Biomedical subjects
Publications and source records attributed to P G Ambrose.
We report on 28 patients who underwent voriconazole monitoring because of disease progression or toxicity. A relationship (P<0.025) between disease progression and drug concentration was detected. Favorable responses were observed in 10/10 patients with concentrations above 2.05 microg/ml, while disease progressed in 44% (n=18) of patients with concentrations below 2.05 microg/ml.
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The frequency of resistance to beta-lactams among nosocomial isolates has been increasing due to extended-spectrum beta-lactamase (ESBL)-producing enteric bacilli. Although clinical outcome data are desirable, assessment of clinical efficacy has been limited due to the lack of a statistically meaningful number of well-documented cases. Since time above the MIC (T>MIC) is the pharmacokinetic-pharmacodynamic (PK-PD) measure that best correlates with in vivo activity of beta-lactams, a stochastic model was used to predict the probability of PK-PD target attainment ranging from 30 (P30) to 70% (P70) T>MIC, for standard dosing regimens of both piperacillin-tazobactam and cefepime against Escherichia coli and Klebsiella pneumoniae ESBL phenotypes. The P70/30 T>MIC for cefepime at 2 g every 12 h against E. coli and K. pneumoniae was 0.99/1.0 and 0.96/1.0 and for a regimen of 1 g every 12 h was 0.96/1.0 and 0.93/0.99, respectively. For piperacillin-tazobactam at 3.375 g every 4 h against E. coli and K. pneumoniae, the P70/30 T>MIC was 0.77/0.96 and 0.48/0.77 and for a regimen of 3.375 g every 6 h was 0.28/0.91 and 0.16/0.69, respectively. These data suggest that the probability of achieving T>MIC target attainment rates is generally higher with cefepime than with piperacillin-tazobactam for present-day ESBL-producing strains when one uses contemporary dosing regimens.
In vitro and in vivo models of infection suggest that the area under the concentration-time curve (AUC): minimum inhibitory concentration (MIC) ratio is the pharmacodynamic parameter that is most predictive of bactericidal activity for the fluoroquinolones. Additionally, this parameter has also been correlated with clinical outcomes in humans with respiratory tract infection. Despite these defined relationships, broad-scale application of these principles in the section of optimal therapy in the clinical arena has been restricted by the imprecise estimates of drug exposures (ie, AUC:MIC ratio) in the infected population. In an effort to best describe the known variability in the pharmacokinetic and susceptibility profile of agents of interest, Monte Carlo simulation has been employed to assess the probability of attaining the desired AUC:MIC ratio. In this report Monte Carlo simulation was used to estimate the probability of attaining various target AUC:MIC ratios using AUC values from patients treated with either gatifloxacin or levofloxacin and the in vitro potency of the compounds as assessed in 881 clinical isolates of Streptococcus pneumoniae isolated from outpatients. Using a simulated patient population of 5,000, the median AUC:MIC ratios were 144 and 50 for gatifloxacin and levofloxacin, respectively. The probability of attaining AUC:MIC ratios of 30, 40, 65, 100, and 125 for gatifloxacin were 99%, 95%, 85%, 68%, and 60%, respectively. For levofloxacin, similar dynamic hit rates were 82%, 61%, 35%, 17%, and 12% over the range of target values. Regardless of the optimal ratio selected, gatifloxacin had a higher probability of achieving the AUC:MIC target than did levofloxacin. Simulations of this type can assist in the decision process surrounding the choice of optimal therapies based on our current understanding of antimicrobial pharmacodynamic principles.
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Over the last decade or so there has been a growing interest in routes of antimicrobial administration other than by the conventional intravenous route for institutionalized patients and for some outpatients. Both oral (PO) and intramuscular (IM) routes of administration are less costly than giving antimicrobial agents by vein (IV). In addition, fewer complications such as catheter-related sepsis and phlebitis are associated with non-IV routes of administration. Furthermore, a reduced-dosage, reduced-volume IM administration of ceftriaxone may provide a tolerable route of administration and equivalent bactericidal activities compared with higher dose IV ceftriaxone. The purpose of this study was to determine the time that the drug concentration remained in excess of the minimum inhibitory concentration (MIC) (T > MIC) and the duration of bactericidal activities of ceftriaxone one gram administered IV, ceftriaxone 250 mg given IM and cefixime 400 mg given orally against clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in adult volunteers. Single doses of each agent were administered and serum concentrations were collected over the standard dosing period of 24 h for all study regimens. Ceftriaxone, regardless of route of administration and dose, resulted in bactericidal activities and T > MIC for 100% of the dosing period for S. pneumoniae, H. influenzae, and M. catarrhalis. Cefixime maintained at least 50% T > MIC and bactericidal activity against both isolates each of H. influenzae and M. catarrhalis. Against both isolates of S. pneumoniae, cefixime achieved T > MIC for at least 50% of the dosing period, but did not maintain bactericidal activity. Reduced dose ceftriaxone given IM seems to be a viable alternative to ceftriaxone IV if the pathogen, susceptibility and infection site are known. Based on T > MIC exceeding 50% of the dosing interval, cefixime would be considered an effective alternative to IV therapy against common respiratory tract pathogens. Clinical studies need to be conducted to confirm these findings.
Fluoroquinolone antibiotic agents have demonstrated efficacy in the treatment of respiratory tract infections. This analysis was designed to examine the relationship between drug exposure, as measured by the free-drug area under the concentration-time curve at 24 h (AUC(24))/MIC ratio, and clinical and microbiological responses in patients with community-acquired respiratory tract infections involving Streptococcus pneumoniae. The study population included 58 adult patients (34 males, 24 females) who were enrolled in either of two phase III, randomized, multicenter, double-blind studies of levofloxacin versus gatifloxacin for the treatment of community-acquired pneumonia or acute exacerbation of chronic bronchitis. Clearance equations from previously published population pharmacokinetic models were used in conjunction with dose and adjusted for protein binding to estimate individual patient free-drug AUC(24)s. In vitro susceptibility was determined in a central laboratory by broth microdilution in accordance with NCCLS guidelines. Pharmacodynamic analyses were performed on data from all evaluable patients with documented S. pneumoniae infection using univariate and multivariable logistic regression; pharmacodynamic breakpoints were estimated using Classification and Regression Tree analysis. A statistically significant (P = 0.013) relationship between microbiological response and the free-drug AUC(24)/MIC ratio was detected. At a free-drug AUC(24)/MIC ratio of <33.7, the probability of a microbiological response was 64%, and at a free-drug AUC(24)/MIC ratio of >33.7, it was 100% (P < 0.01). These findings may provide a minimum target free-drug AUC(24)/MIC ratio for the treatment of infections involving S. pneumoniae with fluoroquinolone antibiotics and provide a paradigm for the selection of fluoroquinolones to be brought forward from drug discovery into clinical development and dose selection for clinical trials. Further, when target free-drug AUC(24)/MIC ratios are used in conjunction with stochastic modeling techniques, these findings may be used to support susceptibility breakpoints for fluoroquinolone antibiotics and S. pneumoniae.
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The ultimate goal of antimicrobial therapy is to provide the best possible outcomes for patients. For this to occur, the clinician should be cognizant of many clinical, microbiologic, pharmacologic, and epidemiologic data as well as fundamental pharmacodynamic concepts. An understanding of pharmacodynamic principles is essential; it forms the scientific basis for the design of dosing strategies that maximize clinical efficacy and minimize toxicity. In the 1990s, data accumulated from in vitro models of infection, animal models of infection, healthy volunteer studies, and clinical trials that have expanded knowledge on how drugs best kill microorganisms. This knowledge has enabled clinicians to establish the best modes of antibiotic administration to maximize the killing of microorganisms and to optimize clinical outcomes.
The appetite for modification to the basic quinolone nucleus has grown logarithmically since the first quinolone was employed in clinical practice. Important structural refinements have led to expanded microbiologic activity, optimal pharmacokinetics, and increased safety profiles. The practicing clinician and researcher may glean considerable information from the quinolone structure with regard to microbiologic spectra and safety before administering these agents to patients. Although some toxicities can be ominously predictable, such as with the so-called high-risk quinolones (e.g., double-halogenated and trifluorinated quinolones), clinicians must rely on animal models of toxicity and clinical trial data to discern other toxicities (e.g., Q-Tc interval prolongation). A few quinolones enjoy a relatively clean safety profile and are well tolerated (e.g., gatifloxacin, levofloxacin, ciprofloxacin). Other quinolones may be associated with significant collateral system toxicity during therapy; however, under certain conditions, albeit rare, their potential for benefit may outweigh the existing risk. Clinafloxacin, for use in the management of lung infections caused by multiply resistant B. cepacia in cystic fibrosis patients, is an example of a risk that may be outweighed by its therapeutic benefit. Because there are many treatment alternatives within the clinician's armamentarium, the obligation is to select the safest, most therapeutically effective, and most cost-effective agent that is available. In addition to increasing mortality and morbidity, the development of toxicity or an adverse event during therapy may compromise the immediate effectiveness of treatment as well as affect the cost of the patient's care significantly. With the immediate abundance of quinolones available for use, the safest, most effective, and best-tolerated agents will likely emerge as the most appropriate therapeutic choices when a quinolone is indicated.
BACKGROUND: For fluoroquinolones, AUC:MIC ratios correlate with maximal bacterial eradication in in vitro models of infection and favorable cure rates in humans with respiratory tract infection. Inter-subject pharmacokinetic and MIC variability may impact the probability of attaining optimal AUC:MIC ratios and hence favorable clinical outcome. METHODS: Monte Carlo simulation was utilized to estimate the probability of attaining AUC:MIC ratios of 30, 40, 50, 60, 70, 80, 90, 100, 110 and 120 using AUC values from patients treated with either gatifloxacin or levofloxacin and microbiologic activity against S. pneumoniae observed in 1997 SENTRY Antimicrobial Surveillance Program. RESULTS: The probability curves for 5000 patient simulations were plotted. The median AUC:MIC ratios were 120 for gatifloxacin and 50.5 for levofloxacin. The probability of attaining AUC:MIC ratios of 30, 50, 70 and 100 for gatifloxacin were 94%, 86%, 78% and 62%, and for levofloxacin were 80%, 51%, 31% and 17%, respectively. CONCLUSION: Gatifloxacin has a higher probability of achieving target AUC:MIC ratios than levofloxacin. Monte Carlo simulation, using patient-based AUC and MIC distributions, may have implications for selection of optimal antibiotics for the empiric treatment of infections. Moreover, Monte Carlo simulation may have utility in the determination of MIC breakpoints.
Considerable advancements have been made in providing informative, relevant interpretations of the results of antimicrobial susceptibility tests to clinicians, clinical microbiologists, epidemiologists, and researchers. At the same time, the science of pharmacokinetics has flourished, and the importance of drug exposure in vivo on outcome is now recognized by researchers and clinicians alike. More recently, pharmacokinetic and quantitative measures of antimicrobial susceptibility have been integrated using pharmacokinetic-pharmacodynamic (PK-PD) models to forecast clinical and microbiological outcomes. Stochastic methods utilizing patient population pharmacokinetics, target organism minimum inhibitory concentration (MIC) distributions, and PK-PD targets from non-clinical models of infection or clinical data have established a new paradigm for determining in vitro susceptibility breakpoints and selection of empirical therapy in clinical practice. Given the increasing problem of antimicrobial resistance, these new tools are valuable additions for clinicians, researchers, and regulatory authorities.
The primary goal in the treatment of respiratory tract infections is to provide the best possible clinical outcome for the patients. In order for this to occur, one must consider and synthesize a tremendous amount of data, much of it changing continually. Important considerations include the pharmacokinetics of the selected agent, its microbiological potency when used alone and in combination with various other agents, and the susceptibilities of the target organisms. Gram-negative bacilli remain among the most frequent cause of bacterial infection in the intensive care unit and in debilitated populations. They also have the ability to resist the best therapies. Among the topics to be discussed here are the important pharmacodynamic concepts and their role in the determination of clinical efficacy, the newer quinolone agents, newly emerging mechanisms of resistance, and recent countermeasures that have been added to the therapeutic armamentarium. In addition, specific strategies designed to combat current resistance trends supported by several recent publications will be reviewed.
Ninety-two laboratories in the USA submitted isolates of Streptococcus pneumoniae to a single laboratory for susceptibility testing. Overall, 64% of 4489 isolates were susceptible to penicillin, 24% were intermediate and 13% were resistant to penicillin, although susceptibilities varied depending on geographical region. Macrolide/azalide resistance varied from 4 to 30%, with some regions having macrolide/azalide resistance higher than penicillin resistance. Children 12 years of age were significantly more likely to be infected with a penicillin-resistant pneumococcus than were adolescents or adults. Isolates from the respiratory tract were more likely to be penicillin resistant and >50% of pneumococci from the ear were resistant to penicillin. Almost 25% of penicillin-susceptible isolates had cefaclor MICs 2.0 mg/L and 15% of penicillin-susceptible isolates had loracarbef MICs 2.0 mg/L. These isolates would be erroneously reported as susceptible using NCCLS guidelines, and this finding may explain the lack of clinical response in patients treated with these antibiotics. The predicted plasma concentrations of all cephalosporins tested exceeded the geometric mean MIC for at least 40% of the dosing interval for penicillin-susceptible S. pneumoniae; for penicillin-intermediate S. pneumoniae, only cefprozil (56%), cefuroxime (64%) and cefpodoxime (63%) reached >40% of time above the geometric mean MIC in the dosing interval. None of the cephalosporins evaluated achieved a substantial time above the geometric mean MIC during its dosing interval for fully penicillin-resistant S. pneumoniae.
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The antimicrobial management of patients in the critical care unit is complex. Not only must the clinician be familiar with a number of clinical, microbiological, pharmacological, and epidemiological observations but also fundamental pharmacodynamic concepts. It is an understanding of these concepts that forms the basis for the design of dosing strategies that maximize clinical efficacy and minimize toxicity. Antimicrobial selection is further complicated by the plethora of new antimicrobial agents available with varying clinical utility. Nowhere is this more evident than in the quinolone class of antibiotics. To aid the clinician in differentiating between quinolones it now seems reasonable to create a classification system akin to the generation grouping applied to the cephalosporins. Our classification is based upon the pharmacodynamic principles discussed within this article.
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In comparison with imipenem, meropenem exhibits closely similar microbiological activity. Although meropenem has slightly greater gram-negative activity against organisms, like Pseudomonas aeruginosa and Burkholderia cepacia, imipenem demonstrates more intense gram-positive activity, particularly towards Enterococcus faecalis which may reduce or even cancel out, the clinical relevance of these microbiological differences. However, an aminoglycoside is usually added in the treatment of serious infections from these bacteria. The pharmacokinetics of these two agents are also closely similar both in normal healthy volunteers and in patients with normal or impaired renal function. Moreover, there is little, if any, difference in the acquisition costs for meropenem and imipenem in most hospitals. Cost-avoidance with meropenem is, therefore, mainly the result of less frequent dosing and the ability to administer meropenem by rapid intravenous injection. Additionally, meropenem's FDA approved indication for central nervous system infection offers an additional advantage when compared to imipenem/cilastatin. It was for these reasons that our hospital's Pharmacy and Therapeutics Committee replaced imipenem/cilastatin with meropenem.