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1.  Gentamicin uptake in Staphylococcus aureus possessing plasmid-encoded, aminoglycoside-modifying enzymes. 
[3H]gentamicin uptake and killing were studied in three strains of gentamicin-resistant Staphylococcus aureus possessing plasmid-encoded, gentamicin-modifying enzymes and in three isogenic, enzyme-free, gentamicin-susceptible derivatives. At low (less than or equal to 2.0 micrograms/ml) concentrations of gentamicin, uptake by resistant organisms was impaired compared with that of susceptible strains, and no killing was noted. In contrast, at higher (2.5 to 10.0 micrograms/ml) concentrations (which were below the MIC for the resistant strains), rapid gentamicin uptake similar to that seen in susceptible isolates was observed. Although growth inhibition at these concentrations was apparent, there was no loss of viability in resistant strains. Consistently, the membrane H+-ATPase inhibitor N,N'-dicyclohexyl carbodiimide caused resistant strains to take up low concentrations (1.0 microgram/ml) of gentamicin at rates comparable to those seen in susceptible organisms without causing an associated loss of viability. These studies show differences between gentamicin uptake in S. aureus and streptomycin uptake in Escherichia coli (Dickie et al., Antimicrob. Agents Chemother. 14:569-580, 1978) regarding the kinetics of uptake in resistant strains with plasmid-encoded aminoglycoside-modifying enzymes. Specifically, they suggest that for 2-deoxystreptamine compounds such as gentamicin, ribosomal binding followed by accelerated uptake and subsequent interference with cell growth may occur without invariably being associated with lethal effect.
PMCID: PMC179964  PMID: 6517546
2.  Effect of saturable clearance during high-dose mezlocillin therapy. 
As mezlocillin has been shown to display nonlinear pharmacokinetics in single-dose evaluations, we evaluated a crossover trial in patients with renal dysfunction the impact on serum clearance of fixed-dose versus fixed-interval administration of identical daily doses of the drug. In four patients with creatinine clearances of 0.00 to 1.78 liters/h per 1.73 m2, equal serum clearances were observed when the calculated daily total dose of mezlocillin was given either as a fixed dose of 5,000 mg at various intervals or every 4 h at various doses. We found that repetitive large daily doses that are equivalent to 30 g/day in patients with normal renal function can be administered to patients with impaired renal function as a reduced dose every 4 h instead of prolonging the dosing interval, as suggested by Mangione et al. (Antimicrob. Agents Chemother. 21:428-435, 1982). The observed serum clearances were equal for the two schedules, probably owing to the degree of continuing saturation of the nonlinear clearance mechanisms of mezlocillin.
PMCID: PMC179995  PMID: 6517555
3.  Activity of apalcillin against Pseudomonas aeruginosa. 
The in vitro activity of apalcillin was tested against 107 clinical isolates of Pseudomonas aeruginosa, and the results were compared to those for piperacillin, mezlocillin, azlocillin, and carbenicillin. MIC analysis showed that 97% of the isolates were susceptible to piperacillin, 97% were susceptible to apalcillin, 93% were susceptible to azlocillin, 87% were susceptible to mezlocillin, and 84% were susceptible to carbenicillin.
PMCID: PMC176180  PMID: 6439115
4.  Augmentation of the in vitro activity of azlocillin against Bacteroides fragilis by clavulanic acid. 
Azlocillin was active against 90% of 154 strains of Bacteroides fragilis at a concentration of 64 micrograms/ml. Twenty-eight strains of B. fragilis with an azlocillin MIC of greater than or equal to 8 micrograms/ml were retested with a combination of azlocillin plus clavulanic acid. Of these strains, 71% showed a 4- to 32-fold decrease in the MIC of azlocillin plus clavulanic acid.
PMCID: PMC179977  PMID: 6517552
5.  Ornithyl amphotericin methyl ester treatment of experimental candidiasis in rats. 
After intravenous Candida albicans infection, rats received orinthyl amphotericin methyl ester, amphotericin B, or diluent intravenously. At doses of 0.1 and 0.5 mg/kg, the drugs were equally effective in preventing deaths. However, at doses of 2.0 mg/kg, mortality after treatment with amphotericin B was greater than that after placebo, whereas orinthyl amphotericin methyl ester was fully protective.
PMCID: PMC179929  PMID: 6476814
6.  In vitro activities of aztreonam, piperacillin, and ticarcillin combined with amikacin against amikacin-resistant Pseudomonas aeruginosa and P. cepacia isolates from children with cystic fibrosis. 
Amikacin, combined with aztreonam, piperacillin, or ticarcillin, synergistically inhibited amikacin-resistant sputum isolates of Pseudomonas aeruginosa and P. cepacia from children with cystic fibrosis. Ticarcillin-amikacin was the least active combination. Aminoglycoside resistance should not preclude the use of beta-lactam-aminoglycoside combinations in the treatment of pulmonary infections in cystic fibrosis.
PMCID: PMC185490  PMID: 6561954
7.  In vitro susceptibilities of 40 Campylobacter fetus subsp. jejuni strains to niridazole and metronidazole. 
The activities of niridazole and metronidazole were compared by an agar dilution method against 40 strains of Campylobacter fetus subsp. jejuni of human origin. Niridazole had a markedly higher activity than metronidazole.
PMCID: PMC185456  PMID: 6703680
8.  Single-dose pharmacokinetics of Ro 17-2301 (AMA-1080), a monocyclic beta-lactam, in humans. 
Ro 17-2301 (AMA-1080) is a new N-sulfonated monocyclic beta-lactam that is highly active against gram-negative bacteria, especially against Enterobacteriaceae and Haemophilus, Neisseria, and Pseudomonas spp. (Kondo et al., Proc. Int. Congr. Chemother. 13th, Vienna, Austria, p. 56/1-56/5, 1983). The single-dose pharmacokinetics of this compound were studied in six healthy male volunteers who received intravenous infusions of 500, 1,000, and 2,000 mg. A good linear correlation (r2 = 0.99) was found between the dose infused and the resulting area under the plasma concentration-time curve. Maximal plasma concentrations of 36, 78, and 150 micrograms/ml appeared after doses of 500, 1,000, and 2,000 mg, respectively. The mean terminal elimination half-life was 1.8 h (range, 1.4 to 2.3 h), the apparent volume of distribution at steady state was 17 liters, and the total systemic clearance was 150 ml/min. Within 72 h 78 to 89% of the dose was recovered intact from urine. After administration of 14C-labeled Ro 17-2301, 96% of the radioactivity was found in the urine and 3% was found in the feces. The concomitant administration of probenecid did not affect the renal clearance or urinary excretion of this beta-lactam, an indication that the renal elimination of this substance is only by glomerular filtration. Ro 17-2301 was 18% bound to human plasma protein, and this binding was independent of concentration between 25 and 400 micrograms/ml. Based on these data, the pharmacokinetics of this monocyclic beta-lactam should be predictable in the foreseen dose ranges.
PMCID: PMC180046  PMID: 6395801
9.  In vitro comparison of amifloxacin and six other antibiotics against aminoglycoside-resistant Pseudomonas aeruginosa. 
The in vitro activity of the synthetic fluoroquinolone amifloxacin was compared with those of six other antibiotics: ampicillin, aztreonam, cefotaxime, cephalexin, cinoxacin, and gentamicin. Amifloxacin had the lowest 50% MIC of any of the antibiotics tested against aminoglycoside-resistant Pseudomonas aeruginosa, 4 micrograms/ml.
PMCID: PMC284138  PMID: 6435518
10.  Enhanced efficacy of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine in combination with beta-interferon against herpes simplex virus type 2 in mice. 
The acyclic nucleoside 9-(1,3-dihydroxy-2- propoxymethyl )guanine (DHPG) and natural mouse interferon beta ( MuIFN -beta) were evaluated for their efficacy alone and in combination against herpes simplex virus type 2 systemic infections in mice. Intraperitoneally infected animals were treated once a day with the drugs at various concentrations for 5 days starting 24 h after inoculation. DHPG was injected subcutaneously at doses of 0.7 to 6 mg/kg. MuIFN -beta was given intraperitoneally at doses ranging from 3 X 10(3) to 3 X 10(4) IU per mouse. For DHPG alone, the effective dose at which 50% of the mice survived (ED50) was greater than 6 mg/kg. However, when given in combination with an ineffective dose of MuIFN -beta (10(4) IU per mouse), the ED50 for DHPG was 0.8 mg/kg. In addition, at the highest dose tested, MuIFN -beta alone had no protective activity against herpes simplex virus type 2 (ED50, greater than 3 X 10(4) IU per mouse). However, when given in combination with a marginally effective dose of DHPG (2 mg/kg), the ED50 for MuIFN -beta was less than 3 X 10(3) IU per mouse. Calculation of the fractional protective dose index (less than 0.23 where values of less than or equal to 0.5 are considered synergistic) indicates an enhanced protective interaction by the combination of the two drugs. These results represent the first time that potentiation of the antiviral activity of an acyclic nucleoside by interferon has been demonstrated in animal studies.
PMCID: PMC185586  PMID: 6610387
11.  Comparison of azlocillin, ceftizoxime, cefoxitin, and amikacin alone and in combination against Pseudomonas aeruginosa in a neutropenic-site rabbit model. 
The efficacy of beta-lactam antibiotics and amikacin alone and in various combinations against Pseudomonas aeruginosa was studied in a rabbit model simulating a closed-space infection in a locally neutropenic site. Six strains of P. aeruginosa were studied in semipermeable chambers placed subcutaneously in rabbits. Therapy was begun 4 h after inoculation of 5 X 10(4) CFU of bacteria per ml of pooled rabbit serum into the chambers. Antibiotics were administered intramuscularly every 6 h for 16 doses. Quantitative bacteriology was measured at the start of therapy and at 20, 44, and 92 h thereafter. Antibiotic concentrations were measured in blood and chamber fluid. Results were compared with in vitro tests of susceptibility and synergy. No single-agent therapy eradicated any of the six test organisms. Azlocillin (100 mg/kg per dose) plus amikacin (20 mg/kg per dose) eliminated five of six organisms by 92 h, and ceftizoxime (100 mg/kg per dose) plus amikacin (20 mg/kg per dose) eliminated three of six test strains. Azlocillin plus ceftizoxime (each 100 mg/kg per dose) failed to eliminate any of the six strains. To eliminate P. aeruginosa in this model, two drugs were required, with one being an aminoglycoside. In vitro susceptibility tests of synergy were predictive of successful therapy whenever the antibiotic concentrations (free and total) at the infection site exceeded the MBC for both the aminoglycoside alone and the beta-lactam when tested in combination with amikacin.
PMCID: PMC185582  PMID: 6329087
12.  Antibiotic resistance of degraded strains of Bordetella pertussis. 
The susceptibilities to erythromycin, rifampin, polymyxin B, ampicillin, tetracycline, gentamicin, fusidic acid, trimethoprim, and spectinomycin of five virulent phase I strains of Bordetella pertussis and their degraded phase IV descendants were compared. Increases in MICs of 2- to 16-fold were observed for erythromycin, rifampin, tetracycline, fusidic acid, trimethoprim, and spectinomycin for four of the five degraded strains.
PMCID: PMC185576  PMID: 6329086
13.  Infection caused by vancomycin-resistant Streptococcus sanguis II. 
A patient with bacteremia caused by vancomycin-resistant Streptococcus sanguis II is presented. This rare occurrence suggests that vancomycin may not be a completely reliable antibiotic in the treatment of infections due to viridans species of the genus Streptococcus. Gram-positive isolates from blood and otherwise sterile body fluids should be tested for susceptibility to vancomycin.
PMCID: PMC185572  PMID: 6732222
14.  Common beta-lactamase-specifying plasmid in Haemophilus ducreyi and Neisseria gonorrhoeae. 
Eighty-nine strains of Haemophilus ducreyi from a chancroid epidemic in Orange County, California, were examined for plasmid content. Seventy-eight (88%) of these isolates were found to contain a plasmid of 3.2 megadaltons which conferred beta-lactamase production. Restriction endonuclease digests indicated that this was the same plasmid that was found in some strains of beta-lactamase-producing Neisseria gonorrhoeae.
PMCID: PMC185496  PMID: 6424563
15.  High-pressure liquid chromatographic method for determination of Sch 28191 in biological fluids. 
A high-pressure liquid chromatographic method has been developed for the measurement of N-D-ornithyl amphotericin B methyl ester (Sch 28191) in biological fluid. The method involves protein precipitation with methanol, followed by separation of the supernatant on a reverse-phase column and quantitation by absorbance at 405 nm. This technique resulted in a recovery of 97%. There was a good linear relationship between the peak height ratio and Sch 28191 concentrations ranging from 0.015 to 20 micrograms/ml. In addition, this method was specific for Sch 28191 since all of its analogs tested did not interfere with the assay. The method was reproducible with a lower limit of quantitation of 0.015 microgram/ml. Serum levels obtained from this method were in good agreement with those obtained from a microbiological assay only when drug concentrations were higher than 1.5 microgram/ml. The high-pressure liquid chromatographic method is useful in monitoring serum and urine drug levels in animals and should prove to be useful for pharmacokinetic studies of the drug with therapeutic doses in humans.
PMCID: PMC185432  PMID: 6703683
16.  Ciprofloxacin penetration into extravascular spaces in a rabbit model. 
Ciprofloxacin penetration into extravascular spaces was studied in a rabbit Visking chamber model. The drug was administered (7 mg/kg) intramuscularly every 4 h for eight doses. Peak and trough drug levels by dose 8 were 1.3 and 0.35 micrograms/ml in serum and 0.61 and 0.50 micrograms/ml in extravascular sites. The ratio of extravascular site to serum free drug area under the drug curve by dose 8 was 91.1%. This potent, new antimicrobial agent appears to distribute freely to extravascular spaces in this animal model.
PMCID: PMC180055  PMID: 6524907
17.  Effect of exchange transfusion with an oxygen-carrying resuscitation fluid on the efficacy of penicillin therapy of pneumococcal infection in rats. 
The effects of exchange transfusion with Fluosol DA (FDA) or stroma-free hemoglobin on the outcome of pneumococcal infection in rats were determined. Rats were sham transfused or exchange transfused with 25 ml of FDA or stroma-free hemoglobin. They were then challenged intraperitoneally with Streptococcus pneumoniae type 3 and treated with penicillin for 120 h. Only 2 of 15 (13.3%) FDA-transfused rats were alive at 312 h compared with 11 of 15 (73.3%) concurrently studied sham-transfused control rats (P = 0.0016). Of 10 stroma-free hemoglobin-transfused rats and 10 concurrently studied sham-transfused control rats (P = 0.98), 8 from each group (80%) were alive at 312 h. Penicillin therapy only suppressed pneumococcal infection in FDA-transfused rats, and relapse occurred after therapy was stopped. This effect could not be attributed to interference with the bactericidal activity of penicillin against pneumococci, to an alteration in the pneumococcal burden before penicillin therapy or to an alteration of the leukocyte and polymorphonuclear leukocyte response by FDA. In contrast, pneumococcal infection in stroma-free hemoglobin-transfused rats was cured with penicillin therapy. These data showed that FDA altered the ability of rats to respond to pneumococcal infection.
PMCID: PMC180047  PMID: 6524905
18.  Pharmacokinetics of trimethoprim and sulfamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges. 
The pharmacokinetics of trimethoprim (TMP) and sulfamethoxazole (SMX) in cerebrospinal fluid (CSF) and serum after a single intravenous infusion of 5 mg of TMP and 25 mg of SMX per kg of body weight over approximately 120 min were studied i nine patients who had uninflamed meninges and were undergoing elective myelography. Peak concentrations of TMP and SMX in CSF were 1 microgram/ml and 13.8 micrograms/ml, respectively. The peak TMP concentration in CSF occurred significantly earlier than the peak SMX concentration (60 versus 480 min postinfusion). At 15 h, there was no detectable TMP in the CSF, and there was 4.7 micrograms of SMX per ml of CSF. In the postdistribution phase (in CSF), simultaneous CSF-to-serum concentration ratios ranged from 0.23 to 0.53 for TMP and from 0.20 to 0.36 for SMX. CSF penetration (measured by comparison of the area under the curve of the composite CSF and serum concentration-time curves) was 18% for TMP and 12% for SMX. A loading dose of TMP-SMX (bases on TMP) of 10 to 12 mg/kg and a maintenance dose of 6 mg/kg every 8 h or 8 mg/kg every 12 h (with a 2-h infusion) should yield steady-state peak concentrations of at least 5 micrograms of TMP per ml of serum and 160 micrograms of SMX per ml of serum. Further studies of TMP-SMX administered in these doses in the treatment of serious bacterial infection, including meningitis, are warranted.
PMCID: PMC180029  PMID: 6335381
19.  Amifloxacin activity against well-defined gentamicin-resistant, gram-negative bacteria. 
Amifloxacin (WIN 49375) activity against a well-defined group of gentamicin-resistant gram-negative bacilli was compared with the activity of 11 other antimicrobial agents. For all strains, amifloxacin and norfloxacin were the most active agents, followed by cefotaxime and moxalactam. For Acinetobacter sp. only amifloxacin had an achievable MIC for 90% of the strains. Amifloxacin joins other newly developed DNA gyrase inhibitors as potentially useful agents for infections due to aminoglycoside-resistant gram-negative bacilli.
PMCID: PMC180015  PMID: 6440481
20.  Comparative pharmacokinetics of Sch 28191 and amphotericin B in mice, rats, dogs, and cynomolgus monkeys. 
The pharmacokinetics of Sch 28191, the N-D-ornithyl methyl ester of amphotericin B, and amphotericin B were studied in mice, rats, dogs, and cynomolgus monkeys after an intravenous dose of 0.6 mg/kg was administered. The decline in the concentrations of Sch 28191 and amphotericin B in serum appeared to be biphasic in nature. The half-life at the distribution phase and the half-life at the elimination phase of Sch 28191 were similar to those of amphotericin B in all animals studied. The half-life at the distribution phase in serum was 0.9 to 1.5 h in all animals studied. The half-lives at the elimination phase in serum were 25 to 28 h in mice, 16 to 18 h in rats, 44 to 47 h in dogs, and 35 h in cynomolgus monkeys. The areas under the serum concentration-time curves of Sch 28191 were five- to eightfold larger than those of amphotericin B in rats, dogs, and cynomolgus monkeys but were only slightly larger than those of amphotericin B in mice. In dogs, the urinary excretion (over 9 days) of unchanged drug accounted for 23% of the Sch 28191 dose and 25% of the amphotericin B dose. The concentrations of Sch 28191 in serum were also studied after the intravenous administration of 0.3, 0.6, or 1.25 mg/kg to dogs. The serum concentration-time curves were parallel for these doses. There was a linear relationship between the areas under the concentration-time curves and the doses, indicating dose proportionality.
PMCID: PMC179942  PMID: 6517539
21.  Antimicrobial activities of BMY-28142, cefbuperazone, and cefpiramide compared with those of other cephalosporins. 
The antimicrobial activities of BMY-28142, cefbuperazone (BMY-25182; formerly T-1982), and cefpiramide (WY-44635; formerly SM-1652) were compared with those of cefmenoxime, cefoperazone, cefotaxime, ceftizoxime, and moxalactam. BMY-28142 was the most active cephalosporin against the majority of aerobic and facultatively anaerobic microorganisms studied. Its spectrum of activity was very similar to that of cefotaxime. However, BMY-28142, cefbuperazone, cefmenoxime, cefotaxime, ceftizoxime, and moxalactam were equivalent in activity and rate of killing against members of the family Enterobacteriaceae. Cefpiramide was considerably less active than the other cephalosporins against the Enterobacteriaceae.
PMCID: PMC179970  PMID: 6549120
22.  Pharmacokinetics of cefotiam administered intravenously and intramuscularly to healthy adults. 
We studied the pharmacokinetics of cefotiam, a parenteral cephalosporin, at intravenous doses of 0.5, 1, and 2 g and intramuscular doses of 0.5 and 1 g in two groups of eight healthy adult volunteers. The concentrations of cefotiam in plasma were determined over a period of 5 or 6 h and in urine over 24 h, using high-pressure liquid chromatographic procedures. Plasma concentration-time data were fitted to a three-exponential equation for the intravenous administration, and after intramuscular administration, the data were analyzed by a two-compartment or a one-compartment open model. Over the above dosing range and routes of administration, cefotiam pharmacokinetics were essentially linear, with plasma clearances varying from 19.6 to 22.5 liters/h. No significant differences were observed with respect to the terminal half-life (1 h) and the area under the curve versus the dose. Intramuscularly injected cefotiam was 63 to 74% available. The fraction of dose excreted unchanged in urine (0.50 to 0.67) indicated a substantial nonrenal mechanism of elimination. The apparent volume of distribution (about 30 liters) was higher than those of other parenteral cephalosporins.
PMCID: PMC179955  PMID: 6097166
23.  In vitro activity of WIN 49375 compared with those of other antibiotics in isolates from cancer patients. 
The activity of WIN 49375 [6-fluoro-1, 4-dihydro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid], a new synthetic quinolone, was tested in vitro against 587 clinical isolates. The MICs for 90% of isolates of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae were 0.20, 1.56, and 0.39 microgram/ml, respectively. The MICs for 90% of isolates of Pseudomonas aeruginosa and Serratia marcescens were both 3.12 micrograms/ml. WIN 49375 was minimally active against gram-positive cocci. Its in vitro activity suggests that it may be useful for the treatment of gram-negative bacillary infections.
PMCID: PMC176185  PMID: 6508271
24.  Bactericidal activity of ceftazidime in serum compared with that of ticarcillin combined with amikacin. 
We compared the bactericidal activity of serum attained 1 and 6 h after the termination of infusions of either ceftazidime (2 g) or ticarcillin plus amikacin (5 g and 7.5 mg/kg, respectively) in 6 volunteers against a panel of the most common pathogens found in the blood of febrile granulocytopenic cancer patients. Ceftazidime consistently produced significantly higher serum bactericidal titers at both 1 and 6 h against all species of gram-negative bacilli. Its performance against Pseudomonas aeruginosa was especially impressive. The geometric mean titer against this organism was 1:41 at 1 h, contrasted with 1:12 for ticarcillin plus amikacin (P = 0.025). However, for Staphylococcus aureus, the geometric mean serum bactericidal titer of ceftazidime was 1:3.6 at 1 h and undetectable at 6 h. Ceftazidime shows promise as single-agent therapy for serious gram-negative bacillary infections. Whether this promise is fulfilled and whether the observed antistaphylococcal activity is adequate for empiric therapy in infected granulocytopenic patients need further investigation.
PMCID: PMC176165  PMID: 6439114
25.  Affinity of temocillin for Escherichia coli K-12 penicillin-binding proteins. 
Temocillin is a 6 alpha-methoxy penicillin which shows poor affinity for the penicillin-binding proteins (PBPs) of Escherichia coli K-12 when tested by competition with [14C]penicillin G or [125I]penicillin X. When the reaction conditions for the radiolabeled penicillin used in this procedure were modified by lowering the temperature (2 degrees C) and reducing the incubation time (3 min), temocillin showed a much higher affinity for PBP-3 and improved affinity for the other PBPs, with the exception of PBP-2. Direct labeling procedures with [14C]temocillin also showed that the compound had affinity for PBPs 1a and 3. These results are more consistent with the effects of temocillin on the morphology of E. coli than the poor affinity values obtained by the classical competitive procedure. Reasons for the disparity between these assay systems are discussed.
PMCID: PMC176164  PMID: 6391369

Results 1-25 (431)