Antibody to endotoxin in the treatment of gram-negative sepsis.
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Antibodies, Monoclonal↗
Biomedical subjects
J J Schentag
Publications and source records attributed to J J Schentag.
Quinolone pharmacokinetics in the elderly.
As a class, quinolones undergo both renal excretion and hepatic metabolism. The dominant elimination pathway is usually renal, where secretion by the proximal tubule results in renal clearances 1.5-4 times greater than creatinine clearance. The benefit of this two-pathway elimination is protection from excessive accumulation in patients with single-organ dysfunction. A number of investigations have been performed to assess how the changes in renal and hepatic function that occur in the elderly influence quinolone pharmacokinetics. For example, lomefloxacin serum concentrations are slightly higher in elderly subjects, whereas total clearance, renal clearance, and nonrenal clearance are reduced, in comparison with younger subjects. The decline in renal clearance can be explained, in part, by the parallel decline in creatinine clearance in the elderly. Dosage adjustments should not be necessary in elderly patients with only minor changes in renal function caused by age-related changes in physiology. Although the relationship between nonrenal clearance of lomefloxacin and age is slightly less precise than the relationship between total clearance and age, this may be explained by the age-related decline in hepatic function and perhaps by changes in metabolic function. Quinolones show little evidence of altered absorption or altered pharmacodynamics in the elderly. These age-related alterations in drug elimination due to normal physiologic changes are generally not significant enough to warrant changes in dosage regimens; however, disease effects, particularly alterations of renal function, appear to be more important than gradual changes in physiology characteristic of the aging population.
Aged↗
Effect of gastric acidity on enoxacin absorption.
The effect of gastric acidity on the oral absorption of the quinolone antibiotic enoxacin was evaluated in 12 healthy volunteers. In a randomized, crossover design, single 400 mg oral enoxacin doses were administered on four occasions: alone, after 50 mg intravenous ranitidine, after 2 micrograms/kg subcutaneous pentagastrin, and after combined ranitidine and pentagastrin treatment. Gastric pH was monitored by radiotelemetry capsule for 4 hours after enoxacin administration. Ranitidine pretreatment reduced enoxacin oral bioavailability by an average of 26%. This effect was abolished when pentagastrin was used to maintain low gastric pH. Thus the ranitidine-induced decrease in enoxacin oral bioavailability probably results from a decrease in gastric acidity rather than from an interaction with ranitidine itself.
Administration, Oral↗
Cerebrospinal fluid penetration of cefpirome in patients with non-inflamed meninges.
Twenty patients (mean age 52 +/- 12 years, mean weight 75 +/- 15 kg) scheduled for elective myelogram or spinal anaesthesia were enrolled to determine the cerebrospinal fluid (CSF) penetration of a new expanded spectrum cephalosporin antibiotic, cefpirome (HR-810). A single 2 g intravenous dose of cefpirome was administered as a bolus between 1 and 8 h before lumbar puncture. Blood samples were collected at 15 pre-determined times and a single CSF sample was obtained at the time of lumbar puncture. Serum and CSF cefpirome concentrations were determined by high performance liquid chromatography. The mean maximal serum concentration of cefpirome was 264 +/- 76 mg/L. A mean steady-state volume of distribution of 20 +/- 4 L, clearance of 7.4 +/- 1.3 L/h, and half-life of 2.5 +/- 0.5 h were determined. Mean CSF concentrations were 0.50 +/- 0.11 mg/L at 1-2 h post dose (n = 4), 0.57 +/- 0.13 mg/L at 2-4 h post dose (n = 4), 0.76 +/- 0.34 mg/L at 4-6 h post dose (n = 7), and 0.83 +/- 0.29 mg/L at 6-8.3 h post dose (n = 5). Blood:brain barrier permeability to cefpirome may not be a limiting factor as CSF concentrations were rapidly attained. Further studies are required to determine the mechanism of cefpirome transport between plasma and CSF.
Adolescent↗
Dose-ranging pharmacokinetic study of ciprofloxacin after 200-, 300-, and 400-mg intravenous doses.
OBJECTIVE: To assess the pharmacokinetics and tolerance of ciprofloxacin after the administration of single intravenous doses of 200, 300, and 400 mg. DESIGN: Double-blind, three-period, randomized, crossover trial. SETTING: Private, university-affiliated, hospital-based, clinical research center. PATIENTS: Normal healthy male volunteers, 18-40 years of age. INTERVENTIONS: Subjects received 200-, 300-, and 400-mg single intravenous doses of ciprofloxacin via 30-minute infusions in random sequence. MAIN OUTCOME MEASURES: Serum ciprofloxacin concentrations were determined by HPLC after each dose and the results were used to derive pharmacokinetic parameters. Tolerance was assessed by reported and observed adverse events, urine microscopic examinations for crystals, and examination of intravenous infusion sites. RESULTS: The mean area under the time curve (AUC) values displayed linearity with respect to the administered dose. No statistical differences were observed in total body clearance, steady-state volume of distribution, or elimination half-life with respect to dose administered. The mean total body clearance, steady-state volume of distribution, or elimination half-life ranged from 36 to 41 L/h, 146 to 169 L, and 3.5 to 3.7 h for the 200-, 300-, and 400-mg doses, respectively. Adverse effects, including venous irritation (four subjects) and crystalluria (two subjects), were mild and did not require withdrawal of any subject from the study. CONCLUSIONS: Intravenous ciprofloxacin in doses ranging from 200 to 400 mg demonstrated linear pharmacokinetics. These single doses were well tolerated, although cases of transient venous irritation and crystalluria were observed.
Adolescent↗
Mathematical examination of dual individualization principles. (III): Development of a scoring system for pneumonia staging and quantitation of response to antibiotics: results in cefmenoxime-treated patients.
OBJECTIVE: In order to quantitatively express the important, time-related aspects of response to antimicrobial therapy in patients with pneumonia, we required validated measures of the time course of events during the infection. To quantitate the changes in clinical status in relation to changes in cultures, we developed a scoring system to be used for patient assessment during therapy. DESIGN: Retrospective data collection, prospective analysis of factors. SETTING: Intensive care unit, Millard Fillmore Hospital. PATIENTS: Twenty-eight patients with nosocomial pneumonia. MAIN OUTCOME MEASURES: Clinical parameters were assessed daily for the duration of antimicrobial therapy. Using linear regression, the rate of clinical change in each patient treated was quantified. Eradication of the pathogen was determined by serial cultures of the infection site. RESULTS: Seventeen of the patients demonstrated eradication of the organism, and 11 demonstrated persistence of the pathogen (7 were considered colonization). The system described the patients at baseline in that the mean baseline scores were similar in both groups of patients (p = 0.79). Patients in whom the pathogen was eradicated showed a rate of clinical improvement significantly different from those who had persistence of the organism (p = 0.04). In patients demonstrating eradication, the time to eradication inversely correlated with the rate of clinical improvement (p < 0.05). Of the ten parameters descriptive of the disease, those most sensitive to change after eradication of bacteria were body temperature, bacterial Gram stain, white blood cell Gram stain, and volume of sputum. CONCLUSIONS: In this set of pneumonia patients, the scoring system effectively quantified both baseline and time-related changes in clinical status. The system distinguished between the clinical course of the patient with organism eradication versus organism persistence. A shorter time to eradication was associated with a better clinical response. Prospective study of the system will determine its sensitivity.
Aged↗
Trends in antibiotic utilization and bacterial resistance. Report of the National Nosocomial Resistance Surveillance Group.
The increasing use of "third-generation" cephalosporins has been associated with a rising prevalence of resistant bacteria possessing type-I beta-lactamases. At Millard Fillmore Hospital (Buffalo, New York), we observed an unusually high occurrence of multiply resistant Enterobacter cloacae infections, especially in the intensive care unit. Susceptibilities were found to have declined substantially from 1988 to 1990, most notably for ceftazidime and mezlocillin, which decreased from 83% to 54% and from 85% to 64%, respectively. During the same period, there was a substantial increase in the use of ceftazidime and a decline in the use of the broad-spectrum penicillins. The latter drugs had been used in combination with an aminoglycoside as the primary empiric antibiotic therapy for nosocomial infections. This change in antibiotic-prescribing patterns was coincident with the decline in E. cloacae susceptibility, and therefore the emergence of multiply resistant E. cloacae was probably a direct consequence of the increased prescribing of ceftazidime. The experience at out institution led to the formation of the National Nosocomial Resistance Surveillance Group (NNRSG) to determine whether this antibiotic use-mediated resistance was a nationwide phenomenon. Clinical pharmacists and medical microbiologists were recruited and asked to complete a survey of hospital demographics, antibiotic purchases (between the beginning of 1988 and the third quarter of 1990), and bacterial susceptibilities of six representative organisms to 12 commonly used antibiotics (primarily broad-spectrum penicillins and cephalosporins). Evaluable data were obtained from 18 hospitals varying widely in bed capacity, antibiotic use, and geographic location.(ABSTRACT TRUNCATED AT 250 WORDS)
Anti-Bacterial Agents↗
Tissue-directed pharmacokinetics.
Azalide antibiotics demonstrate pharmacokinetics distinct from all antibacterial agents in common use. Following oral absorption, conventional oral antibiotics diffuse through serum and interstitial compartments and are eliminated rapidly. A minimal to moderate degree of intracellular penetration may be observed. The pharmacokinetics of azithromycin, the first azalide, are characterized by a rapid and extensive movement of the drug from the serum into intracellular compartments. A dynamic equilibrium exists between the intracellular, interstitial, and serum compartments, with predominant flux into tissue sites. Azithromycin is concentrated to a high degree within phagocytes and transported by chemotactic mechanisms to the site of infection. High concentrations of azithromycin are found in pulmonary, genital, and lymphatic tissues. Azithromycin's serum levels decline in a polyphasic manner with a terminal half-life of approximately 60 hours. These kinetics allow azithromycin to be administered once daily. It is predicted that after drug administration for 5 days, therapeutic levels of azithromycin will be maintained at the tissue sites of infection for an additional 4-7 days. Consideration of the extravascular pharmacodynamics of azithromycin is necessary when making predictions regarding its therapeutic application.
Animals↗
Increased gastric pH and the bioavailability of fluconazole and ketoconazole.
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Adult↗
Clinical and economic evaluation of oral ciprofloxacin after an abbreviated course of intravenous antibiotics.
PURPOSE: Oral ciprofloxacin has the requisite pharmacokinetic and antibacterial properties to rival the potency of intravenous antibiotics. This study was designed to determine whether oral ciprofloxacin could abbreviate the course of intravenous antibiotics in the treatment of serious infections. PATIENTS AND METHODS: Hospitalized adult patients were eligible for enrollment if they had a serious infection that was expected to require 8 or more days of intravenous antibiotic treatment. After conventional intravenous antibiotics were administered for 3 days, informed consent was obtained and patients were randomly assigned to either continue parenteral antibiotics (n = 53) or switch to oral ciprofloxacin 750 mg taken twice daily (n = 52). Ninety-nine of the 105 patients were evaluable for the assessment of efficacy. Clinical and bacteriologic efficacy, adverse events, and costs of the two treatments were compared. RESULTS: The two treatment groups were comparable for demographic characteristics, types of infections, bacteria isolated, initial intravenous antibiotic regimens, and duration of antibiotic treatment. The most common infections were of the skin and skin structure; bacteremia and infections of the lower respiratory tract, urinary tract, and bone and joint were also represented. The most commonly isolated pathogens were Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The most frequently prescribed intravenous antibiotics before randomization included aminoglycosides, cephalosporins, vancomycin, and nafcillin; 52 evaluable patients were treated with combination therapy while 47 received monotherapy. The clinical and bacteriologic outcomes and adverse reaction frequency with oral ciprofloxacin were comparable to those of the continued intravenous antibiotic regimens. Ciprofloxacin was associated with an average cost savings of $293 per patient. CONCLUSION: When used after 3 days of intravenous antibiotics, oral ciprofloxacin was as safe and effective as full courses of intravenous antibiotics and provided substantial cost savings.
Administration, Oral↗
Effect of fluconazole on the disposition of phenytoin.
In a randomized, placebo-controlled, parallel study, phenytoin was given in the presence and absence of fluconazole. Twenty healthy male subjects received phenytoin, 200 mg orally, on study days 1 to 3 and 18 to 20 and 250 mg intravenously on study days 4 and 21. Ten subjects received fluconazole, 200 mg orally, and 10 received placebo daily on study days 8 to 21. Serial blood samples were collected during a 24-hour period after the intravenous phenytoin dose. Fluconazole trough concentrations were determined on days 14, 18, and 21. Serum phenytoin area under the concentration-time curve from 0 to 24 hours increased 75% and minimum plasma drug concentration increased 128% after administration of fluconazole, 200 mg/day, for 14 days. These values were significantly greater than the 5% increase in area under the concentration-time curve from 0 to 24 hours and 11.6% increase in minimum plasma drug concentration in the placebo group. Fluconazole trough concentrations remained unchanged during the coadministration of phenytoin. The increased phenytoin concentrations in the presence of fluconazole suggest that fluconazole inhibits phenytoin metabolism. Serum concentration monitoring with a reduction in phenytoin dosage is clinically warranted in patients receiving phenytoin and concomitant fluconazole therapy.
Administration, Oral↗
Antibiotic tissue penetration and its relevance: models of tissue penetration and their meaning.
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Anti-Bacterial Agents↗
Antibiotic tissue penetration and its relevance: impact of tissue penetration on infection response.
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Animals↗
Kinetics and dynamics of tobramycin action in patients with bacteriuria given single doses.
We studied the effect of a single intravenous dose of tobramycin on the rate of bacterial eradication from urine in 10 patients with bladder catheters. The catheter was replaced 4 to 6 h after the tobramycin dose. Pseudomonas aeruginosa was found in 7 of the 10 patients, while members of the family Enterobacteriaceae accounted for the remaining pathogens. The MIC for each bacterium was determined in both broth and urine. Tobramycin eradicated the bacteria from eight patients. Bacteriuria resolved in 21.8 +/- 18.0 h, and urine bactericidal activity persisted for 43.4 +/- 20.3 h after the dose of tobramycin. Most patients were recolonized by another bacterial species if use of Foley catheters was resumed on a continuous basis. Two patients required additional doses of tobramycin to eradicate the original pathogen. There were significant temporal relationships between the pharmacokinetics of tobramycin and the change in colony count of bacteria in urine.
Aged↗
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.
Adult↗
Mathematical examination of dual individualization principles (I): Relationships between AUC above MIC and area under the inhibitory curve for cefmenoxime, ciprofloxacin, and tobramycin.
Traditional antibiotic dosage adjustments target predetermined serum concentrations, whereas a host of in vitro studies and recent clinical trials establish that bacteria vary in their susceptibility. Dual individualization, which considers the variance in both antibiotic pharmacokinetics and bacterial susceptibility, has been employed to describe different rates of bacterial eradication in relation to varying serum concentrations. In patients with nosocomial pneumonia, one of the model compounds studied was cefmenoxime, where a target six-hour area under the serum concentration-time curve (AUC) of 140 micrograms.h/mL above minimum inhibitory concentration (MIC) was previously associated with bacterial eradication in an average of four days. The target AUC value of 140 micrograms.h/mL above MIC is unique to cefmenoxime. Ideally, there should be a dual individualized target useful to adjust the dose of any antibiotic. Computer simulations performed to evaluate this hypothesis suggested that each antibiotic had a unique value for target AUC above MIC. These simulations indicated that an optimal AUC above MIC was about 80 percent of the total AUC above the MIC. Predictable rates of bacterial eradication would presumably result from maintaining these relationships across the range of bacterial susceptibility and the range of serum concentration profiles. Each antibiotic has a unique and different 24-hour AUC over MIC value associated with bacterial eradication in 4 days. For cefmenoxime, the target was 540 area units over MIC per 24 hours, tobramycin with 34 area units, and ciprofloxacin with 23 area units per 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Cefmenoxime↗
Cefmetazole sodium: pharmacology, pharmacokinetics, and clinical trials.
Cefmetazole sodium is a semisynthetic cephamycin antibiotic. It has a broad spectrum of activity comparable to that of the second-generation cephalosporins, covering gram-positive, gram-negative, and anaerobic bacteria. Unlike the second-generation cephalosporins, cephamycins such as cefmetazole are usually active against Bacteroides fragilis. Cefmetazole is also active against beta-lactamase-producing organisms that are resistant to first-generation cephalosporins or penicillins. The pharmacokinetics of cefmetazole allow parenteral administration (intravenous or intramuscular) 2-3 times daily for treatment of infection. The drug has been studied in gynecologic, intraabdominal, urinary tract, respiratory tract, and skin and soft tissue infections. Administered preoperatively, it may reduce the frequency of infection in certain clean-contaminated or potentially contaminated procedures, including cesarean section, abdominal or vaginal hysterectomy, cholecystectomy (high-risk patients), and colorectal surgery. On the basis of in vitro spectrum, pharmacokinetics, and data from a relatively small number of clinical trials, this agent may be considered when a second-generation cephalosporin is indicated.
Abdomen↗
Pharmacokinetics of lomefloxacin in renally compromised patients.
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.
4-Quinolones↗