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.

Community transmission in the United States of a CTX-M-15-producing sequence type ST131 Escherichia coli strain resulting in death.

A middle-aged woman developed fatal urosepsis due to a multidrug-resistant Escherichia coli strain representing sequence type ST131, a recently emerged, disseminated, multidrug-resistant extraintestinal pathogen, after presumably having acquired it from her extensively antibiotic-exposed sister with chronic recurrent cystitis. Susceptibility results (reported on day 4) showed resistance to the initially selected regimen.

Treatment of Clostridium difficile infection.

Recent outbreaks of Clostridium difficile infection (CDI) in North America have been due to a more virulent, possibly more resistant strain that causes more-severe disease, making prompt recognition of cases and optimal management of infection essential for a successful therapeutic outcome. Treatment algorithms are presented to help guide the management of patients with CDI. Metronidazole has been recommended as initial therapy since the late 1990s and continues to be the first choice for all but seriously ill patients and those with complicated or fulminant infections or multiple recurrences of CDI, for whom vancomycin is recommended. Other options for recurrent CDI, such as probiotics and currently available anion-exchange resins, have limited efficacy and are potentially harmful. Intravenous immunoglobulin may benefit patients with refractory, recurrent, or severe disease, but no controlled data are available. Two antimicrobials available in the United States for other indications, nitazoxanide and rifaximin, have been used successfully for CDI treatment but, like metronidazole, lack United States Food and Drug Administration approval for this indication. Experimental treatments currently in clinical development include a toxin-binding polymer, tolevamer; 2 poorly absorbed antimicrobials, OPT-80 (formerly known as Difimicin) and ramoplanin; monoclonal antibodies; and a C. difficile vaccine.

Measures to control and prevent Clostridium difficile infection.

Control of Clostridium difficile infection (CDI) outbreaks in health care facilities presents significant challenges to infection control specialists and other health care workers. C. difficile spores survive routine environmental cleaning with detergents and hand hygiene with alcohol-based gels. Enhanced cleaning of all potentially contaminated surfaces with 10% sodium hypochlorite reduces the environmental burden of C. difficile, and use of barrier precautions reduces C. difficile transmission. Thorough handwashing with chlorhexidine or with soap and water has been shown to be effective in removing C. difficile spores from hands. Achieving high-level compliance with these measures is a major challenge for infection control programs. Good antimicrobial stewardship complements infection control efforts and environmental interventions to provide a comprehensive strategy to prevent and control outbreaks of CDI. The efficacy of metronidazole or vancomycin prophylaxis to prevent CDI in patients who are receiving other antimicrobials is unproven, and treatment with these agents is ineffective against C. difficile in asymptomatic carriers.

Antimicrobial-associated risk factors for Clostridium difficile infection.

Antimicrobial therapy plays a central role in the pathogenesis of Clostridium difficile infection (CDI), presumably through disruption of indigenous intestinal microflora, thereby allowing C. difficile to grow and produce toxin. Investigations involving animal models and studies performed in vitro suggest that inhibitory activity against C. difficile and differences in the propensity to stimulate toxin production may also influence the likelihood that particular drugs may cause CDI. Although nearly all antimicrobial classes have been associated with CDI, clindamycin, third-generation cephalosporins, and penicillins have traditionally been considered to harbor the greatest risk. Recent studies have also implicated fluoroquinolones as high-risk agents, a finding that is most likely to be related in part to increasing fluoroquinolone resistance among epidemic strains (i.e., restriction-endonuclease analysis group BI/North American PFGE type 1 strains) and some nonepidemic strains of C. difficile. Restrictions in the use of clindamycin and third-generation cephalosporins have been associated with reductions in CDI. Because use of any antimicrobial has the potential to induce the onset of CDI and disease caused by other health care-associated pathogens, antimicrobial stewardship programs that promote judicious use of antimicrobials are encouraged in concert with environmental and infection control-related efforts.

An epidemic, toxin gene-variant strain of Clostridium difficile.

BACKGROUND: Recent reports suggest that the rate and severity of Clostridium difficile-associated disease in the United States are increasing and that the increase may be associated with the emergence of a new strain of C. difficile with increased virulence, resistance, or both. METHODS: A total of 187 C. difficile isolates were collected from eight health care facilities in six states (Georgia, Illinois, Maine, New Jersey, Oregon, and Pennsylvania) in which outbreaks of C. difficile-associated disease had occurred between 2000 and 2003. The isolates were characterized by restriction-endonuclease analysis (REA), pulsed-field gel electrophoresis (PFGE), and toxinotyping, and the results were compared with those from a database of more than 6000 isolates obtained before 2001. The polymerase chain reaction was used to detect the recently described binary toxin CDT and a deletion in the pathogenicity locus gene, tcdC, that might result in increased production of toxins A and B. RESULTS: Isolates that belonged to one REA group (BI) and had the same PFGE type (NAP1) were identified in specimens collected from patients at all eight facilities and accounted for at least half of the isolates from five facilities. REA group BI, which was first identified in 1984, was uncommon among isolates from the historic database (14 cases). Both historic and current (obtained since 2001) BI/NAP1 isolates were of toxinotype III, were positive for the binary toxin CDT, and contained an 18-bp tcdC deletion. Resistance to gatifloxacin and moxifloxacin was more common in current BI/NAP1 isolates than in non-BI/NAP1 isolates (100 percent vs. 42 percent, P<0.001), whereas the rate of resistance to clindamycin was the same in the two groups (79 percent). All of the current but none of the historic BI/NAP1 isolates were resistant to gatifloxacin and moxifloxacin (P<0.001). CONCLUSIONS: A previously uncommon strain of C. difficile with variations in toxin genes has become more resistant to fluoroquinolones and has emerged as a cause of geographically dispersed outbreaks of C. difficile-associated disease.

Antimicrobial stewardship: concepts and strategies in the 21st century.

Large worldwide surveillance studies report that resistance to nearly all classes of antimicrobial is increasing, as is the emergence of what have been termed pan-drug-resistant and extremely drug-resistant pathogens. Concomitantly, bacterial binding sites have been exploited by available antimicrobials, and there has been a decline in the development of antimicrobials using novel mechanisms of action. These trends have prompted healthcare facilities to adopt antimicrobial stewardship programs (ASPs) and infection control programs (ICPs) to monitor antimicrobial use while simultaneously optimizing treatment, outcome, and cost. This article outlines the development of an effective ASP and the key components and operating principles, and also provides insight into the production of materials that will facilitate the execution of these programs at healthcare facilities. In this discussion, education of healthcare providers is emphasized, and a rationale is provided with regard to the health, safety, and financial benefits that can be obtained from an ASP. A brief history of antimicrobial stewardship is included, providing the context for several studies of antimicrobial stewardship practice, which are also reviewed. Programs for optimal use are illustrated, including a prospective audit and feedback strategy and preauthorization procedure. The components of an effective ASP are described in depth, drawing examples from the literature, as well as from the author's personal experience at the Maine Medical Center, Portland, ME.

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

The US Institute of Medicine's 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 beta-lactam specific adverse events will be provided. Finally, new methods of administration are being evaluated that may influence peak concentration-related antimicrobial adverse events.

Pharmacokinetics-pharmacodynamics, computer decision support technologies, and antimicrobial stewardship: the compass and rudder.

The first guidelines for conducting antimicrobial stewardship in the hospitalized setting were published in 2007. These guidelines recommend that stewardship programs employ the science of pharmacokinetics-pharmacodynamics (PK-PD) as well as adopting computerized decision support technologies when possible. The United States Food and Drug Administration have adopted PK-PD as a cornerstone in the evaluation of antimicrobial agents during clinical development. The core principles of PK-PD center around describing the relationship between drug exposure indexed to the susceptibility of the infecting bacterial pathogen and patient response. Using such relationships with population pharmacokinetic models and simulation, rational drug and dosing regimens can be selected. But because PK-PD modeling and simulation programs are generally absent in clinical practice, systematic application of this science is missing. Herein we explain advances in technology that allow clinicians to apply PK-PD to optimize the agents and dosing regimens selected for the treatment of hospitalized patients with infection.

Clostridium difficile-associated disease: changing epidemiology and implications for management.

Clostridium difficile-associated disease (CDAD) is increasingly being reported in many regions throughout the world. The reasons for this are unknown, are likely to be multifactorial, and are the subject of several current investigations. In addition to the upsurge in frequency of CDAD, an increased rate of relapse/recurrence, disease severity and refractoriness to traditional treatment have also been noted. Moreover, severe disease has been reported in non-traditional hosts (e.g. younger age, seemingly healthy, non-institutionalised individuals residing in the community, and some without apparent antimicrobial exposure). A previously uncommon and more virulent strain of C. difficile has been reported at the centre of multiple transcontinental outbreaks. The appearance of this more virulent strain, in association with certain environmental and antimicrobial exposure factors, may be combining to create the 'perfect storm'. It is human nature to be reactive; however, the successful control of C. difficile will require healthcare systems (including administrators, and leadership within several departments such as environmental services, infection control, infectious diseases, gastroenterology, surgery, microbiology and nursing), clinicians, long-term care and rehabilitation facilities, and patients themselves to be proactive in a collaborative effort. Guidelines for the management of CDAD were last published over a decade ago, with the next iteration due in the fall (autumn) of 2007. Several newer therapies are under investigation but it is unclear whether they will be superior to current treatment options.

Efficacy of hospital cleaning agents and germicides against epidemic Clostridium difficile strains.

OBJECTIVE: To compare the effects of hospital cleaning agents and germicides on the survival of epidemic Clostridium difficile strains. METHODS: We 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. RESULTS: Cleaning 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%). CONCLUSIONS: These 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.

Antimicrobial stewardship and the role of pharmacokinetics-pharmacodynamics in the modern antibiotic era.

Antimicrobial stewardship, a term coined by Dale Gerding, is defined as the optimal selection, dose, and duration of an antimicrobial that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance development. Methods to promote and ensure good antimicrobial stewardship have been implemented and studied, and have typically provided tangible benefits in terms of a reduction in overall or targeted antimicrobial usage and resistance emergence. Although most of the programmatic antimicrobial stewardship efforts have been conducted in acute care inpatient settings, some strategies usually involving education have been evaluated in the outpatient venue. In this review, we shall discuss issues related to why antimicrobial stewardship is of particular importance in the modern antibiotic era. In addition, general pharmacokinetic-pharmacodynamic (PK-PD) concepts will be reviewed and specific PK-PD analyses that support the optimal selection, dosing, and duration of therapy for beta-lactam antimicrobials will be provided.

Antimicrobial-associated QT interval prolongation: pointes of interest.

Until recently, cardiac toxicity manifesting in the form of arrhythmias related to QT interval prolongation was uncommonly appreciated within the antimicrobial class of drugs, but it was well described among antiarrhythmic agents. Antimicrobials that are associated with QT prolongation include the macrolides/ketolides, certain fluoroquinolones and antimalarials, pentamidine, and the azole antifungals. Although, in most cases, mild delays in ventricular repolarization caused by these drugs are clinically unnoticeable, they may serve to amplify the risk for torsades de pointes (TdP) when prescribed in the setting of other risk factors. Conditions or variables that influence proarrhythmic risk include sex, age, electrolyte derangements, structural heart disease, pharmacokinetic/pharmacodynamic interactions, and genetic predisposition. It is important that clinicians be knowledgeable about drugs with QT liability, as well as the risk factors that increase the probability of TdP. Additionally, because TdP remains a difficult-to-measure adverse event, we must rely upon multiple data sources to determine the risk versus the benefit for newly approved drugs.

Hospital-based strategies for combating resistance.

Selective pressures generated by the indiscriminate use of beta-lactam antibiotics have resulted in increased bacterial resistance across all beta-lactams classes. In particular, the use of third-generation cephalosporins has been associated with the emergence of extended-spectrum beta-lactamase-producing and AmpC beta-lactamase-producing Enterobacteriaceae and vancomycin-resistant enterococci. Conversely, beta-lactams (e.g., cefepime, piperacillin-tazobactam, and ampicillin-sulbactam) have not demonstrated such strong selective pressures. Chief among institutional strategies to control outbreaks of multidrug-resistant bacteria are infection-control measures and interventional programs designed to minimize the use of antimicrobial agents that are associated with strong relationships between use and resistance. Successful programs include antimicrobial stewardship programs (prospective audit and feedback), formulary interventions (therapeutic substitutions), formulary restrictions, and vigilant infection control. Fourth-generation cephalosporins, such as cefepime, have proven to be useful substitutes for third-generation cephalosporins, as a part of an overall strategy to minimize the selection and impact of antimicrobial-resistant organisms in hospital settings.

Stability of cefepime and metronidazole prepared for simplified administration as a single product.

The stabilities of cefepime and metronidazole were determined after preparation of a single admixture product in view of its potential use as a simple and cost-effective therapeutic alternative for infections caused by many aerobic and anaerobic pathogens. The stability of cefepime 1000 or 2000 mg mixed with metronidazole 500 or 1500 mg was evaluated via high-performance liquid chromatography after storage for up to 336 h at 4 or 23 degrees C. Cefepime was stable in all 4 degrees C samples for up to 336 h, retaining > or =95% of initial concentrations. Samples of cefepime 1000 and 2000 mg mixed with metronidazole 500 mg were stable at 23 degrees C for up to 48 h, whereas those mixed with metronidazole 1500 mg and cefepime controls were stable at 23 degrees C for up to 72 h. Metronidazole was stable in all samples for up to 336 h, retaining > or =94% of initial concentrations. These data suggest that therapeutic use of cefepime and metronidazole as a single intravenous admixture product is feasible and practical.

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.

Antimicrobial safety: focus on fluoroquinolones.

BACKGROUND/PURPOSE: Infrequent toxicities associated with certain drugs and drug classes have recently gained much attention from different health-care perspectives. To protect the patient, continued surveillance of safety and tolerability data is essential. Data from preclinical testing, phase 1-3 trials, and postmarketing surveillance may be used to objectively assess the risks associated with a specific drug or family of compounds. This review summarizes safety and tolerability data for the quinolones. MAIN FINDINGS: The most common adverse events associated with the quinolone class involve the gastrointestinal tract (nausea and diarrhea) and central nervous system (CNS) (headache and dizziness). These adverse events are usually mild and do not require discontinuation of therapy. Uncommon and potentially serious quinolone-related adverse events involve the cardiovascular system (rate-corrected electrocardiographic QT interval prolongation), musculoskeletal system (tendinitis and tendon rupture), endocrine system (glucose homeostasis dysregulation), renal system (crystalluria, interstitial nephritis, and acute renal failure), and the CNS (seizures). Severe idiosyncratic adverse events are specific to individual agents that may share some structural congruity, such as the 1-(2,4)-difluorophenyl group shared by trovafloxacin (associated with hepatitis), temafloxacin (associated with hemolytic-uremic syndrome), and tosufloxacin (associated with eosinophilic pneumonitis). Overall, discontinuation rates from clinical trials were <4% for the currently marketed quinolones. Quinolones with higher discontinuation rates, such as trovafloxacin (7.0%) and grepafloxacin (6.4%), are no longer available for general use. CONCLUSIONS: The currently marketed quinolones are well tolerated, with safety profiles similar to those of other antimicrobial classes. Although adverse effects are unusual, some, including tendinitis and CNS-related effects, are more common with quinolones than with other antimicrobial classes. Rare adverse effects attributed to some members of the quinolone family (e.g., Torsades de Pointes, hepatotoxicity, and dysglycemias) are more likely to occur in select "susceptible" populations. These adverse events can often be circumvented by avoiding exposure to the specific quinolone. In some cases, the therapeutic value offered by a quinolone may outweigh its potential risks.

Assessment of pharmacokinetic-pharmacodynamic target attainment of gemifloxacin against Streptococcus pneumoniae.

The treatment of community-acquired respiratory tract infections has been complicated by the emergence of multidrug-resistant Streptococcus pneumoniae. Although traditionally rare, a growing concern for fluoroquinolone-resistant pneumococci has surfaced. More pharmacodynamically potent antimicrobial agents are clearly needed, as the use of such agents may further optimize clinical and microbiological outcomes for patients and slow the emergence of fluoroquinolone resistance. For fluoroquinolones, the ratio of the 24-h area under the concentration-time curve of the agent to the minimum inhibitory concentration of the agent against the pathogen for the fraction of unbound drug is the major pharmacokinetic-pharmacodynamic (PK-PD) measure correlating with efficacy in nonclinical models and infected patients. A 2500-patient Monte Carlo simulation, utilizing a patient-population pharmacokinetic model derived from phase 3 registration trials and the minimum inhibitory concentration distribution for gemifloxacin against 3117 clinical strains of S. pneumoniae, was carried out to estimate the probability of gemifloxacin attaining exposures associated with efficacy. The overall probability PK-PD target attainment for gemifloxacin was greater than 0.99. Gemifloxacin is among the most pharmacodynamically potent fluoroquinolones and is more potent than ciprofloxacin, ofloxacin, and levofloxacin. Preferential use of pharmacodynamically potent agents over other alternatives may lead to improved clinical outcomes and decreased selection of fluoroquinolone-resistant pneumococci.

Pharmacokinetics, Safety, and Tolerability of a Single 500-mg or 1000-mg Intravenous Dose of Dalbavancin in Healthy Japanese Subjects.

BACKGROUND AND OBJECTIVES: Dalbavancin is a novel, once-weekly glycopeptide antibiotic approved for treatment of acute bacterial skin infections. Given the importance of understanding any pharmacokinetic variability across different patient populations, a double-blind, placebo-controlled study was conducted to evaluate the pharmacokinetics, safety, and tolerability of a single 500-mg and a single 1000-mg intravenous dose of dalbavancin in healthy Japanese subjects. METHODS: Ten subjects received intravenous dalbavancin 1000 mg, five subjects received intravenous dalbavancin 500 mg, and three subjects received intravenous placebo. RESULTS: After a single infusion of dalbavancin, the maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC) increased in a proportional manner from 500 mg to 1000 mg (C max: 157 µg/ml and 299 µg/ml; AUClast: 10,850 µg·h/ml and 22,679 µg·h/ml, on the 500-mg and 1000-mg regimens, respectively) with low inter-subject variability. The mean terminal phase half-life (t 1/2) was 204 and 193 h after the 500-mg and 1000-mg dose, respectively. Clearance and volume of distribution were similar for the two dose concentrations. Treatment-emergent adverse events reported were considered to be of mild intensity. There were no relevant changes in laboratory values or vital signs over time in subjects in either treatment group. CONCLUSIONS: Overall, dalbavancin 500 mg and dalbavancin 1000 mg, administered as a single 30-min infusion, was well tolerated in this population and resulted in plasma exposures similar to those in non-Asians.

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.