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Biomedical subjects

W A Craig

Publications and source records attributed to W A Craig.

158 records · Page 9Linked to original sources
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Bioavailability of chlorothiazide from 50, 100, and 250 MG solution doses.

The bioavailability of chlorothiazide was examined following single oral solution doses to eight healthy male volunteers. Drug was administered in 250 ml of water after overnight fast. Bioavailability was determined by measuring 72 h urinary recovery of unchanged drug. Mean urinary recovery from 50, 100, and 250 mg doses was, respectively, 28.3, 47.0 and 83.3 mg, representing 56.4, 47.0, and 33.3 per cent of the administered dose. The correlation coefficient between dose size and percentage recovery was -0.662. These results add support to previous suggestions that the absorption of chlorothiazide from the gastrointestinal tract is saturable, and that the availability of chlorothiazide may be similar to that of hydrochlorothiazide when these compounds are administered in the same dosage range.

Adult↗
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A pharmacokinetic comparison of cephalexin and cefadroxil using HPLC assay procedures.

The pharmacokinetics of cephalexin and cefadroxil were compared following single 500 mg oral doses to 12 healthy male volunteers. Doses were administered after an overnight fast according to a crossover design. Plasma and urinary levels of both compounds were determined by HPLC procedures. Cephalexin was absorbed rapidly, achieving a mean peak plasma level of 17.5 micrograms ml-1 at 1 h, compared to 16 micrograms ml-1 at 1.8 h for cefadroxil. Elimination half-lives of cephalexin and cefadroxil were 0.7 and 1.1 h, respectively. The area under the cefadroxil plasma curve was significantly larger than that for cephalexin. However, after allowing for differences in elimination rate constants and assuming equal distribution volumes, plasma data indicated the compounds were equally well absorbed. Only 70 per cent of cefadroxil was recovered in urine compared to 87 per cent of cephalexin during the 12 h following drug administration. The therapeutic significance of the different pharmacokinetic characteristics of cephalexin and cefadroxil, if any, may be a function also of their pharmacologic activity and/or the sensitivity of the target organism.

Adult↗
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Netilmicin sulfate: a comparative evaluation of antimicrobial activity, pharmacokinetics, adverse reactions and clinical efficacy.

Netilmicin, the 1-N-ethyl derivative of sisomicin, is a new aminoglycoside antibiotic that was recently marketed in the United States. Its role in therapeutics is not yet established. The pharmacokinetic profile of netilmicin is very similar to that of gentamicin. Its antimicrobial spectrum and clinical efficacy is similar to that of gentamicin, tobramycin and amikacin. It is less active in vitro against Pseudomonas aeruginosa that gentamicin and tobramycin, but in clinical trials the efficacy of netilmicin against the organism has been similar to other aminoglycosides. Netilmicin is active against some gentamicin and tobramycin-resistant strains of gram-negative bacilli, particularly those harboring adenylating and phosphorylation enzymes. Most of these strains are sensitive to amikacin as well, and amikacin is also active against most netilmicin-resistant strains of these bacteria. Therefore, amikacin remains the aminoglycoside of choice against gentamicin tobramycin and netilmicin-resistant gram-negative bacilli. In comparison to other currently available aminoglycosides, a lower frequency of nephrotoxicity and ototoxicity has been observed in laboratory animals given netilmicin. This has not been unequivocally demonstrated in humans. The frequency of nephrotoxicity in humans has been similar to that of other aminoglycosides. The frequency of ototoxicity associated with netilmicin in humans has been low but not significantly less than in other aminoglycosides, except in one trial. If further studies document a significantly lower frequency of ototoxicity with netilmicin, it may become the aminoglycoside of choice for patients with significant risk factors for ototoxicity, such as advanced age, renal impairment, concomitant ototoxic drug therapy and prolonged aminoglycoside administration.

Animals↗
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Qualitative susceptibility tests versus quantitative MIC tests.

Qualitative susceptibility categories show reasonable, but incomplete, correlation with therapeutic outcome. Studies using quantitative MIC tests have demonstrated that treatment failures within the susceptible category are associated with higher minimum inhibitory concentrations (MICs) than with therapeutic successes. Other trials have exhibited enhanced response for increasing ratios of a pharmacokinetic parameter to MIC (for example, peak level to MIC ratio for aminoglycosides). Dose-response studies in animal infection models also demonstrate an excellent correlation between the dose of drug required for a given response and the infecting organism MIC. These studies suggest that the use of quantitative MIC tests may enable more individualization of the therapeutic regimen, especially in regards to dose and dosing frequency, than provided by qualitative category susceptibility tests. However, there are only rare studies that have used MIC results or pharmacokinetic parameters to improve efficacy. Furthermore, these studies have not consistently documented enhanced clinical efficacy. MICs can also be used to reduce drug dosage and cost of antimicrobial therapy for very susceptible organisms. Additional studies are clearly needed to define the full potential of the quantitative MIC test result.

Animals↗
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Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins.

The broad-spectrum cephalosporins exhibit time-dependent bactericidal activity and produce prolonged postantibiotic effects only with staphylococci. The duration of time that serum levels exceed the minimum inhibitory concentration (MIC) is the important pharmacodynamic parameter correlating with efficacy for these drugs. Maximal efficacy for cephalosporins in several animal infection models is approached when serum levels are above the MIC for 60%-70% of the dosing interval for Enterobacteriaceae and streptococci and for 40%-50% of the dosing interval for Staphylococcus aureus. Based on MIC90 values of 0.5 microgram/ml for enteric bacilli and 4 micrograms/ml for S. aureus, these time above MIC goals can be easily met in infected and/or elderly patients following 1-2 g of cefotaxime at 12-h intervals. Full knowledge of the interrelationships between pharmacokinetics and pharmacodynamics is important for determining effective dosage regimens for the broad-spectrum cephalosporins.

Animals↗
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The future--can we learn from the past?

We know that the current problems of resistance among bacterial pathogens to commonly prescribed antibiotics is, in part, attributable to inappropriate prescribing. If we are to rectify matters, we must learn from past mistakes and take appropriate measures to ensure that community-acquired infections do not become as untreatable as certain nosocomial infections are now. This means that we must be able to predict efficacy outcomes better so that we can make more effective use of available antibiotics. Animal studies suggest that the duration of time that an antibiotic exceeds the MIC of the causative pathogen (i.e., at least 40 to 50% of the dosing interval) is a good prognostic indicator for the efficacy of beta-lactam antibiotics. Clinical studies are now being published that confirm the value of time above MIC. Use of this information should enhance efficacy and may delay the pace of developing antibiotic resistance, allowing time for new antimicrobial agents to be researched and brought to market.

Anti-Bacterial Agents↗
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Role of antimicrobial pharmacokinetics and pharmacodynamics in surgical prophylaxis.

The pharmacokinetic and pharmacodynamic properties of antimicrobial agents used for surgical prophylaxis are reviewed. Since levels in tissue homogenates depend on the amount of drug present intracellularly, they do not accurately describe the relation between concentrations in serum and those in interstitial fluid. Levels of free drug in serum are good predictors of the time course of concentrations of unbound drug in interstitial fluid. An increase in protein binding does not reduce the area under the curve (AUC) of free drug for beta-lactam agents eliminated predominantly by glomerular filtration. Pharmacodynamic studies of persistent growth suppression and bactericidal activity predict that the period for which the free-drug concentration exceeds the minimal inhibitory concentration (MIC) is an important parameter in the efficacy of beta-lactam antibiotics. In contrast, the AUC is the major parameter in the efficacy of aminoglycosides and quinolones. Although studies with animals support the above concepts, data for humans are limited. Until additional clinical trials dictate other conclusions, the goal of prophylaxis with beta-lactam agents should be to provide serum levels of free drug above the MIC for common contaminating bacteria for the entire surgical period.

Animals↗
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Worldwide experience with bacampicillin administered twice a day.

The safety and clinical efficacy of dosing twice a day with bacampicillin was evaluated in clinical trials conducted at various locations in Latin America, Switzerland, and Scandinavia, Bacampicillin (200, 400, 600, or 800 mg) given twice a day was compared with bacampicillin (400 mg) or ampicillin (500 or 556 mg) administered three times a day in eight double-blind and six open randomized trials involving 750 patients with respiratory and urinary tract infections. In a noncomparative study, 47 additional patients were treated with 600 mg of bacampicillin twice a day. High rates of clinical cure or improvement were achieved for all types of infections investigated. Microbiologic cure was observed in greater than 90% of respiratory infections due to beta-hemolytic streptococci, Streptococcus pneumoniae, or Hemophilus influenzae. There were no significant differences between the responses of groups treated twice and those treated three times a day. Adverse effects of both regimens of bacampicillin were similar and occurred less frequently than in patients treated with ampicillin. Dosing twice daily with bacampicillin appears to be effective against numerous gram-positive and gram-negative bacteria in a variety of mild clinical infections. Studies comparing identical dosage regimens of bacampicillin and other aminopenicillins are needed to determine whether bacampicillin given twice a day has a therapeutic advantage.

Adolescent↗
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Postantibiotic suppression of bacterial growth.

Persistent suppression of bacterial growth following exposure of both gram-positive and gram-negative bacteria to numerous antimicrobial agents was studied. The persistent, or postantibiotic, effect was quantitated by periodic counts of colony-forming units after removal of the drug by washing, dilution, or inactivation with penicillinase. Although a postantibiotic effect was observed with all drugs studied, there were marked differences among drugs in their postantibiotic effects on certain organisms. With gram-positive organisms, concentrations of beta-lactam antibiotics near the minimal inhibitory concentration produced persistent effects lasting 1-3 hr. With gram-negative organisms much higher concentrations were required to elicit a postantibiotic effect. Inhibitors of protein and RNA synthesis produced the longest persistent suppression of growth, which was of comparable duration in gram-positive and gram-negative bacteria. Only a short persistent effect of gentamicin was observed with Staphylococcus aureus and Escherichia coli, but a postantibiotic effect lasting 1.6-2.6 hr was observed with Pseudomonas aeruginosa. The duration of the postantibiotic effect was related linearly to concentration of drug and duration of exposure up to a point of maximal response. Persistent effects following exposure to antibiotics were also demonstrated in 90% human serum.

Anti-Bacterial Agents↗
PubMedDate not supplied

Pharmacokinetics of cefoperazone in patients with normal and impaired hepatic and renal function.

The pharmacokinetics of cefoperazone in normal subjects and in patients with hepatic and renal dysfunction are reviewed. Peak serum concentrations and areas under serum level-time curves are linearly related to dose. The range of mean peak serum concentrations after a 2-g dose of cefoperazone is 202-375 micrograms/ml with iv injection or infusion and 111 micrograms/ml with im injection. The serum half-life is 1.6-2.6 hr. Urinary excretion is rapid, but only 15%-37% of the dose is recovered in urine. The drug is not metabolized significantly. Levels of drug in bile are many times higher than serum levels, and biliary excretion represents the major pathway of cefoperazone elimination. Serum kinetics of cefoperazone are not significantly altered by renal impairment. However, hepatic dysfunction is associated with a two- to fourfold increase in serum half-life. Even in these patients, drug accumulation was not observed after repeated administration of 1 g of cefoperazone at 12-hr intervals. Major dosage modification should only be required with concomitant renal and hepatic dysfunction.

Biliary Tract Diseases↗