Background.Piperacillin-tazobactam is frequently used to treat Pseudomonas aeruginosa infections in critically ill patients. In an effort to improve clinical outcomes, an extended-infusion dosing ...scheme for piperacillin-tazobactam therapy was devised using a Monte Carlo simulation and was adopted into clinical practice at Albany Medical Center (Albany, New York). This study evaluates the clinical implications of extended infusion of piperacillin-tazobactam therapy for critically ill patients with P. aeruginosa infection. Methods.We performed a cohort study of patients who received piperacillin-tazobactam therapy for a P. aeruginosa infection that was susceptible to piperacillin-tazobactam during the period January 2000–June 2004. Prior to February 2002, all patients received intermittent infusions of piperacillin-tazobactam (3.375 g intravenously for 30 min every 4 or 6 h); after this time, all patients received extended infusions of piperacillin-tazobactam (3.375 g intravenously for 4 h every 8 h). Data on demographic characteristics, disease severity, and microbiology were collected, and outcomes were compared between groups. Results.A total of 194 patients comprised the 2 study groups: 102 patients received extended infusions of piperacillin-tazobactam, and 92 patients received intermittent infusions of piperacillin-tazobactam. No differences in baseline clinical characteristics were noted between the 2 groups. Among patients with Acute Physiological and Chronic Health Evaluation-II scores ⩾17, 14-day mortality rate was significantly lower among patients who received extended-infusion therapy than among patients who received intermittent-infusion therapy (12.2% vs. 31.6%, respectively; P = .04), and median duration of hospital stay after collection of samples for culture was significantly shorter for patients who received extended-infusion therapy than for patients who received intermittent-infusion therapy (21 days vs. 38 days; P = .02). Conclusions.These results indicate that extended-infusion piperacillin-tazobactam therapy is a suitable alternative to intermittent-infusion piperacillin-tazobactam therapy, and they strongly suggest that improved outcomes may be realized by administering extended-infusion piperacillin-tazobactam therapy to critically ill patients with P. aeruginosa infection.
We are in a crisis of bacterial resistance. For economic reasons, most pharmaceutical companies are abandoning antimicrobial discovery efforts, while, in health care itself, infection control and ...antibiotic stewardship programs have generally failed to prevent the spread of drug-resistant bacteria. At this point, what can be done? The first step has been taken. Governments and international bodies have declared there is a worldwide crisis in antibiotic drug resistance. As discovery efforts begin anew, what more can be done to protect newly developing agents and improve the use of new drugs to suppress resistance emergence? A neglected path has been the use of recent knowledge regarding antibiotic dosing as single agents and in combination to minimize resistance emergence, while also providing sufficient early bacterial kill. In this review, we look at the data for resistance suppression. Approaches include increasing the intensity of therapy to suppress resistant subpopulations; developing concepts of clinical breakpoints to include issues surrounding suppression of resistance; and paying attention to the duration of therapy, which is another important issue for resistance suppression. New understanding of optimizing combination therapy is of interest for difficult-to-treat pathogens like Pseudomonas aeruginosa, Acinetobacter spp., and multidrug-resistant (MDR) Enterobacteriaceae. These lessons need to be applied to our old drugs to preserve them as well and need to be put into national and international antibiotic resistance strategies. As importantly, from a regulatory perspective, new chemical entities should have a corresponding resistance suppression plan at the time of regulatory review. In this way, we can make the best of our current situation and improve future prospects.
Optimization of Aminoglycoside Therapy DRUSANO, G. L; LOUIE, Arnold
Antimicrobial Agents and Chemotherapy,
06/2011, Letnik:
55, Številka:
6
Journal Article
We are in a crisis of bacterial resistance. For economic reasons, most pharmaceutical companies are abandoning antimicrobial discovery efforts, while, in health care itself, infection control and ...antibiotic stewardship programs have generally failed to prevent the spread of drug-resistant bacteria. At this point, what can be done? The first step has been taken. Governments and international bodies have declared there is a worldwide crisis in antibiotic drug resistance. As discovery efforts begin anew, what more can be done to protect newly developing agents and improve the use of new drugs to suppress resistance emergence? A neglected path has been the use of recent knowledge regarding antibiotic dosing as single agents and in combination to minimize resistance emergence, while also providing sufficient early bacterial kill. In this review, we look at the data for resistance suppression. Approaches include increasing the intensity of therapy to suppress resistant subpopulations; developing concepts of clinical breakpoints to include issues surrounding suppression of resistance; and paying attention to the duration of therapy, which is another important issue for resistance suppression. New understanding of optimizing combination therapy is of interest for difficult-to-treat pathogens like Pseudomonas aeruginosa, Acinetobacter spp., and multidrug-resistant (MDR) Enterobacteriaceae. These lessons need to be applied to our old drugs as well to preserve them and to be put into national and international antibiotic resistance strategies. As importantly, from a regulatory perspective, new chemical entities should have a resistance suppression plan at the time of regulatory review. In this way, we can make the best of our current situation and improve future prospects.
Gram-negative organisms have become increasingly resistant to both β-lactam antibiotics and fluoroquinolones. Consequently, aminoglycoside antibiotics have undergone a resurgence in use. Because of ...the known toxicities of aminoglycoside antibiotics, clinicians have avoided their use, unless no other alternatives were extant. Over the past 2 decades, we have learned much about the relationship between aminoglycoside exposure and the likelihood of a good clinical outcome or the occurrence of nephrotoxicity. For example, minimum inhibitory concentration values ⩾2.0 mg/L lead to unacceptably low probabilities of a good clinical outcome, and infrequent administration of doses (i.e., intervals of 24 h and longer intervals for patients with compromised renal function) plays a central role in minimizing the likelihood of toxicity. Using these new insights, we suggest ways of evaluating the dose and schedule of administration of aminoglycosides in empirical therapy to obtain the highest likelihood of an efficacious and nontoxic therapy.
Drug-resistant microorganisms have become a major problem around the world. In nosocomial and community settings, many important pathogens have demonstrated high-grade resistance to many of our most ...important agents. In addition, the adverse impact of resistance has not been limited to the bacterial realm. In chemotherapy to treat human immunodeficiency virus (HIV) and other viral diseases, resistance has become a major problem. We are starting to see the beginnings of a resistance problem, even among fungi. Strangely, little attention has been focused on the impact of dosing on the probability with which emergence of resistance occurs. After delineation of the pharmacodynamically linked variable, it is possible to generate dosing regimens that can lower the probability of resistance. In addition, circumstances exist in which combination therapy may be required (e.g., therapy of HIV and tuberculosis). Here, too, it is possible to optimize therapy to prevent resistance by understanding how the drugs in the regimen interact. We can do better with our choices of dose, schedule, and combinations of agents. We will need to lower the probability of resistance and maintain the utility of the drugs currently in our therapeutic armamentarium.
Antibiotics are some of our most commonly used drugs. Until recently, little has been known about how to optimize administration of these agents. Unfortunately, the rate of discovery of new ...antibiotics has been declining, coincident with the explosion in the number of multidrug-resistant organisms in both the community and hospital environments. This development makes the identification of optimal regimens that will result in good clinical and microbiological outcomes important, but it also makes clear the necessity of identifying regimens that will suppress the emergence of resistant organisms. Given that new agents for multidrug-resistant pathogens will take nearly a decade to become available to physicians, keeping organisms susceptible to drugs that are already available is even more critical. Pharmacodynamics allows identification of the drug exposure measure that is closely associated with the ability to kill organisms and, also, to suppress the emergence of resistant subpopulations of organisms. Use of Monte Carlo simulation allows identification of drug doses in the clinical arena to accomplish these ends. Such approaches should be applied to all old and new antibacterial agents.
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