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.

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.

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.

Antimicrobial stewardship: application in the intensive care unit.

Critical-care units can be barometers for appropriate antimicrobial use. There, life and death hang on empirical antimicrobial therapy for treatment of infectious diseases. With increasing therapeutic empiricism, triple-drug, broad-spectrum regimens are often necessary, but cannot be continued without fear of the double-edged sword: a life-saving intervention or loss of life following Clostridium difficile infection, infection from a resistant organism, nephrotoxicity, cardiac toxicity, and so on. While broadened initial empirical therapy is considered a standard, it must be necessary, dosed according to pharmacokinetic-pharmacodynamic principles, and stopped when no longer needed. Antimicrobial stewardship interventions shepherd these considerations in antimicrobial therapy. With pharmacists and physicians trained in infectious disease and critical care, clear-cut interventions can be focused on beginning or growing a stewardship program, or proposing future studies.

Antimicrobial stewardship: shepherding precious resources.

PURPOSE: Differences in antimicrobial stewardship program (ASP) strategies, evidences supporting the benefits of ASPs, barriers to implementing ASPs, and suggestions for overcoming the barriers are discussed. SUMMARY: Developing and implementing an ASP can facilitate more judicious use of antimicrobials. Prior authorization and prospective audit with feedback are two distinct methods of ASPs. Supplemental and combined strategies of ASPs also exist. Tangible benefits have been demonstrated with using ASPs, such as a reduction in antimicrobial consumption and reductions in costs. In addition, reduced use of certain antimicrobial agents has been correlated with reduction in antimicrobial resistance. Most importantly, ASP implementation may increase patient safety with minimization of antimicrobial-related medication errors such as unnecessary or duplicate antimicrobial use. However, barriers to ASP implementation exist such as acquiring funding for an ASP, a lack of pharmacy leadership supporting ASPs, a shortage of adequately trained infectious disease physicians and pharmacists, competition for funding with other programs in the hospital, and communicating with antagonizing colleagues. CONCLUSION: In the setting of increasing antimicrobial resistance, ASPs provide a formalized, practical, and manageable approach to improving the use of antimicrobials in our health care systems where their use is widespread and often suboptimal. Governmental agencies that require institutions to practice some form of antimicrobial stewardship can be the means to incentivize institutions to allocate resources for such programs.

Guidelines and quality for community-acquired pneumonia: measures from the Joint Commission and the Centers for Medicare and Medicaid Services.

PURPOSE: The rationales for and recent updates on quality measures for the treatment of community-acquired pneumonia (CAP) are reviewed. SUMMARY: CAP continues to be among the most common causes of emergency department visits, hospitalization, and death in the United States. The Joint Commission of Accredited Health Care Organizations in conjunction with the Centers for Medicare and Medicaid Services (CMS) and the Infectious Diseases Society of America have published seven quality measures designed to improve the overall treatment of CAP. To encourage and enforce compliance with the measures, adherence is publicly reported, and several measures are used in the CMS pay-per-performance initiative. The quality measures are oxygen assessment, pneumococcal conjugate vaccination, blood cultures, adult smoking cessation advice/counseling, antimicrobial timing, initial antimicrobial selection in immunocompetent intensive care unit (ICU) and non-ICU patients, and influenza vaccination. CONCLUSION: The Joint Commission, CMS, and IDSA guidelines for the management of patients with CAP address basic aspects of preventive care and treatment for CAP. The guidelines emphasize the importance of vaccination as well as the need for appropriate and timely antimicrobial therapy. Adherence to guidelines is associated with improved patient outcomes, and compliance is being enforced by public reporting and pay-per-performance measures.

Rational dosing of antimicrobial agents: pharmacokinetic and pharmacodynamic strategies.

PURPOSE: Using the principles of pharmacokinetic (PK) and pharmacodynamic (PD) dosing, the optimal dosing strategies of beta-lactams, macrolides, fluoroquinolones, and aminoglycosides for the treatment of community-acquired pneumonia (CAP) are reviewed. SUMMARY: The optimal dosing of antimicrobials according to PK and PD principles is one method to reduce the misuse and overuse of the agents and antimicrobial resistance. Based on PK/PD profiles, antimicrobial agents are divided into three groups: agents with concentration-dependent killing (e.g., fluoroquinolones, aminoglycosides), agents with time- dependent killing and minimal or no persistent effects (e.g., beta-lactams in most circumstances), and agents with time-dependent killing and moderate-to-prolonged persistent effects (e.g., azithromycin).(19) With concentration-dependent agents such as fluoroquinolones, it is the total amount of drug administered that determines efficacy. With time-dependent agents such as macrolides and beta-lactams, it is the duration of exposure to a specific minimum inhibitory concentration (MIC). That part is straight forward. When a concentration-dependent killing drug is able to achieve its optimal peak:MIC, peak:MIC becomes the determinant of efficacy. When such a drug cannot achieve its optimal peak:MIC, AUC:MIC should be used to determine efficacy. CONCLUSION: Optimizing the dose and duration of antimicrobial therapy via PK/PD principles is one strategy to reduce antimicrobial resistance. PK/PD-based dosing provides patient- and pathogen-specific therapy and have the potential to make antimicrobial therapy safer and more effective by accounting for factors such as renal function, underlying pathogen, and local patterns of resistance.

Quality pneumonia care: distinguishing community-acquired from health care-associated pneumonia.

PURPOSE: Differences in the definition, demographics, risk factors, etiology, and treatment for health care-associated pneumonia (HCAP) versus community-acquired pneumonia (CAP) are discussed. SUMMARY: Health care-associated infections (HCAI) represent a population of outpatients with exposure to health care institutions and procedures who develop nosocomial-like infections. HCAI are etiologically similar to nosocomial infections with gram-negative organisms, methicillin-resistant Staphylococcus aureus (MRSA), and multidrug-resistant (MDR) pathogens predominating. These patients are ambulatory, community residents who often present to hospital emergency departments as would patients with community-acquired infection. Although many differences between HCAI and community-acquired infections, as well as HCAP and CAP, remain to be elucidated, the emerging evidence has identified multiple and important differences. Because of etiologic differences between CAP and HCAP, treatment strategies necessarily differ. Mistaking HCAP for CAP may result in the use of inappropriate empirical therapy, which is an established source of treatment failure, morbidity, and mortality. Thus, it is essential for physicians to be capable of recognizing risk factors for HCAI and HCAP as well as competently select and implement appropriate treatment strategies. CONCLUSION: The etiologic differences between HCAP and CAP require different treatment strategies. No clinical or demographic characteristics nor signs and symptoms distinguish HCAP from CAP. Rather, physicians must rely on a thorough and careful history of each patient as well as their own clinical judgment.

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, de-escalation 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.

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.

Clostridium difficile infection: a critical overview.

Clostridium difficile is a gram-positive, spore-forming, toxin-producing anaerobic bacillus identified as the causal agent of a variety of manifestations typically isolated to the colon, but in its severe form, it can lead to sepsis and death. C. difficile infection due to a toxin gene variant strain (BI/NAP1) has been identified at the center of outbreaks and has resulted in increased mortality. Many questions remain as to how this strain appeared so quickly and has harmed or killed so many patients. We present a review of C. difficile infection, discussing its clinical presentation, diagnosis, management, and prevention.

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.

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.

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.

Postmarketing clinical experience in patients with skin and skin-structure infections treated with daptomycin.

A registry describing daptomycin's clinical use was analyzed to describe treatment of skin and skin-structure infections (SSSIs). The Cubicin Outcomes Registry and Experience (CORE) 2004 retrospectively collected demographic, microbiologic, and clinical outcome information of patients treated with daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA). The database was accessed to identify patients with a diagnosis of an SSSI with an outcome determined. Of 577 patients identified with a SSSI, 522 (90%) were evaluable. Diabetes mellitus and peripheral vascular disease were present in 27% and 10% of the population, respectively. Pathogens were identified for 65% of all patients-Staphylococcus aureus (75%; 85% methicillin-resistant) and Enterococcus species (19%; 44% vancomycin-resistant) most commonly. Concomitant use of other antibiotics was common (42%). Of 522 patients studied, 334 (64%) had complicated infections (cSSSIs), and 188 (36%) had uncomplicated infections (uSSSIs). Overall cure, improved, and failure rates were 53%, 43%, and 4%, respectively, for cSSSI and 66%, 32%, and 2%, respectively, for uSSSI. The median dose administered was 4.0 mg/kg for cSSSI (mean, 4.5+/-1.0 mg/kg; range, 2.3 to 12 mg/kg) and 4.0 mg/kg for uSSSI (mean, 4.2+/-0.8 mg/kg; range, 2.1 to 9 mg/kg); the dose was significantly higher in cSSSI (P <0.001, median test). Median daptomycin treatment duration was 12 days (range, 1 to 148 days) and was longer for cSSSI than for uSSSI (14 vs. 10 days, P = 0.002). The results of this study support previously published reports and suggest that daptomycin is effective for the treatment of skin infections due to gram-positive pathogens.

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.

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.