The impact of managed care on providing renal nutrition services.
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Delivery of Health Care↗
Biomedical subjects
W A Craig
Publications and source records attributed to W A Craig.
Pharmacokinetics and pharmacodynamics of antibiotics in meningitis.
The penetration of antimicrobials into the CSF is dependent on lipid solubility, molecular size, capillary and choroid plexus efflux pumps, protein binding, and the degree of inflammation. Penicillins, certain cephalosporins, carbapenems, fluoroquinolones, vancomycin, and rifampin provide the highest ratios of CSF levels to the MBC for common infecting organisms. For beta-lactam antibiotics, it is the duration of time that CSF concentrations exceed the MBC that determines the rate of bactericidal activity. It appears that levels should exceed the MBC for more than 50% of the dosing interval. The peak/MBC and AUC/MBC ratios are important determinants of efficacy for aminoglycosides and fluoroquinolones. Once-daily dosing of aminoglycosides is as effective as multiple-daily dosing regimens in experimental meningitis, probably because of drug-induced prolonged persistent effects. Fluoroquinolones do not produce as prolonged persistent effects and are slightly less effective when administered once daily. Although steroid use can reduce the penetration and decrease the bactericidal activity of some antimicrobials, such as vancomycin, in experimental meningitis, the clinical impact of steroid use in human meningitis is still unclear.
Aminoglycosides↗
Use of pharmacodynamic indices to predict efficacy of combination therapy in vivo.
Although combination therapy with antimicrobial agents is often used, no available method explains or predicts the efficacies of these combinations satisfactorily. Since the efficacies of antimicrobial agents can be described by pharmacodynamic indices (PDIs), such as area under the concentration-time curve (AUC), peak level, and the time that the concentration is above the MIC (time>MIC), it was hypothesized that the same PDIs would be valid in explaining efficacy during combination therapy. Twenty-four-hour efficacy data (numbers of CFU) for Pseudomonas aeruginosa in a neutropenic mouse thigh model were determined for various combination regimens: ticarcillin-tobramycin (n = 41 different regimens), ceftazidime-netilmicin (n = 60), ciprofloxacin-ceftazidime (n = 59), netilmicin-ciprofloxacin (n = 38) and for each of these agents given singly. Multiple regression analysis was used to determine the importance of various PDIs (time>MIC, time>0.25 x the MIC, time>4 x the MIC, peak level, AUC, AUC/MIC, and their logarithmically transformed values) during monotherapy and combination therapy. The PDIs that best explained the efficacies of single-agent regimens were time>0.25 x the MIC for beta-lactams and log AUC/MIC for ciprofloxacin and the aminoglycosides. For the combination regimens, regression analysis showed that efficacy could best be explained by the combination of the two PDIs that each best explained the response for the respective agents given singly. A regression model for the efficacy of combination therapy was developed by use of a linear combination of the regression models of the PDI with the highest R(2) for each agent given singly. The model values for the single-agent therapies were then used in that equation, and the predicted values that were obtained were compared with the experimental values. The responses of the combination regimens could best be predicted by the sum of the responses of the single-agent regimens as functions of their respective PDIs (e.g., time>0.25 x the MIC for ticarcillin and log AUC/MIC for tobramycin). The relationship between the predicted response and the observed response for the combination regimens may be useful for determination of the presence of synergism. We conclude that the PDIs for the individual drugs used in this study are class dependent and predictive of outcome not only when the drugs are given as single agents but also when they are given in combination. When given in combination, there appears to be a degree of synergism independent of the dosing regimen applied.
Animals↗
Pharmacokinetics and pharmacodynamics of outpatient intravenous antimicrobial therapy.
Outpatient intravenous antimicrobial therapy has been widely accepted over the past decade. Knowledge of both the pharmacokinetics of antimicrobials and the pharmacodynamics predictive of antimicrobial efficacy enables one to design reasonable outpatient intravenous regimens for most agents. This article summarizes current knowledge of the pharmacokinetics and pharmacodynamics of agents commonly used in outpatient intravenous treatment regimens.
Anti-Bacterial Agents↗
Pharmacodynamics of fluoroquinolones in experimental models of endocarditis.
We calculated the magnitude of various serum pharmacodynamic parameters for fluoroquinolones in models of experimental endocarditis (EE) described in the literature. Nineteen publications contained data that allowed calculation of these parameters. Data were available for eight fluoroquinolones against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, methicillin-resistant Staphylococcus epidermidis, viridans streptococci, Enterobacter aerogenes, and Pseudomonas aeruginosa in rabbit or rat models. Enterococci were excluded because of poor bactericidal activity. A 24-hour area under the concentration curve (AUC)/minimal inhibitory concentration (MIC) ratio > or = 100, a peak level/MIC ratio > 8, and continuous levels above the time were associated with a significantly lower number of cfu per vegetation after 3-6 days of therapy. The 24-hour AUC/MIC exhibited the best linear correlation with cfu per vegetation after 3-6 days of therapy (r2 = 45%). The pharmacodynamic parameters predictive of efficacy for fluoroquinolones in the treatment of experimental endocarditis are similar to those for other infectious models.
Animals↗
Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.
Investigations over the past 20 years have demonstrated that antibacterials can vary markedly in the time course of antimicrobial activity. These differences in pharmacodynamic activity have implications for optimal dosage regimens. The results of more recent studies suggest that the magnitude of the pharmacokinetic/pharmacodynamic parameters required for efficacy are relatively similar in animal infection models and in human infections. However, there is still much to learn. Additional studies are needed to further correlate pharmacokinetic/pharmacodynamic parameters for many antibacterials with therapeutic efficacy in a variety of animal infection models and in human infections. The potential value of using pharmacokinetic/pharmacodynamic parameters as guides for establishing optimal dosing regimens for new and old drugs and for new emerging pathogens and resistant organisms, for setting susceptibility breakpoints, and for reducing the cost of drug development should make the continuing search for the therapeutic rationale of antibacterial dosing of mice and men worthwhile.
Animals↗
In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations.
The in vivo activities of amoxicillin and amoxicillin-clavulanate against 17 strains of Streptococcus pneumoniae with penicillin MICs of 0.12-8.0 mg/liter were assessed in a cyclophosphamide-induced neutropenic murine thigh infection model. Renal impairment was produced by administration of uranyl nitrate to prolong the amoxicillin half-life in the mice from 21 to 65 min, simulating human pharmacokinetics. Two hours after thigh infection with 10(5) to 10(6) CFU, groups of mice were treated with 7 mg of amoxicillin per kg of body weight alone or combined with clavulanate (ratio, 4:1) every 8 h for 1 and 4 days. There was an excellent correlation between the MIC of amoxicillin (0.03 to 5.6 mg/liter) and (i) the change in log10 CFU/thigh at 24 h and (ii) survival after 4 days of therapy. Organisms for which MICs were 2 mg/liter or less were killed at 1.4 to 4.2 and 1.6 to 4.1 log10 CFU/thigh at 24 h by amoxicillin and amoxicillin-clavulanate, respectively. The four strains for which MICs were >4 mg/liter grew 0.2 to 2.6 and 0.6 to 2. 3 logs at 24 h despite therapy with amoxicillin and amoxicillin-clavulanate, respectively. Infection was uniformly fatal by 72 h in untreated mice. Amoxicillin therapy resulted in no mortality with organisms for which MICs were 1 mg/liter or less, 20 to 40% mortality with organisms for which MICs were 2 mg/liter, and 80 to 100% mortality with organisms for which MICs were 4.0-5.6 mg/liter. Lower and higher doses (0.5, 2, and 20 mg/kg) of amoxicillin were studied against organisms for which MICs were near the breakpoint. These studies demonstrate that a reduction of 1 log10 or greater in CFU/thigh at 24 h is consistently observed when amoxicillin levels exceed the MIC for 25 to 30% of the dosing interval. These studies would support amoxicillin (and amoxicillin-clavulanate) MIC breakpoints of 1 mg/liter for susceptible, 2 mg/liter for intermediate, and 4 mg/liter for resistant strains of S. pneumoniae.
Amoxicillin↗
Choosing an antibiotic on the basis of pharmacodynamics.
Although standard parameters of antimicrobial activity such as minimal inhibitory concentration (MIC) and minimal bactericidal concentration are useful, they do not provide information about the time course or rate of kill relative to concentration or whether post-antibiotic effects on leukocytes contribute to activity. Antibiotics can be divided into two major groups: those that exhibit concentration-dependent killing and prolonged persistent effects and those that exhibit time-dependent killing and minimal-to-moderate persistent effects. With drugs that fall into the former group, the area under the concentration-time curve (AUC) and peak levels are the major parameters correlating with efficacy. The ratio of peak concentration to MIC is a measure of potency that also indicates the efficacy of the drug. With drugs that exhibit time-dependent killing and minimal-to-moderate persistent effects, time above MIC is the major parameter determining efficacy. Beta-lactam and macrolide antibiotics fall into this second group. Studies in otitis media show that there appears to be a relationship between the time above MIC in serum and in middle ear fluid (MEF) for beta-lactam antibiotics. It is predicted that to achieve at least 80-85% bacteriologic cure in otitis media, serum concentrations should exceed the MIC of pathogens for at least 40% of the dosing interval. For the same cure rate, the peak MEF to MIC ratio should be in the range of 3-6. If the MICs for pathogens are known, it will be possible to predict those for which adequate concentrations can be achieved.
Anti-Bacterial Agents↗
Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals.
Antimicrobial resistance results in increased morbidity, mortality, and costs of health care. Prevention of the emergence of resistance and the dissemination of resistant microorganisms will reduce these adverse effects and their attendant costs. Appropriate antimicrobial stewardship that includes optimal selection, dose, and duration of treatment, as well as control of antibiotic use, will prevent or slow the emergence of resistance among microorganisms. A comprehensively applied infection control program will interdict the dissemination of resistant strains.
Anti-Bacterial Agents↗
Practice guidelines for community-based parenteral anti-infective therapy. ISDA Practice Guidelines Committee.
This is the fourth in a series of practice guidelines commissioned by the Infectious Diseases Society of America through its Practice Guidelines Committee. The purpose of this guideline is to provide assistance to clinicians when making decisions on when and how to best administer parenteral antimicrobial therapy. The targeted providers are internists, pediatricians, family practitioners, and other providers of outpatient antiinfective therapy. Criteria for selecting the appropriate patients and settings to deliver therapy in the community are described. Panel members represented experts in adult and pediatric infectious diseases. The guidelines are evidence-based. A standard ranking system is used for the strength of the recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee and was approved by the IDSA Council. An executive summary and tables highlight the major recommendations.
Adult↗
Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals.
Antimicrobial resistance results in increased morbidity, mortality, and costs of health care. Prevention of the emergence of resistance and the dissemination of resistant microorganisms will reduce these adverse effects and their attendant costs. Appropriate antimicrobial stewardship that includes optimal selection, dose, and duration of treatment, as well as control of antibiotic use, will prevent or slow the emergence of resistance among microorganisms. A comprehensively applied infection control program will interdict the dissemination of resistant strains.
Anti-Bacterial Agents↗
The pharmacology of meropenem, a new carbapenem antibiotic.
Meropenem, a new carbapenem antibiotic, is more active against gram-negative bacilli and less active against gram-positive cocci than is imipenem, and there are several important structural differences between meropenem and the older carbapenem. These differences may be responsible for the lower potential for the induction of epileptogenic activity observed with meropenem as well as for its increased stability to degradation by dehydropeptidase-I. The pharmacokinetics of meropenem are typical of those of a parenteral beta-lactam antibiotic with low protein binding and predominantly renal excretion. Dosage reduction is required in patients with reduced renal function; no dosage adjustment is required for patients with hepatic impairment. Meropenem has excellent penetration in abdominal tissues, bile, blister fluid, inflammatory exudate, cerebrospinal fluid (in the presence of inflammation), gynecologic tissues, respiratory tract tissues, and urinary tract tissues; tissue levels are generally equal to or above the levels needed for the treatment of patients with susceptible pathogens.
Adult↗
Daily dosage of aminoglycosides.
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Aminoglycosides↗
Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections.
The pharmacodynamic principles that link the concentrations of antibiotics within body systems and their effects have been elucidated only recently. Animal work, now confirmed by clinical studies, has shown that for beta-lactam antibiotics, the time that the serum concentration exceeds the minimum inhibitory concentration (MIC) value of the pathogen is a key parameter in predicting a successful clinical and bacteriological outcome. The situation with the macrolides is less clear; time above MIC is the dynamic variable likely to be most closely linked to efficacy for erythromycin and clarithromycin but for azithromycin it appears to be the area under the plasma concentration-time curve: MIC ratio. Different antibiotics are appropriate for the key pathogens in community-acquired respiratory tract infections. For Streptococcus pneumoniae, amoxycillin/clavulanate is effective with varying dosage regimens providing around 40% time above the MIC90, in contrast to the oral cephalosporins and the macrolides for which serum concentrations do not exceed the MIC90. For Haemophilus influenzae, amoxycillin/clavulanate and cefixime are suitable antibiotics whereas macrolides have limited activity. With the exception of amoxycillin, all the beta-lactam and macrolide antibiotics reviewed here perform better against Moraxella catarrhalis than against the other two principal community-acquired respiratory tract pathogens and there is a wide choice of appropriate agents. Knowledge of the pharmacodynamically-linked variables for different antibiotics allows optimization of dosage regimens and direct comparisons across agents for the same variables.
Animals↗
Aminoglycosides are useful for severe respiratory tract infections.
Clinical trials comparing the efficacy of monotherapy with aminoglycosides versus beta-lactams suggest that standard multiple-daily dosing regimens of aminoglycosides are less effective than the newer broad-spectrum beta-lactams, especially against Pseudomonas aeruginosa. However, the addition of an aminoglycoside to a beta-lactam has increased survival in patients with gram-negative bacteremia, particularly in those with hypotension and severe illness. This reduction in mortality has not yet been observed with other popular combinations, such as the fluoroquinolones with beta-lactams. The ability of aminoglycosides to prevent the emergence of resistance is less well documented. Newer studies on the pharmacodynamics of antimicrobials have shown that once-daily dosing optimizes the efficacy and minimizes the toxicities of aminoglycosides. Meta-analyses of large numbers of clinical trials have suggested that this method of drug administration can facilitate the increased usage of the aminoglycosides while limiting nephrotoxicity and the cost of antimicrobial therapy. The use of aminoglycosides by once-daily dosing for adjunctive therapy in severe respiratory tract infections is both efficacious and safe.
Aminoglycosides↗
Antimicrobial resistance issues of the future.
Increasing antimicrobial resistance among respiratory pathogens has the potential to reduce the efficacy of standard dosage regimens for many oral drugs. The goal of antimicrobial therapy is to maximize bactericidal activity. The duration of time that serum concentrations exceed the MIC is the pharmacokinetic/pharmacodynamic parameter that determines efficacy for beta-lactams, macrolides, and trimethoprim/sulfamethoxazole. Studies in animal models suggest that serum levels of beta-lactams need to exceed the MIC for about half of the dosing interval to obtain maximum antimicrobial efficacy. Studies in children with acute otitis media also demonstrate that serum concentrations need to exceed the MIC for 40% or more of the dosing interval to obtain bacteriologic cure in over 85% of patients. With the oral beta-lactams used against penicillin-resistant Streptotoccus pneumoniae, this goal is obtained only with amoxicillin and amoxicillin/clavulanate. For Haemophilus influenzae, several beta-lactams including cefixime, cefpodoxime, and amoxicillin/clavulanate provide serum levels with the longest durations above the MIC. Antimicrobial resistance has also stimulated the search for new potent antimicrobials, altered but effective dosing regimens, and resistance control measures, such as the prudent use, optimal infection control practices, and vaccines to reduce colonization and subsequent infection.
Animals↗
Pharmacokinetics and pharmacodynamics of antibiotics in otitis media.
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Anti-Bacterial Agents↗
Antibiotic selection factors and description of a hospital-based outpatient antibiotic therapy program in the USA.
A variety of pharmacodynamic, pharmacokinetic and drug stability factors can influence the choice of drug, the dosing regimen and the method of drug administration for out-patient parenteral antibiotic therapy (OPAT). Beta-lactam antibiotics exhibit little if any concentration-dependent killing and produce short-term or no persistent effects with most bacterial pathogens. Optimal dosing regimens for these agents should provide serum levels that continually exceed the minimal inhibitory concentration (MIC) of the pathogen. Beta-lactam agents with long half-lives (greater than 2 hours) can provide these levels with intermittent dosing once or twice daily. Beta-lactam agents with shorter half-lives can be administered by programmable pumps or by continuous infusion providing the drug is sufficiently stable to degradation in solution. Imipenem and ampicillin are examples of drugs with short half-lives that are unstable in solution and must be dosed intermittently. Intramuscular administration slows absorption and can also prolong the length of time during which serum levels exceed the MIC of infecting bacteria. Aminoglycosides and fluoroquinolones, on the other hand, exhibit concentration-dependent killing and produce prolonged persistent effects. Optimal dosage regimens of these drugs should maximize serum levels. Once-daily dosing regimens for the aminoglycosides meet this goal and also appear to reduce drug-induced nephrotoxicity. Application of these principles to drug selection and administration in a hospital-based OPAT program has provided efficacious therapy and a low incidence of adverse reactions in an elderly population distributed over a wide geographic area.
Anti-Bacterial Agents↗