Robert C. Owens

Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship

Timothy H. Dellit, Robert C. Owens, John E. McGowan, Jr., Dale N. Gerding, Robert A. Weinstein, John P. Burke, W. Charles Huskins, David L. Paterson, Neil O. Fishman, Christopher F. Carpenter, P. J. Brennan, Marianne Billeter, and Thomas M. Hooton Harborview Medical Center and the University of Washington, Seattle; Maine Medical Center, Portland; Emory University, Atlanta, Georgia; Hines Veterans Affairs Hospital and Loyola University Stritch School of Medicine, Hines, and Stroger (Cook County) Hospital and Rush University Medical Center, Chicago, Illinois; University of Utah, Salt Lake City; Mayo Clinic College of Medicine, Rochester, Minnesota; University of Pittsburgh Medical Center, Pittsburgh, and University of Pennsylvania, Philadelphia, Pennsylvania; William Beaumont Hospital, Royal Oak, Michigan; Ochsner Health System, New Orleans, Louisiana; and University of Miami, Miami, Florida

Efficacy of Hospital Cleaning Agents and Germicides Against Epidemic Clostridium difficile Strains

OBJECTIVEnTo compare the effects of hospital cleaning agents and germicides on the survival of epidemic Clostridium difficile strains.nnnMETHODSnWe compared the activity of and effects of exposure to 5 cleaning agents and/or germicides (3 containing chlorine, 1 containing only detergent, and 1 containing hydrogen peroxide) on vegetative and spore forms of epidemic and non-epidemic C. difficile strains (3 of each). We carried out in vitro exposure experiments using a human fecal emulsion to mimic conditions found in situ.nnnRESULTSnCleaning agent and germicide exposure experiments yielded very different results for C. difficile vegetative cells, compared with those for spores. Working-strength concentrations of all of the agents inhibited the growth of C. difficile in culture. However, when used at recommended working concentrations, only chlorine-based germicides were able to inactivate C. difficile spores. C. difficile epidemic strains had a greater sporulation rate than nonepidemic strains. The mean sporulation rate, expressed as the proportion of a cell population that is in spore form, was 13% for all strains not exposed to any cleaning agent or germicide, and it was significantly increased by exposure to cleaning agents or germicides containing detergent alone (34%), a combination of detergent and hypochlorite (24%), or hydrogen peroxide (33%). By contrast, the mean sporulation rate did not change substantially after exposure to germicides containing either a combination of detergent and dichloroisocyanurate (9%) or dichloroisocyanurate alone (15%).nnnCONCLUSIONSnThese results highlight differences in the activity of cleaning agents and germicides against C. difficile spores and the potential for some of these products to promote sporulation.

QT Prolongation with Antimicrobial Agents

Cardiac toxicity has been relatively uncommon within the antimicrobial class of drugs, but well described for antiarrhythmic agents and certain antihistamines. Macrolides, pentamidine and certain antimalarials were traditionally known to cause QT-interval prolongation, and now azole antifungals, fluoroquinolones and ketolides can be added to the list. Over time, advances in preclinical testing methods for QT-interval prolongation and a better understanding of its sequelae, most notably torsades de pointes (TdP), have occurred. This, combined with the fact that five drugs have been removed from the market over the last several years, in part because of QT-interval prolongation-related toxicity, has elevated the urgency surrounding early detection and characterisation methods for evaluating non-antiarrhythmic drug classes. With technological advances and accumulating literature regarding QT prolongation, it is currently difficult or overwhelming for the practising clinician to interpret these data for purposes of formulary review or for individual patient treatment decisions.Cardiac toxicity has been relatively uncommon within the antimicrobial class of drugs, but well described for antiarrhythmic agents and certain antihistamines. Macrolides, pentamidine and certain antimalarials were traditionally known to cause QT-interval prolongation, and now azole antifungals, fluoroquinolones and ketolides can be added to the list. Over time, advances in preclinical testing methods for QT-interval prolongation and a better understanding of its sequelae, most notably torsades de pointes (TdP), have occurred. This, combined with the fact that five drugs have been removed from the market over the last several years, in part because of QT-interval prolongation-related toxicity, has elevated the urgency surrounding early detection and characterisation methods for evaluating non-antiarrhythmic drug classes. With technological advances and accumulating literature regarding QT prolongation, it is currently difficult or overwhelming for the practising clinician to interpret these data for purposes of formulary review or for individual patient treatment decisions.Certain patients are susceptible to the effects of QT-prolonging drugs. For example, co-variates such as gender, age, electrolyte derangements, structural heart disease, end organ impairment and, perhaps most important, genetic predisposition, underlie most if not all cases of TdP. Between and within classes of drugs there are important differences that contribute to delayed repolarisation (e.g. intrinsic potency to inhibit certain cardiac ion currents or channels, and pharmacokinetics). To this end, a risk stratification scheme may be useful to rank and compare the potential for cardiotoxicity of each drug. It appears that in most published cases of antimicrobial-associated TdP, multiple risk factors are present. Macrolides in general are associated with a greater potential than other antimicrobials for causing TdP from both a pharmacodynamic and pharmacokinetic perspective. The azole antifungal agents also can be viewed as drugs that must be weighed carefully before use since they also have both pharmacodynamic and pharmacokinetic characteristics that may trigger TdP. The fluoroquinolones appear less likely to be associated with TdP from a pharmacokinetic perspective since they do not rely on cytochrome P450 (CYP) metabolism nor do they inhibit CYP enzyme isoforms, with the exception of grepafloxacin and ciprofloxacin.Nonetheless, patient selection must be carefully made for all of these drugs. For clinicians, certain responsibilities are assumed when prescribing antimicrobial therapy: (i) appropriate use to minimise resistance; and (ii) appropriate patient and drug selection to minimise adverse event potential. Incorporating information learned regarding QT interval-related adverse effects into the drug selection process may serve to minimise collateral iatrogenic toxicity.

Safety profile of oral and intravenous moxifloxacin: Cumulative data from clinical trials and postmarketing studies

BACKGROUNDnThe established safety profile of the fluoroquinolones has been disrupted in the past decade by the detection of low-frequency but potentially serious adverse events that have led to the license suspension, voluntary withdrawal, or restricted use of specific members of the class. Moxifloxacin is a broad-spectrum, advanced-generation fluoroquinolone that has potent activity against respiratory tract infections in adults in both oral and IV formulations.nnnOBJECTIVEnThe goal of this article was to provide an overview of the cumulative safety data on both oral and IV moxifloxacin, including data from the most recent clinical trials and postmarketing studies.nnnMETHODSnData from clinical trials of moxifloxacin were captured from an electronic database maintained by the manufacturer. Safety data for oral moxifloxacin were obtained from 30 Phase II/III comparator studies (n = 7,368 moxifloxacin, n = 5,687 comparators), 1 Phase IV study (n = 18,374), and 4 postmarketing observational studies (n = 27,756). Safety data for IV moxifloxacin were obtained from 2 Phase III comparator studies (n = 550 maxifloxacin, n = 579 comparators). In addition, pharmacokinetic data were reviewed.nnnRESULTSnIn Phase II/III comparator studies, gastrointestinal complaints were the most common adverse drug reactions (ADRs) associated with both formulations of moxifloxacin, with nausea occurring in 7.1% and 3.1% of patients receiving oral and IV moxifloxacin, respectively, and diarrhea occurring in 5.2% and 6.2% of patients. Discontinuation rates due to ADRs with oral and IV moxifloxacin were 2.7% and 6.0%, and mortality rates were 0.3% and 4.0%. Similar rates of withdrawal and mortality were observed in the comparator groups. There was no evidence that moxifloxacin caused disturbances in glucose metabolism in patients with or without diabetes mellitus, and there was no evidence of an increased risk for cardiovascular adverse events. Pharmacokinetic analyses indicated that dose adjustment of moxifloxacin does not appear to be necessary in elderly patients, those with renal dysfunction, or those with mild to moderate hepatic impairment. The pharmacokinetics of moxifloxacin have not been studied in patients with severe hepatic insufficiency. Moxifloxacin does not interact with a number of commonly prescribed drugs, although its absorption is decreased by concomitant administration of iron and cationic antacids.nnnCONCLUSIONSnBased on evidence from >7000 patients in clinical trials and >46,000 patients in postmarketing studies, moxifloxacin is generally well tolerated. Its lack of significant drug interactions in target groups makes it an option in diabetic patients or the elderly, as well as in those with renal impairment.

Need and Potential of Antimicrobial Stewardship in Community Hospitals

Preventing, reducing, and controlling the emergence of antimicrobial-resistant organisms is a major public health challenge requiring the participation of the entire medical community and public health agencies. Antimicrobial stewardship programs (ASPs) have the potential to integrate the many and sometimes disparate individuals and organizations that rely on antimicrobial agents in an effort to better control antimicrobial prescribing, possibly minimizing the emergence of resistant organisms. Developing and implementing ASPs can be a major challenge for community-based hospitals. In addition to specific and localized patterns of resistance-a consideration for every hospital-community hospitals must develop strategies that appropriately conform to their size, staffing, personnel, and infrastructure. This article reviews the ASP strategies and resources currently available to community hospitals for improving if, when, and how antimicrobial agents are prescribed and delivered.

Insights from the Society of Infectious Diseases Pharmacists on Antimicrobial Stewardship Guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America

In 2007, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America published a document that addressed the major considerations for the justification, description, and conduct of antimicrobial stewardship programs. Our document is intended to continue the dialogue of these formalized programmatic strategies. We briefly review the guidelines, including the two primary strategies (prospective auditing with feedback, and preauthorization), and the supplemental strategies (education, information technology, transitional therapy, deescalation or streamlining, and dose optimization). Discussions are introduced or furthered in the areas of program goals, barriers and solutions, and outcome measures. Definition and training of infectious diseases pharmacists are presented in detail. We offer keys to future success, which include continued collaboration and expanded use of information technology.

Clostridium difficile-associated disease: An emerging threat to patient safety : Insights from the society of infectious diseases pharmacists

A formerly infrequently isolated strain of Clostridium difficile known as BI/NAP1 has resulted in geographically diverse outbreaks of C. difficile – associated disease. Such rapid dissemination and distribution of an outbreak strain of C. difficile are unprecedented, with many regions across North America, as well as several countries in Europe, being affected, all in such a short period of time. Also of note is that nontraditional hosts (e.g., otherwise healthy, noninstitutionalized persons residing in the community, some without antimicrobial exposure) have been reported to have severe disease. Data suggest that certain virulence characteristics may be responsible for more severe clinical presentations and poor outcomes. These factors (e.g., hypertoxin production, hypersporulation, antimicrobial resistance) possessed by a previously uncommon strain of C. difficile, in conjunction with particular host and environmental factors, may have precipitated the now widespread establishment of this pathogen. Antimicrobial intervention has traditionally been a mainstay of combating C. difficile – associated disease. Efforts to combat BI/NAP1 should include good antimicrobial stewardship in addition to effective infection control and environmental intervention.

Gatifloxacin-Associated Corrected QT Interval Prolongation, Torsades de Pointes, and Ventricular Fibrillation in Patients with Known Risk Factors

Drugs not commonly considered to be cardioactive agents have been reported to cause prolongation of the corrected QT interval with resultant torsades de pointes or ventricular fibrillation. We report 4 cases of gatifloxacin-associated cardiac toxicity in patients with known risk factors for this adverse event.

Fluoroquinolone‐Associated Dysglycemias: A Tale of Two Toxicities

In this issue of Pharmacotherapy, Dr. Mohr and colleagues and Dr. Graumlich and colleagues evaluate the impact of fluoroquinolones on perturbations in blood glucose concentrations, namely, hypoglycemia and hyperglycemia. In this editorial, I elaborate on the tale of two toxicities, that is, hypoglycemia and hyperglycemia. Charles Dickens, in his famous book with a title similar to this editorial’s, opened with the sentence, “It was the best of times, it was the worst of times.” Similar to Dickens’ book, which was set in 1775, it is the best of times—the stringency with which drugs are scrutinized from a toxicologic perspective has significantly increased—and it is the worst of times—10.2% of drugs approved by the United States Food and Drug Administration (FDA) during the past 20 years have received one or more black-box warnings after approval. The literature has offered a steady diet of postmarketing safety and toxicity studies over the last several years for clinicians to digest. After FDA approval of a drug for general use, unusual and serious events—such as hepatic toxicity, seizures, toxic epidermal necrolysis, cardiac toxicity (including torsade de pointes), to name a few—may be identified from these studies and from voluntary, spontaneous reports of adverse drug reactions (ADRs) to the FDA. Although identification of signals related to these ADRs may occur after approval, difficulties arise when attempts are made to compare incidence rates or determine causality. Because studies cite incidence rates, it can become confusing when two or more studies yield apparently dissimilar rates of occurrence for the same ADR.

An overview of harms associated with β-lactam antimicrobials: where do the carbapenems fit in?

The US Institute of Medicines focus on patient safety has motivated hospital administrators to facilitate a culture of safety. As a result, subcommittees of the pharmacy and therapeutics committee have emerged in many hospitals to focus on adverse events and patient safety. Antimicrobial harms have gained the attention of practicing clinicians and hospital formulary committees, because they top the list of drugs that are associated with adverse events and because of certain serious harms that have ultimately led to the withdrawal of some antimicrobial agents. In the near future, several antimicrobials in the late phase of development will become available for clinical use (ceftobiprole, ceftaroline, and telavancin), and others (doripenem and dalbavancin) have recently joined the armamentarium. Because new antimicrobials will become part of the treatment armamentarium, it is important to discuss our current understanding of antimicrobial harms in general. Although not thought of as traditional adverse events, Clostridium difficile infection and development of resistance during therapy are adverse events that occur as a result of antimicrobial exposure and therefore are discussed. In addition, a distillation of our current understanding of β-lactam specific adverse events will be provided. Finally, new methods of administration are being evaluated that may influence peak concentration-related antimicrobial adverse events.