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1.  In vitro pharmacodynamics of piperacillin, piperacillin-tazobactam, and ciprofloxacin alone and in combination against Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa. 
The time-kill curve methodology was used to determine the pharmacodynamics of piperacillin, ciprofloxacin, piperacillin-tazobactam and the combinations piperacillin-ciprofloxacin and ciprofloxacin-piperacillin-tazobactam. Kill curve studies were performed for piperacillin, ciprofloxacin, and piperacillin-tazobactam at concentrations of 0.25 to 50 times the MICs for 13 strains of bacteria: four Pseudomonas aeruginosa, three Enterobacter cloacae, three Klebsiella pneumoniae, and three Staphylococcus aureus isolates (tazobactam concentrations of 0.5, 4, and 12 micrograms/ml). By using a sigmoid Emax model and nonlinear least squares regression, the 50% lethal concentrations and the maximum lethal rates of each agent were determined for each bacterial strain. For piperacillin-ciprofloxacin and ciprofloxacin-piperacillin-tazobactam, kill curve studies were performed with concentrations obtained by the fractional maximal effect method (R. C. Li, J. J. Schentag, and D. E. Nix, Antimicrob. Agents Chemother. 37:523-531, 1993) and from individual 50% lethal concentrations and maximum lethal rates. Ciprofloxacin-piperacillin-tazobactam was evaluated only against the four P. aeruginosa strains. Interactions between piperacillin and ciprofloxacin were generally additive. At physiologically relevant concentrations of piperacillin and ciprofloxacin, ciprofloxacin had the highest rates of killing against K. pneumoniae. Piperacillin-tazobactam (12 micrograms/ml) had the highest rate of killing against E. cloacae. Piperacillin-ciprofloxacin with relatively higher ciprofloxacin concentrations had the greatest killing rates against S. aureus. This combination had significantly higher killing rates than piperacillin (P < 0.002). For all the bacterial strains tested, killing rates by ciprofloxacin were significantly higher than those by piperacillin-tazobactam (4 and 12 micrograms/ml had significantly higher killing rates than piperacillin alone (P < 0.02 and P < 0.004, respectively). The effect of the combination of piperacillin-ciprofloxacin, in which piperacillin concentrations were relatively higher, was not statistically different from that of piperacillin alone (p > or = 0.71). The combination of ciprofloxacin-piperacillin-tazobactam achieved greater killing than other combinations or monotherapies against P. aeruginosa. The reduction in the initial inoculum was 1 to 4 logs greater with ciprofloxacin-piperacillin-tazobactam at 4 and 12 micrograms/ml than with any other agent or combination of agents. On the basis of the additive effects prevalently demonstrated in the in vitro study, the combinations of piperacillin-ciprofloxacin and piperacillin-tazobactam are rational therapeutic options. Greater killing of P. aeruginosa was demonstrated with ciprofloxacin-piperacillin--tazobactam. Since treatment failure of P. aeruginosa pneumonia is a significant problem, clinical studies are warranted.
PMCID: PMC162813  PMID: 7486906
3.  Degradation kinetics of imipenem in normal saline and in human serum. 
The stability of imipenem in 0.9% sodium chloride and in human serum was measured at controlled temperatures over time. The degradation was characterized by a first-order process and was consistent with an apparent hydrolysis reaction.
PMCID: PMC284186  PMID: 3460525
4.  Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients. 
We studied 201 critically ill patients during 267 courses of gentamicin (139 courses) or tobramycin (128 courses) therapy. Clinical and pharmacokinetic data were obtained on 240 of 267 courses (120 courses each of gentamicin and tobramycin). Two judgments of nephrotoxicity and its cause were made independently in this study, using a clinical and a pharmacokinetic definition of nephrotoxicity. The two sets of criteria were generally in good agreement, as all but 10 of 41 patients who were judged nephrotoxic by pharmacokinetic criteria were independently judged nephrotoxic by the clinical definition. Groups of patients judged nontoxic did not differ from groups judged nephrotoxic in age, sex, weight, initial creatinine clearance, total dose given, duration of treatment, initial aminoglycoside trough serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Prior aminoglycosides (usually gentamicin) had been used more frequently in the nontoxic group (P less than 0.05). Two major conclusions of this study are at variance with those of previous investigators; (i) we found no clinical parameters of value in predicting nephrotoxicity in critically ill patients; and (ii) aminoglycoside serum concentrations, once in the therapeutic range, were of limited value in prevention of aminoglycoside nephrotoxicity in our patients.
PMCID: PMC182000  PMID: 7103453
5.  Predicted tissue accumulation of netilmicin in patients. 
The two-compartment pharmacokinetics of netilmicin were investigated in 11 patients with stable renal function who were being treated for gram-negative infections. The initial dosage of netilmicin ranged from 2.5 to 5.0 mg/kg per day, with subsequent changes made on the basis of serum concentrations. Venous blood samples were obtained every 2 to 4 days during therapy and daily for an average of 10 days after the final dose. Serum concentrations were measured by both microbiological assay and radioimmunoassay. Peak and trough netilmicin concentrations were significantly greater (P less than 0.01) at the end of therapy than at the first dose, even though renal function was stable throughout treatment in all patients. After the final dose, serum concentrations declined in a biphasic manner, with a first-phase half-life of 5.4 h and a terminal half-life of 198 h. The total body clearance averaged 31 ml/min. An average of 99 mg of netilmicin (approximately 5% of the total dose) was predicted to be in the tissue compartment at the end of therapy. A comparison of these pharmacokinetic parameters with those obtained in a previously reported but similar study with gentamicin showed no significant differences between the two aminoglycosides with respect to peak and trough concentrations (initially or at the end of therapy), volumes of distribution, total body clearance, or amount of drug in the tissue compartment at the end of therapy. The terminal half-life of netilmicin was significantly greater than that of gentamicin, whereas the rate constant of netilmicin for tissue influx (k12) was significantly less.
PMCID: PMC181787  PMID: 7325637
6.  Pharmacokinetics of lomefloxacin in renally compromised patients. 
Antimicrobial Agents and Chemotherapy  1990;34(12):2364-2368.
The single-dose pharmacokinetics of orally administered lomefloxacin (400 mg) were studied in normal subjects and in patients with various degrees of renal function. The subjects were classified by creatinine clearance (CLCR) normalized for body surface area: group 1, CLCR of greater than 80 ml/min/1.73 m2; group 2, CLCR of 80 to greater than 40 ml/min/1.73 m2; group 3, CLCR of 40 to greater than 10 ml/min/1.73 m2; and group 4, CLCR of less than or equal to 10 ml/min/1.73 m2. Each group consisted of eight subjects. The pharmacokinetics of lomefloxacin were significantly influenced by renal function. There were significant differences in the elimination rate constant, half-life, area under the concentration-time curve from 0 h to infinity, apparent total drug clearance, renal clearance, and apparent nonrenal drug clearance between the four renal function groups. Mean half-lives for groups 1, 2, 3, and 4 were 8.09, 9.11, 20.90, and 44.25 h, respectively. There were no significant differences between the renal groups for maximum concentration of the drug in serum and apparent volume of distribution. Age had no apparent effect on lomefloxacin disposition. There was a significant relationship between CLCR and lomefloxacin total body clearance (r = 0.92, P = 0.001) and renal clearance (r = 0.94, P = 0.001). Despite a predominate renal route of elimination, nonrenal lomefloxacin clearance significantly decreased with decreasing renal function (r = 0.72, P = 0.001). Mean lomefloxacin excretion rates over 48 h were 60.7, 56.0, 29.1, and 1.0% of the administered dose for groups 1, 2, 3, and 4, respectively. Mean glucuronide excretion rates over 48 h were 7.8, 6.3, 10.0, and 0.6% of the administered dose for groups 1, 2, 3, and 4, respectively. Hemodialysis had no effect on lomefloxacin concentrations in plasma. In patients with normal to moderate renal function, 400 mg of lomefloxacin per day should provide therapeutic concentrations in blood. The lomefloxacin dose should be reduced to 200 mg/day as the CL(CR) falls below 30 ml/min/1.73 m2. No additional dosage adjustments appear to be necessary for hemodialysis patients.
PMCID: PMC172062  PMID: 2088191
7.  Single-dose accumulation pharmacokinetics of tobramycin and netilmicin in normal volunteers. 
The two-compartment tissue accumulation pharmacokinetics of tobramycin and netilmicin were compared in 11 normal volunteers by using a crossover design. After each 1.0-mg/kg (body weight) dose, serum was collected for 96 h, and complete 24-h urine collections were obtained for a total of 30 days. Two months of washout were required before crossover. Concentrations in serum and urine were measured by radioimmunoassay, and concentrations in serum and urinary excretion rates were simultaneously fitted to a two-compartment pharmacokinetic model. Netilmicin exhibited significantly lower total body clearance (48 versus 90 ml/min) and longer terminal elimination half-life (161 versus 96 h) than tobramycin. As a result of these pharmacokinetic differences, the predicted tissue accumulation of netilmicin at steady state was significantly higher than that of tobramycin (P less than 0.05). Relative rates of aminoglycoside nephrotoxicity probably depend on both the differential tissue uptake (accumulation) and the concentration of the aminoglycoside which produces intracellular toxicity. Because the steady-state tissue accumulation of netilmicin is nearly 2.5 times greater than that of tobramycin, its potency in the production of intracellular toxicity needs to be that much less for the two agents to produce the same incidence of clinical nephrotoxicity.
PMCID: PMC174785  PMID: 3606064
8.  Two-compartment comparison of gentamicin and tobramycin in normal volunteers. 
The objective of this study was to determine whether differences in tissue accumulation observed upon multiple dosing of aminoglycosides in hospitalized patients could be identified in appropriate single-dose studies in normal volunteers. Ten volunteers received single intravenous doses of 1.0 mg of gentamicin and tobramycin per kg of body weight in randomized crossover fashion. Multiple serum and urine samples were collected during the next 30 days. Serum aminoglycoside concentrations and urinary excretion rates were fitted to a two-compartment pharmacokinetic model, and parameters were derived. Tobramycin exhibited a higher clearance (P less than 0.08) and a lower volume of distribution at steady state (P less than 0.1), neither of which was significant. Tobramycin also showed a significantly lower predicted amount of drug in the body at steady state (P less than 0.05). These differences are consistent with observations made in patients receiving multiple doses. Single-dose studies appear to be capable of discriminating pharmacokinetic characteristics relevant to the comparative nephrotoxic potential of these two aminoglycosides.
PMCID: PMC185663  PMID: 7181489
9.  Amikacin and gentamicin accumulation pharmacokinetics and nephrotoxicity in critically ill patients. 
Twenty-five critically ill adults receiving blood level-adjusted doses of amikacin were prospectively studied with serum, urine, and, when possible, tissue amikacin concentrations. These data were fitted to a two-compartment pharmacokinetic model. Prolonged urine collections or postmortem tissues (or both) were used to confirm predicted tissue accumulation. Nephrotoxicity was also investigated. Patients were defined as having renal damage if they showed an increase in serum creatinine of greater than 0.5 mg/100 ml, an increase in urine beta 2-microglobulin of greater than 50 mg/day, and presence of urinary casts of greater than 500/ml. Renal damage was attributed to amikacin if there was, in addition to the above, tissue accumulation of amikacin of greater than 600 mg. These patients were matched with 25 patients treated with gentamicin during the same time period. There were no statistical differences between the gentamicin- and amikacin-treated patients in age, sex, weight, base-line creatinine clearance, concurrent cephalosporins or diuretics, treatment duration, site of infection, normalized (amikacin/gentamicin dosing ratio of 3:1) total dose, mortality, or tissue accumulation. More amikacin-treated patients (19 of 25) than gentamicin-treated patients (9 of 25) received prior aminoglycosides (P less than 0.01). The only pharmacokinetic parameter that differed between amikacin and gentamicin was a greater K21 for gentamicin. Nephrotoxicity was observed in 4 gentamicin was a greater K21 for gentamicin. Nephrotoxicity was observed in 4 gentamicin-treated patients (16%) and 5 amikacin-treated patients (20%). At a 3:1 dosing ratio, there were no significant differences between amikacin and gentamicin two-compartment pharmacokinetics and nephrotoxic potential in matched critically ill patients, but the trend of these data showed greater amikacin tissue accumulation. However, at an amikacin/gentamicin dosing ratio of 4:1, their tissue accumulation potential appeared to be almost identical.
PMCID: PMC181374  PMID: 7247354
10.  Animal model distinguishing in vitro from in vivo carbenicillin-aminoglycoside interactions. 
Aminoglycosides and carbenicillin are frequently co-administered to patients with serious gram-negative infections. Aminoglycosides are inactivated by carbenicillin in vitro, and a loss of antibacterial activity of both antibiotics results. Although these interactions are presumed to occur in vivo, previous studies have not used assay methodology that can distinguish inactivation occurring prior to and during microbiological assay from inactivation in vivo. To address this problem, we gave seven bilaterally nephrectomized mongrel dogs doses designed to achieve simultaneous therapeutic serum concentrations of aminoglycosides and carbenicillin. Serum samples were tested by radioimmunoassay on three occasions: immediately, to determine in vivo interactions, and at 24 h and 1 week to assess the time course of in vitro inactivation. In comparison with immediate radioimmunoassay, gentamicin and tobramycin concentrations decreased by 39 and 53%, respectively, when assayed at 24 h (P < 0.05) and by 75 and 82% when assayed at 7 days (P < 0.001). In contrast, amikacin concentrations were reduced by only 9 and 30% at 24 h and 7 days. Tobramycin concentrations were also determined by immediate microbiological assay and were found to be similar to those in samples stored for 24 h before radioimmunoassay. Immediate radioimmunoassay demonstrated that carbenicillin reduced in vivo serum half-lives of gentamicin and tobramycin by 40% (P < 0.05). The half-life of amikacin in vivo was not significantly altered. In the presence of carbenicillin, amikacin was the most stable aminoglycoside both in vivo and in vitro, and it is the aminoglycoside of choice in patients with renal failure who require this combination.
PMCID: PMC284057  PMID: 6969576
11.  Effect of lomefloxacin on theophylline pharmacokinetics. 
A study involving 25 health male volunteers was conducted to evaluate the effect of lomefloxacin on the pharmacokinetics of theophylline. The mean age was 22.4 +/- 3.0 years, and the mean weight was 77.3 +/- 7.7 kg. A single 6-mg/kg aminophylline dose was given intravenously on study days 1 and 15. The subjects received a 400-mg lomefloxacin dose (four 100-mg capsules) on study days 9 through 15. No treatment was given on study days 2 through 8. Thirteen blood samples were collected within 24 h after each aminophylline dose. Theophylline concentrations in serum were measured by enzyme immunoassay (EMIT). The mean aminophylline dose was 437 +/- 36 mg, equivalent to 344 mg of theophylline. Multiple doses of lomefloxacin had no effect on the area under the concentration-time curve from 0 h to infinity, maximal concentration, or clearance of theophylline from serum. There was a slight increase in the theophylline half-life from 6.72 +/- 1.63 to 7.02 +/- 1.37 h after lomefloxacin dosing (P = 0.04); however, the change was clinically insignificant. No change in theophylline dose is required when lomefloxacin therapy is instituted in a patient receiving theophylline.
PMCID: PMC176053  PMID: 2675751
12.  High-pressure liquid chromatography analysis and single-dose disposition of tobramycin in human volunteers. 
A sensitive and specific fluorometric high-pressure liquid chromatography technique was developed to measure both tobramycin and an internal standard (gentamicin C2). The assay utilizes direct extraction of the o-phthalaldehyde derivatives from serum and urine. Coefficients of variation were 7.9% (serum) and 6.0% (urine) at a tobramycin concentration of 1.0 microgram/ml. The lower limit of assay sensitivity was 0.2 microgram/ml. Results obtained from high-pressure liquid chromatography were in excellent agreement with those from radioimmunoassay for both serum (r = 0.97) and urine (r = 0.91). No other aminoglycoside antibiotics and no other antibiotics that were tested caused interfering peaks. Tobramycin (1 mg/kg intravenous bolus) was administered to three healthy volunteers. Tobramycin concentrations were detectable for 10 h in serum and for 240 h in urine after a 1-mg/kg intravenous dose. A two-compartment pharmacokinetic model was required to describe the tobramycin disposition. Urinary recovery of tobramycin over a 10-day period accounted for 95.8, 94.3, and 83.1% of the administered dose. High-pressure liquid chromatography methodology is sufficiently sensitive to determine single-dose, two-compartment tobramycin pharmacokinetics from urinary excretion data, thus verifying the prolonged excretion of tobramycin after a single dose. The analytical methodology and pharmacokinetic techniques described may be useful in studying other aminoglycosides.
PMCID: PMC283846  PMID: 7396455
13.  New turbidimetric assay for quantitation of viable bacterial densities. 
A turbidimetric assay was developed and validated against Escherichia coli for the quantitation of viable bacterial densities. The Abbott MS-2 research system was employed for continuous 5-min measurements of optical density. A linear standard curve was obtained by regressing the initial bacterial density (log CFU per milliliter) against the time required for bacterial growth causing a 5% decrease in optical transmittance. Slope and intercept values obtained from eight standard curves showed excellent assay reproducibility. Results obtained by the turbidimetric assay compared favorably to those obtained by the conventional pour plate assay. Prior to the application of the new assay, possible interferences of postantibiotic effect induced by the test antibiotics were excluded. The turbidimetric assay, which is presumably more efficient and less expensive, was implemented for the time-kill studies of three different beta-lactams against E. coli.
PMCID: PMC187673  PMID: 8452373
14.  Inhibition of theophylline clearance by coadministered ofloxacin without alteration of theophylline effects. 
The influence of multiple doses of ofloxacin (ORF 18489) on the disposition of theophylline was studied in 15 male volunteers. Subjects were confined in the Clinical Research Unit for 13 days and given a xanthine-free diet. A single dose (3 mg/kg) of theophylline was given orally, and blood samples were collected at fixed time intervals for 36 h. The concentrations of theophylline were measured with TDX (Abbott Diagnostics, Irving, Tex.), and clearance was calculated. Theophylline clearance was used to individualize subsequent doses to achieve average steady-state theophylline concentrations in plasma of 10 mg/liter. Individualized theophylline doses were administered every 8 h until steady-state conditions were reached. Theophylline clearance was determined again at steady state and on days 7 and 8. On day 8, ofloxacin (400 mg every 12 h) was given concomitantly with theophylline. Theophylline clearance was measured again on day 12, after the last theophylline dose. Administration of ofloxacin for 1 day did not change theophylline clearance, but coadministration for 4 days significantly decreased theophylline clearance by 12.1% (P less than 0.05). The area under the concentration-time curve for theophylline increased 9.9% (P less than 0.05), and average steady-state concentrations in plasma increased 10.3% (P less than 0.05). Despite changes in clearance, adverse effects of theophylline did not increase during coadministration of ofloxacin. Although statistically significant, the interaction between ofloxacin and theophylline is unlikely to be of major clinical importance.
PMCID: PMC174735  PMID: 3472488
15.  Urinary casts as an indicator of renal tubular damage in patients receiving aminoglycosides. 
We assessed the value of quantitative cast excretion as an early marker of renal tubular damage in 154 seriously ill patients. One hundred twenty-four of these received aminoglycoside antibiotics, and 30 of the 124 experienced a rise in serum creatinine of 0.5 mg/dl or more during therapy. The remaining 30 of the 154 patients were treated with other antibiotics and served as controls. Casts were quantitated in random urines collected before morning diuretic doses. Cast counts in control patients averaged 44 +/- 51 casts during the intensive care unit admission. Patients given aminoglycosides without a significant rise in serum creatinine of 0.5 mg/dl or more excreted 153 +/- 196 casts, significantly more than controls. In comparison to both the control and nontoxic patients, the 30 nephrotoxic patients excreted significantly more casts (625 +/- 364) and were significantly higher as early as 9 days before serum creatinine first rose. Daily urinary cast counts are a rapid and inexpensive means of identifying early renal tubular damage in critically ill patients given aminoglycosides.
PMCID: PMC352884  PMID: 518076
16.  Inhibition of enoxacin absorption by antacids or ranitidine. 
Ten normal volunteers participated in a randomized, five-way crossover study to determine the effect of concurrent enoxacin and antacid or ranitidine administration on enoxacin absorption. The bioavailability of a single oral 400-mg enoxacin dose was significantly decreased, by 73 and 49%, when Maalox TC was administered 0.5 and 2 h before enoxacin, respectively. Enoxacin bioavailability was not significantly altered when the antacid was given 8 h before or 2 h after enoxacin administration. Ranitidine, administered intravenously 2 h before enoxacin, also significantly decreased enoxacin bioavailability, by 40%. The correlation between the proximity of antacid administration and the magnitude of the decrease in enoxacin bioavailability supports complexation as the mechanism of the antacid-enoxacin interaction. However, reduction of enoxacin bioavailability by ranitidine suggests that elevated gastric pH may also play a role in the antacid-enoxacin drug-drug interaction.
PMCID: PMC172500  PMID: 2751276
17.  Sucralfate reduces the gastrointestinal absorption of norfloxacin. 
The effect of sucralfate on the bioavailability of norfloxacin after single 400-mg doses of norfloxacin was evaluated in eight healthy males. Subjects received each of the following treatments in random sequence: (i), norfloxacin, 400 mg alone; (ii) sucralfate, 1 g, concurrently with norfloxacin, 400 mg; and (iii) sucralfate, 1 g, followed by norfloxacin, 400 mg, 2 h later. One day before administration of treatments 2 and 3, 1 g of sucralfate was given at 7 a.m., 11 a.m., 5 p.m., and 10 p.m. Blood samples were collected immediately before the norfloxacin dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 h postdose. Urine was collected in divided intervals: from 0 to 12, from 12 to 24, and from 24 to 48 h. Norfloxacin concentrations in plasma and urine were determined by high-performance liquid chromatography. Mean area under the plasma concentration-versus-time curve extrapolated to infinity decreased significantly (P less than 0.001) after norfloxacin was given with and 2 h after sucralfate. The relative bioavailabilities were 1.8% when norfloxacin was taken with sucralfate and 56.6% when it was taken 2 h after sucralfate. After norfloxacin was given alone, the mean norfloxacin concentrations in urine collected during intervals of 0 to 12, 12 to 24, and 24 to 28 h were 118.9 +/- 72.3, 18.8 +/- 12.5, and 2.4 +/- 2.2 micrograms/ml, respectively. After norfloxacin was given with sucralfate, however, the mean norfloxacin concentrations in urine collected during the same time intervals were 6.8 +/- 4.7, 1.8 +/- 1.4, and 0 +/- 0 microgram/ml, respectively. Because of low pH and relatively high magnesium concentration in urine, susceptibilities of bacteria in urine are 8- to 32-fold lower than in broth. This fact, in combination with the reduced bioavailability of norfloxacin in the presence of sucralfate or antacids, is likely to result in treatment failure. The effect of sucralfate given after norfloxacin was not examined, nor was the effect of sucralfate given more than 2 h before norfloxacin. Administration or norfloxacin with sucralfate should therefore by avoided.
PMCID: PMC171428  PMID: 2712548
18.  Pharmacokinetics of ceftazidime in patients with renal insufficiency. 
The pharmacokinetics of ceftazidime were studied in 14 adult volunteers with different degrees of renal function. The elimination of ceftazidime was totally dependent on renal excretion. The clearance of ceftazidime ranged from 7.5 to 145.1 ml/min and correlated with both renal ceftazidime clearance and creatinine clearance (ClCR). It is recommended that 0.5 to 2.0 g of ceftazidime be given in extended dosages, with intervals dependent on the renal function of the patient. Patients with a ClCR of greater than 50 ml/min should be given ceftazidime every 8 h, those with a ClCR of 30 to 50 ml/min should be given the drug every 12 h, those with a ClCR of 15 to 30 ml/min should be given the drug once a day, and individuals with a ClCR of less than 15 ml/min should be given the drug on a day, and individuals with a ClCR of less than 15 ml/min should be given the drug on a 36- to 48-h regimen.
PMCID: PMC185474  PMID: 6370127
19.  Rate of methicillin penetration into normal heart valve and experimental endocarditis lesions. 
Methicillin concentrations were measured in serum, normal heart valves, damaged heart valves, myocardium, and extravascular fluid from 12 New Zealand white rabbits to assess the influence of valvular damage on methicillin penetrations. Fibrin scarring of the aortic valve was induced by the placement of a polyethylene catheter through the aortic leaflet for 4 days. Each rabbit was then given a 40-mg/kg intravenous bolus dose of methicillin. Serum concentrations were collected, and animals were sacrificed 5, 15, 30, and 60 min after the dose. Normal and damaged heart valves from six different rabbits were desiccated to evaluate the fluid content of each. The time course of methicillin in damaged aortic valves was similar to that in serum and followed a bioexponential decline. The pharmacokinetic profile of methicillin in normal heart muscle and normal heart valves was clearly different from that of serum and damaged heart valves. Damaged valves showed a rapid and complete equilibrium with serum, whereas normal heart valve and muscle methicillin concentrations were consistently lower than serum concentrations at all times after the rapid bolus dose. The greater extravascular fluid content in damaged heart valves (P less than 0.001) compared with that in normal heart valves may be associated with the greater extent of penetration into damaged heart valves. Equilibrium between serum and damaged valves may be achieved more rapidly because the damaged area is composed of platelet and fibrin matrix and lacks the membrane integrity of normal heart valve tissue.
PMCID: PMC181914  PMID: 7103448
20.  Methicillin distribution in serum and extravascular fluid and its relevance to normal and damaged heart valves. 
We evaluated the distribution of methicillin into normal and damaged heart valves and the accuracy with which subcutaneous plastic chambers reflected tissue uptake of this antibiotic. A total of 24 male New Zealand rabbits were given constant infusion doses of methicillin through central venous catheters. Five of these animals had their aortic and mitral valves damaged by catheterization of the left ventricle. A total of 19 rabbits had perforated plastic chambers inserted subcutaneously 7 to 10 days before methicillin infusion. In all animals more than 80% of the total infused dose of methicillin was accounted for in the serum, urine, and tissues. In the 12 animals infused to steady state (less than 7 h), the steady-state serum concentrations (11 to 120 micrograms/ml) were equal to the concentrations attained in either peritoneal or tissue chamber fluids. In the 12 animals sacrificed before 7 h, tissue chamber concentrations lagged behind serum and heart tissue concentrations in attaining steady state. Steady-state concentrations in normal heart valves and heart muscles failed to increase proportionally to increased constant infusion doses (8.7 to 87.2 mg/kg per h). The steady-state methicillin concentrations in fibrin-scarred heart valves were invariably higher than the steady-state concentrations in the normal right heart of the same animals (P less than 0.05). Tissue uptake of methicillin was altered in scarred heart valves as compared to normal heart valves, and large-volume subcutaneous tissue chambers misrepresented the uptake rate of methicillin into heart tissues and valves.
PMCID: PMC181532  PMID: 7294768
21.  Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. 
Seventy-four acutely ill patients were treated with intravenous ciprofloxacin at dosages ranging between 200 mg every 12 h and 400 mg every 8 h. A population pharmacokinetic-pharmacodynamic analysis relating drug exposure (and other factors) to infectious outcome was performed. Plasma samples were obtained and assayed for ciprofloxacin by high-performance liquid chromatography. Samples from patients were frequently cultured so that the day of bacterial eradication could be determined. The pharmacokinetic data were fitted by iterative two-stage analysis, assuming a linear two-compartment model. Logistic regression was used to model ciprofloxacin exposure (and other potential covariates) versus the probabilities of achieving clinical and microbiologic cures. The same variables were also modelled versus the time to bacterial eradication by proportional hazards regression. The independent variables considered were dose, site of infection, infecting organism and the MIC for it, percent time above the MIC, peak, peak/MIC ratio, trough, trough/MIC ratio, 24-h area under the concentration-time curve (AUC), AUC/MIC ratio (AUIC), presence of other active antibacterial agents, and patient characteristics. The most important predictor for all three measures of ciprofloxacin pharmacodynamics was the AUIC. A 24-h AUIC of 125 SIT-1.h (inverse serum inhibitory titer integrated over time) was found to be a significant breakpoint for probabilities of both clinical and microbiologic cures. At an AUIC below 125 (19 patients), the percent probabilities of clinical and microbiologic cures were 42 and 26%, respectively. At an AUIC above 125 (45 patients), the probabilities were 80% (P < 0.005) and 82% (P < 0.001), respectively. There were two significant breakpoints in the time-to-bacterial-eradication data. At an AUIC below 125 (21 patients), the median time to eradication exceeded 32 days; at an AUIC of 125 to 250 (15 patients), time to eradication was 6.6 days: and at AUIC above 250 (28 patients), the median time to eradication was 1.9 days (groups differed; P < 0.005). These findings, when combined with pharmacokinetic data reported in the companion article, provide the rationale and tools needed for targeting the dosage of intravenous ciprofloxacin to individual patients' pharmacokinetics and their bacterial pathogens' susceptibilities. An a priori dosing algorithm (based on MIC, patient creatine clearance and weight, and the clinician-specified AUIC target) was developed. This approach was shown, retrospectively, to be more precise than current guidelines, and it can be used to achieve more rapid bacteriologic and clinical responses to ciprofloxacin, as a consequence of targeting the AUIC.
PMCID: PMC187901  PMID: 8517694
22.  The fractional maximal effect method: a new way to characterize the effect of antibiotic combinations and other nonlinear pharmacodynamic interactions. 
The checkerboard technique leading to the fractional inhibitory concentration indexes and the killing curve method are currently the most widely used methods to study antibiotic combinations. For both methods, experimental conditions and interpretation criteria are somewhat arbitrary. The relevance of the fractional inhibitory concentration index computation, in the classic case of additivity [P = d1/(D1)p + d2/(D2)p, where d1 and d2 are the doses of drugs 1 and 2 in combination to produce an effect at a percent level (P) and (D1)p and (D2)p are the doses required for the two respective drugs alone to produce the same effect] relies on the assumption of a linear relationship between the MIC and the concentration of the test antibiotics. In addition, there is no consensus as to the definition of synergy in killing curve interpretation. The fractional maximal effect (FME) method is a new approach which was developed to handle the nonlinear pharmacodynamics exhibited by antibiotics and other drugs. This method relies on the mathematical linearization of the nonlinear concentration-effect scales and eventual construction of an isobologram-type data plot. The FME method was applied to study interactions between several antibiotic combinations: amoxicillin and tetracycline, ciprofloxacin and erythromycin, and ticarcillin and tobramycin. These combinations were selected because the pharmacologic basis for their interactions has been previously described. The FME method correctly identified antagonism for the first two combinations and synergism for the last combination. Conclusions were reproducible across the range of concentrations studied. Besides providing information on the nature of the interaction, the method can rapidly explore the effect of changing concentration ratios of two antimicrobial agents on the degrees of interaction. The FME method may be applied to interactions between drugs or agents with either a linear or nonlinear endpoint measurement. Methods frequently used for drug combination testing are also discussed in the paper.
PMCID: PMC187702  PMID: 8460921
23.  Effects of ranitidine and sucralfate on ketoconazole bioavailability. 
Ketoconazole is an oral imidazole antifungal agent useful in the treatment of opportunistic fungal infections. Gastrointestinal absorption of this agent is variable and dependent on the presence of gastric acid. This study compared the effects of concomitant sucralfate administration with ranitidine administration on the pharmacokinetic disposition of a 400-mg ketoconazole dose. Six healthy male volunteers were randomized to receive 400 mg of ketoconazole alone, 1.0 g of sucralfate concomitantly with a 400-mg ketoconazole dose, or ranitidine, administered 2 h prior to a 400-mg ketoconazole dose to titrate to a gastric pH of 6. All subjects received all three regimens in crossover fashion. Gastric pH was measured continuously for 4 h after ketoconazole administration in all subjects by using a Heidelberg radiotelemetry pH capsule. Relative ketoconazole bioavailability was compared between treatments. With sucralfate, five of six subjects demonstrated a decrease in the peak drug concentration in serum as well as an increase in the time to peak concentration, indicating a delay in ketoconazole absorption. The mean area under the concentration-time curve from 0 to 12 h for ketoconazole following gastric alkalinization was significantly different from that of either ketoconazole alone or ketoconazole with sucralfate (P less than 0.01). Continuous gastric pH monitoring allowed correlation between the decrease in ketoconazole bioavailability observed with ranitidine and the increase in gastric pH. The apparent decrease in ketoconazole bioavailability observed with sucralfate appears to be caused by an alternative mechanism since a change in gastric pH was not observed. On the basis of these findings, separating the administration of ketoconazole and sucralfate should be considered to decrease the potential for interaction of sucralfate on ketoconazole bioavailability.
PMCID: PMC245265  PMID: 1952845
24.  In vitro selection of resistant Helicobacter pylori. 
Four strains of Helicobacter pylori were subjected to an in vitro serial passage technique to compare the propensity of the organisms to develop resistance to seven classes of antibacterial agents. The passages were made on serially doubling concentrations of antibacterial agents incorporated into agar starting at one-half the base-line MIC. The frequency of spontaneous resistance was also determined for each strain at four and eight times the MIC of each antibacterial agent. Strains resistant to ciprofloxacin, metronidazole, erythromycin, and tobramycin were isolated. The experiments failed to select organisms resistant to bismuth subsalicylate, furazolidone, or amoxicillin, although the MIC of amoxicillin was increased 4- to 16-fold. With the exception of erythromycin, organisms with the selected resistance were stable after at least three passages on antibacterial agent-free medium. Spontaneous resistance rates were generally of a low magnitude and were not predictive of the serial passage results.
PMCID: PMC171897  PMID: 2285275
25.  Effect of oral antacid administration on the pharmacokinetics of intravenous doxycycline. 
The effect of oral antacid administration on the pharmacokinetics of intravenous doxycycline was studied. In a randomized crossover design, six healthy male volunteers received an infusion of 200 mg of doxycycline hyclate on two occasions separated by 7 days. On one occasion, subjects were given 30 ml of aluminum hydroxide orally four times a day for 4 days, beginning 2 days prior to doxycycline dosing. Blood and urine samples were collected up to 48 and 96 h after the infusion, respectively, and were analyzed by a microbial assay. Values for volume of distribution at steady state, nonrenal clearance, urine recovery, and urine pH were not statistically different among treatment groups. With concomitant antacid therapy, the half-life of intravenous doxycycline was shortened from 16.2 +/- 2.6 to 11.2 +/- 1.2 h (P = 0.003), and total body clearance increased from 37.4 +/- 6.5 to 54.1 +/- 12.3 ml/min (P = 0.008). Area under the concentration-time curve for serum was decreased by 18 to 44%, with a 22 to 41% increase in renal clearance. Although the increase in nonrenal clearance ranged from 11 to 128%, the high variability led to a nonsignificant difference (P = 0.07). Concomitant oral antacid therapy may significantly enhance the clearance of intravenous doxycycline.
PMCID: PMC172455  PMID: 2729939

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