8.  Pharmacokinetics and distribution in tissue of FK-037, a new parenteral cephalosporin. 
Antimicrobial Agents and Chemotherapy  1994;38(10):2369-2372.
A single 1-g or 2-g intravenous dose of the cephalosporin FK-037 was given over 30 min in a cross-over-designed study, to each of six healthy male volunteers, and the concentrations of the drug were measured in plasma and cantharides-induced blister fluid over the subsequent 12 h. Urine was collected over 24 h. After a washout period of 6 weeks, during which the blisters healed, the study was repeated at the other dose level. Following the 1-g dose, the mean peak concentration in plasma was 83.8 micrograms/ml, and after the 2-g dose it was 142.6 micrograms/ml. The mean peak concentrations in the inflammatory fluid were 37.9 and 63.3 micrograms/ml, respectively. The mean elimination half-lives from plasma and inflammatory fluid were 2.0 and 2.5 h, respectively, after 1 g and 2.0 h and 3.7 h, respectively, after 2 g. The amounts of penetration into inflammatory fluid (as assessed by ratios of areas under the concentration-time curves) were 109.9 and 110.5% following doses of 1 and 2 g, respectively. The proportions of the administered drug recovered in the urine by 24 h were 87.6 and 85.7%, respectively. Our results indicate that FK-037 should prove to be efficacious in the treatment of a wide range of systemic infections.
PMCID: PMC284746  PMID: 7840572
9.  In vitro activities of two glycylcyclines. 
The in vitro activities of two glycylcyclines, CL 329,998 and CL 331,002 (two new semisynthetic tetracyclines), were evaluated in comparison with those of tetracycline and other available oral antimicrobial agents. A total of 523 recent clinical isolates were studied, including strains resistant to tetracycline. Members of the family Enterobacteriaceae were generally > or = 16-fold more susceptible to the glycylcyclines than to tetracycline (although less difference was seen with Proteus spp.). Pseudomonas aeruginosa was modestly susceptible to both new compounds (MIC for 90% of strains tested [MIC90], 16 micrograms/ml). Tetracycline- and methicillin-susceptible and -resistant strains of Staphylococcus aureus were all susceptible to the glycylcyclines (MIC90 < or = 1 microgram/ml). Streptococci (including Streptococcus pneumoniae) and Enterococcus faecalis and Enterococcus faecium displayed a bimodal distribution of susceptibility to tetracycline yet were uniformly susceptible to the glycylcyclines (MIC90 < or = 0.25 microgram/ml). The glycylcyclines were highly potent against Neisseria, Moraxella, Haemophilus, and Bacteroides spp. (MIC90 < or = 0.5 microgram/ml). Strains of Chlamydia spp. (three C. trachomatis strains and one C. pneumoniae strain) were inhibited by < or = 0.25 microgram of CL 329,998 or CL 331,002 per ml. Two strains of Mycoplasma pneumoniae were inhibited by < or = 0.12 microgram of CL 331,002 per ml and by 1 microgram of CL 329,998 per ml. Mycobacterium tuberculosis and Mycobacterium avium were resistant to the two glycylcyclines (MIC > or = 8 micrograms/ml). These results indicate that the two glycylcyclines have potent in vitro activities against a wide range of clinically important pathogenic bacteria.
PMCID: PMC188156  PMID: 8067744
10.  Pharmacokinetics of rufloxacin in patients with impaired renal function. 
The pharmacokinetics of rufloxacin were investigated in normal subjects and in patients with various degrees of renal failure after the administration of a single oral 400-mg dose. Twenty-four subjects were classified by glomerular filtration rate (GFR) normalized for body surface area. Group 1 subjects had GFRs of > 80 ml/min, group 2 subjects had GFRs from 30 to 80 ml/min, group 3 subjects had GFRs from 8 to 29 ml/min, and group 4 subjects had GFRs of < 8 ml/min. The patients in group 4 were on continuous peritoneal dialysis or underwent hemodialysis 48 h after dosing. Plasma and urinary rufloxacin concentrations were determined by high-performance liquid chromatography. A two-compartment model was used to calculate rufloxacin pharmacokinetic parameters. Apparent total body clearance of the drug was linearly related to GFR (r = 0.696; P < 0.01). The elimination half-life increased proportionally with the severity of renal impairment, with values of 30 +/- 3, 36 +/- 5, and 44 +/- 3 h in groups 1, 2, and 3, respectively. In patients with moderate renal failure, dosage adjustment of rufloxacin is not needed. The rufloxacin dose interval should be prolonged to 48 h as the GFR falls below 30 ml/min/1.73 m2.
PMCID: PMC187727  PMID: 8388194
11.  Pharmacokinetics and inflammatory fluid penetration of sparfloxacin. 
Antimicrobial Agents and Chemotherapy  1992;36(11):2444-2446.
A single 400-mg oral dose of sparfloxacin was given to each of six healthy male volunteers, and the concentrations of the drug were measured in plasma, cantharides-induced inflammatory fluid, and urine over the subsequent 52 h. The mean peak concentration in plasma of 1.6 micrograms/ml was attained at a mean time of 2.7 h postdose. The mean peak concentration in inflammatory fluid of 1.3 micrograms/ml was attained at a mean time of 5 h postdose. The mean elimination half-life in plasma was 17.6 h, and that in inflammatory fluid was 19.7 h. The overall penetration into inflammatory fluid was 117%. Urinary recovery within the first 52 h postdose was 8.8% of the administered dose. Our results indicate that a once-daily dosage of sparfloxacin should be adequate to treat systemic infections caused by most common bacterial pathogens.
PMCID: PMC284350  PMID: 1336947
12.  In vitro activity of RU 29246, the active compound of the cephalosporin prodrug ester HR 916. 
Antimicrobial Agents and Chemotherapy  1992;36(11):2360-2364.
The in vitro activity of RU 29246 was compared with those of other agents against 536 recent clinical isolates. The MICs of RU 29246 for 90% of members of the family Enterobacteriaceae tested (MIC90s) were less than 2 micrograms/ml except those for Morganella spp. (16 micrograms/ml) and Proteus spp. (8 micrograms/ml). RU 29246 was active against Staphylococcus aureus (MIC90, < or = 8 micrograms/ml) and against Staphylococcus saprophyticus and coagulase-negative staphylococci (MIC90s, < or = 2 micrograms/ml). Streptococci and Neisseria gonorrhoeae were highly susceptible to RU 29246, and the activity of the agent against isolates of Streptococcus pneumoniae (MIC90, < or = 0.5 micrograms/ml), Haemophilus influenzae (MIC90, < or = 2 micrograms/ml), and Moraxella catarrhalis (MIC90, < or = 2 micrograms/ml) was comparable to those of the other cephalosporins tested. RU 29246 was insusceptible to hydrolysis by the common plasmid-mediated beta-lactamases (TEM-1 and SHV-1). However, hydrolysis by the new extended-spectrum beta-lactamases (TEM-3, TEM-5, and TEM-9) was detected. Results of the study suggested that RU 29246 should be investigated clinically for use in the treatment of a wide range of infections.
PMCID: PMC284335  PMID: 1489178
13.  Antimicrobial susceptibilities and beta-lactamase characterization of Capnocytophaga species. 
Antimicrobial Agents and Chemotherapy  1992;36(10):2197-2200.
Capnocytophaga species have been associated with a wide variety of infections in both immunocompetent and immunocompromised patients. On the basis of data from antimicrobial susceptibility studies, beta-lactam antibiotics have been considered efficacious therapy. Six of 19 isolates from primarily clinical sources across Canada demonstrated beta-lactamase production, and agar dilution susceptibility testing showed broad resistance to beta-lactam antibiotics. For the beta-lactamase producing isolates, clavulanate reduced the MIC of amoxicillin for 90% of the strains tested by 64-fold. Isolates were highly susceptible to clindamycin, imipenem, and ciprofloxacin. Characterization of the beta-lactamases produced by two of these isolates (Van1 and Van2) was performed. Isoelectric focusing revealed an identical isoelectric point of 5.6 for both enzymes, but they had markedly different relative hydrolysis efficiencies, and different conditions were required to extract the enzymes. This study demonstrates the production of different types of beta-lactamases by Capnocytophaga spp. and suggests the need to screen all clinical isolates of Capnocytophaga spp. for the presence of beta-lactamases.
PMCID: PMC245475  PMID: 1444299
14.  In vitro activity of L-627, a new carbapenem. 
The in vitro activity of L-627, a new parenterally administered carbapenem, was compared with those of imipenem, meropenem, FCE 22101 (a penem), ceftazidime, and ceftriaxone. L-627 was active against members of the family Enterobacteriaceae (MIC for 90% of strains tested [MIC90] ranging from 0.03 to 4 micrograms/ml). L-627 displayed activity equal to that of meropenem against Pseudomonas aeruginosa (MIC90, 2 micrograms/ml), although, as with other carbapenems, the antipseudomonal activity was reduced against D2-deficient strains. Staphylococci and streptococci were susceptible (MIC90 of 1.0 micrograms/ml for Staphylococcus aureus and 0.015 micrograms/ml for group A streptococci). L-627 also had activity against anaerobic bacteria (MIC90, 2.0 micrograms/ml for Bacteroides fragilis). Neisseria gonorrhoeae and Neisseria meningitidis were highly susceptible (MIC90, 0.06 micrograms/ml), and against the common respiratory pathogens (Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis), the MIC90s were less than or equal to 2.0 micrograms/ml. The protein binding of L-627 ranged from 13.8 to 22%, depending on the concentration. The presence of human serum had little effect on the MIC or MBC of L-627. These results suggest that L-627 merits further study in the treatment of infections caused by a wide range of pathogens.
PMCID: PMC192211  PMID: 1416883
17.  Pharmacokinetics and tissue penetration of ampicillin and brobactam following oral administration of 2085P. 
Eight healthy volunteers received a 1,000-mg single oral dose of 2085P which consisted of 800 mg of pivampicillin and 200 mg of brobactam. Concentrations of ampicillin and brobactam in plasma, inflammatory fluid, and urine were measured over the subsequent 24 h. Pivampicillin and brobactam were moderately rapidly absorbed. The mean (standard deviation) maximum concentration in plasma (Cmax) of ampicillin was 8.2 (1.9) micrograms/ml, and that of brobactam was 2.1 (2.0) micrograms/ml at mean times of 1.9 (0.5) and 2.3 (0.8) h, respectively. The elimination half-lives in plasma were 1.8 (0.5) and 1.6 (2.0) h, respectively. Both agents penetrated the experimentally induced inflammatory fluid, reaching a mean maximum at 3 h. The Cmax of ampicillin was 6.8 (2.3) micrograms/ml, and that of brobactam was 1.0 (0.4) micrograms/ml. The penetration (derived by comparing the area under the concentration-time curve from 0 h to infinity for inflammatory fluid with that for plasma) was 97.3% (26.0%) for ampicillin and 81% (22.3%) for brobactam. The 24-h urinary recovery was 54.2% (16.6%) of the administered dose for ampicillin and 40.2% (11.4%) for brobactam. These data suggest that this combination of beta-lactam and inhibitor should be efficacious in treating infections caused by ampicillin-resistant pathogens.
PMCID: PMC188825  PMID: 1324634
18.  Pharmacokinetics and tissue penetration of tazobactam administered alone and with piperacillin. 
The pharmacokinetics of tazobactam (500 mg) administered intravenously alone were compared with the pharmacokinetics of tazobactam coadministered with piperacillin (4 g), and the penetration into an inflammatory exudate in six healthy males was studied. Piperacillin influenced the pharmacokinetics of tazobactam. The mean levels of tazobactam in plasma at 4 h were 0.6 microgram/ml when it was given alone and 1.2 micrograms/ml when it was given with piperacillin (P = 0.0003). The mean total clearances of tazobactam were 203.5 and 134.2 ml/min (P = 0.035) when it was given alone and with piperacillin, respectively There were no significant differences in the elimination half lives, areas under the concentration-time curve from 0 h to infinity, or volumes of distribution. Inflammatory exudate penetration was rapid, and the mean maximum levels of tazobactam attained were 6.4 and 11.3 micrograms/ml when it was given alone or with piperacillin, respectively (P less than 0.06). The mean percent penetration of tazobactam and the area under the concentration-time curve from 0 h to infinity in inflammatory exudate were greater when tazobactam was given with piperacillin. The mean 24-h urinary recoveries of tazobactam were 63.7% +/- 7.9% when it was given alone and 56.8% +/- 2.7% when it was given with piperacillin. The explanation for the differences in the pharmacokinetics of tazobactam when it was administered alone compared with those when it was given with piperacillin was unclear.
PMCID: PMC284290  PMID: 1656853
19.  In vitro activity of a catechol-substituted cephalosporin, GR69153. 
The in vitro activity of GR69153, a new catechol-substituted cephalosporin, was compared with those of ceftazidime, imipenem, meropenem, and ceftriaxone against 604 recent clinical isolates and other strains with known mechanisms of resistance. The MICs of GR69153 for 90% of the members of the family Enterobacteriaceae tested were less than 0.5 micrograms/ml, with the exceptions of those for Serratia spp. (4 micrograms/ml), Citrobacter spp. (2 micrograms/ml), and Enterobacter spp. (8 micrograms/ml). Ninety percent of Pseudomonas aeruginosa isolates were susceptible to less than or equal to 1 microgram of GR69153 per ml. With the exception of methicillin-resistant strains, 90% of Staphylococcus aureus isolates were susceptible to less than or equal to 2 micrograms/ml, and GR69153 was four- to eightfold more active than ceftazidime and ceftriaxone against these strains. Isolates of Haemophilus influenzae, Branhamella catarrhalis, Neisseria spp., and Streptococcus pneumoniae (penicillin susceptible) were highly susceptible (MIC for 90% of the strains, less than or equal to 0.12 micrograms/ml). GR69153 was stable to hydrolysis by the TEM-1 and TEM-5, SHV-1 and SHV-2, and K1 beta-lactamases, but some susceptibility to hydrolysis by the TEM-3, TEM-9, and P99 enzymes was observed. The protein-binding activity of GR69153 was 74.5 to 66.8%, depending on the concentration, and serum had little effect upon activity.
PMCID: PMC245000  PMID: 2024966
20.  Meropenem pharmacokinetics and penetration into an inflammatory exudate. 
The pharmacokinetics and penetration into a cantharidine-induced inflammatory exudate of meropenem was studied in six volunteers following a single 1-g intravenous dose. Concentrations in plasma, urine, and the inflammatory exudate were determined by a microbiological assay. The mean elimination half-life of meropenem in plasma was 1.1 h, with the concentration in plasma declining from a mean of 23.6 micrograms/ml at 1 h to 0.7 micrograms/ml at 6 h. The inflammatory fluid penetration was rapid (time to maximum concentration of drug in serum, 0.75 h), and the penetration was 111%. The recovery of meropenem in urine at 24 h was 65.4% of the administered dose.
PMCID: PMC171864  PMID: 2221860
21.  Mechanism of action of lomefloxacin. 
The inhibition of supercoiling activity of reconstituted Escherichia coli DNA gyrase by lomefloxacin, ciprofloxacin, and norfloxacin was determined. The concentrations of quinolones needed to inhibit DNA synthesis in Escherichia coli, Enterobacter cloacae, Serratia marcescens, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus were also measured. The kinetics of uptake of [14C]lomefloxacin and unlabeled lomefloxacin into whole cells of E. coli KL-16 and S. aureus NCTC 8532 and the induction of RecA in E. coli GC2241 were assayed. All strains had wild-type susceptibilities to quinolones. The concentration of quinolones needed to inhibit DNA synthesis by 50% correlated with the MIC for members of the family Enterobacteriaceae and P. aeruginosa. The concentration of quinolones needed to inhibit DNA synthesis by 50% for late-logarithmic-phase S. aureus also correlated with the MIC, unlike the data from early-logarithmic-phase cultures. E. coli and S. aureus showed a similar pattern of uptake kinetics of [14C]lomefloxacin and unlabeled lomefloxacin, indicating that the difference in the susceptibilities of the two species is probably due to different target site affinities. Essentially, lomefloxacin was less active than ciprofloxacin and ofloxacin and had activity similar to those of norfloxacin and enoxacin.
PMCID: PMC171763  PMID: 2168142
22.  Pharmacokinetics and tissue penetration of ceftibuten. 
The pharmacokinetics of the cephalosporin ceftibuten were determined after the fifth and final dose of 200 mg given every 12 h. Concentrations in plasma and cantharidin-induced inflammatory fluid were determined by a microbiological assay. Samples for three volunteers were assayed by a high-performance liquid chromatographic procedure to determine levels for both cis and trans ceftibuten. The mean peak level of ceftibuten in serum was 10.9 micrograms/ml at a mean time of 1.8 h after administration, and the mean elimination half-life from plasma was 2.5 h. Penetration into the inflammatory fluid was good, the mean peak level being 9.2 micrograms/ml at a mean time of 3.7 h. The mean percent penetration into the inflammatory fluid was 113.4%. High-performance liquid chromatography analysis showed that the mean peak level of the trans isomer was 5.7% that of the cis isomer. This study suggests that twice-daily doses of ceftibuten should be sufficient to treat urinary or systemic infections caused by susceptible pathogens.
PMCID: PMC171757  PMID: 2393265
23.  Concentrations of oral lomefloxacin in serum and bronchial mucosa. 
The bronchial mucosal concentrations of lomefloxacin were determined for specimens obtained by fiber-optic bronchoscopy and compared with simultaneous concentrations in serum. The 23 patients studied were given an oral dose of 400 mg once daily for 4 days to achieve steady-state levels. The median concentration in serum was 2.5 micrograms/ml (range, 1.0 to 5 micrograms/ml), and the median bronchial mucosal concentration was 5.0 micrograms/g (range, 0.7 to 18.6 micrograms/g). The median percent penetration was 177% (range, 69 to 541%). The concentrations in serum and mucosa exceeded the MIC for 90% of strains of organisms causing bronchial infections but not sufficiently to recommend lomefloxacin for the routine treatment of pneumococcal infections.
PMCID: PMC171749  PMID: 2393260
24.  In vitro activity of Bay v 3522, a new cephalosporin, compared with activities of other agents. 
The in vitro activity of Bay v 3522, a new aminobenzothiazol cephem, was compared with those of other oral beta-lactams. Bay v 3522 displayed high activity against Staphylococcus spp. (MICs for 90% of strains tested [MIC90S], 0.5 micrograms/ml), Streptococcus pneumoniae (MIC90, 0.06 micrograms/ml), and Haemophilus influenzae and Branhamella catarrhalis (MIC90S, 2 micrograms/ml). There was limited activity against members of the family Enterobacteriaceae, with the MIC90S being between 4 and greater than 128 micrograms/ml. The stability of Bay v 3522 to hydrolysis by the SHV-1 and TEM-1 enzymes was intermediate to those of cephalexin (least hydrolyzed) and cefaclor, but it was markedly more stable than amoxicillin. There was high affinity to the chromosomally mediated P99 enzyme. The protein binding of Bay v 3522 was 45%. The primary target of Bay v 3522 was penicillin-binding protein 3.
PMCID: PMC171697  PMID: 2360820
25.  Pharmacokinetics and inflammatory fluid penetration of cefpodoxime proxetil in volunteers. 
The pharmacokinetics of cefpodoxime were determined after a single oral dose of 261 mg of cefpodoxime proxetil, equivalent to 200 mg of cefpodoxime, was given to each of six healthy male volunteers. Concentrations in serum, urine, and cantharidin-induced inflammatory fluid were measured by a microbiological assay. The mean peak level in plasma was 2.1 micrograms/ml, attained at a mean time of 2.9 h. The mean half-life of elimination from serum was 2.2 h. The inflammatory exudate was penetrated moderately rapidly, the mean peak level being 1.7 micrograms/ml at 3.5 h. The mean percent penetration of the inflammatory exudate was 103.7. The mean 24-h urine recovery of cefpodoxime was 32.2%. This study suggests that cefpodoxime proxetil taken once or twice daily will be sufficient to treat urinary or systemic infections caused by susceptible pathogens.
PMCID: PMC171563  PMID: 2327771

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