Optimizing antibiotic therapy in the intensive care unit setting

Antibiotics are one of the most common therapies administered in the intensive care unit setting. In addition to treating infections, antibiotic use contributes to the emergence of resistance among pathogenic microorganisms. Therefore, avoiding unnecessary antibiotic use and optimizing the administration of antimicrobial agents will help to improve patient outcomes while minimizing further pressures for resistance. This review will present several strategies aimed at achieving optimal use of antimicrobial agents. It is important to note that each intensive care unit should have a program in place which monitors antibiotic utilization and its effectiveness. Only in this way can the impact of interventions aimed at improving antibiotic use (e.g. antibiotic rotation, de-escalation therapy) be evaluated at the local level.     

Bench-to-bedside review: Antimicrobial utilization strategies aimed at preventing the emergence of bacterial resistance in the intensive care unit

Antimicrobial resistance has emerged as one of the most important issues complicating the management of critically ill patients with infection. This is largely due to the increasing presence of pathogenic microorganisms with resistance to existing antimicrobial agents resulting in the administration of inappropriate treatment. Effective strategies for the prevention of antimicrobial resistance within intensive care units are available and should be aggressively implemented. The importance of preventing antimicrobial resistance is magnified by the limited availability of new antimicrobial drug classes for the foreseeable future.     

Appropriate use of antimicrobial agents: challenges and strategies for improvement

The use of inadequate empirical antimicrobial therapy is common in intensive care unit patients and contributes to a number of poor outcomes. Selecting appropriate antimicrobial therapy is complicated by many factors, including the large number of agents available, the presence of resistant organisms, and the general desire among practitioners to use the most focused therapy available. An important aspect of appropriate antimicrobial use is prompt initiation of adequate empirical therapy, which has been shown to improve mortality rates in hospitalized patients with pneumonia and other serious infections. Other key strategies include streamlining antimicrobial therapy when a pathogen is identified and switching from intravenous to oral therapy when clinically indicated. In addition, antibiotic rotation (or cycling) has been evaluated in several trials as a means to minimize resistance. Promoting appropriate antimicrobial therapy ultimately will require a multidisciplinary, system-oriented, institution-specific approach because each intensive care unit has its own unique flora and antimicrobial resistance patterns.     

Economics of antibiotic resistance

Antibiotics are developed to kill microorganisms; however, microorganisms develop and disseminate resistance as a reaction to antimicrobials in accordance with the laws of evolution and natural selection. Resistant and multidrug-resistant bacterial infections comprise a great problem in both the community and hospital setting. Increasing values of health expenditures, including antibiotics, is a global problem. Antibiotic resistance is not always, but usually, associated with significant morbidity, longer hospitalization, excess costs and mortality. Excess costs associated with resistant microorganisms may be due to: obligation to use more expensive antibiotics, longer hospital stay, higher mortality, delayed appropriate antibiotic therapy or a necessity to perform surgery. Optimal use of existing antimicrobial agents, using alternative treatment options (where possible), reducing the need for antimicrobials by increasing immunity, reducing the use of antimicrobials without providing an alternative form of treatment through education of health professionals and patients, antibiotic policies (including antibiotic stewardship and regulations for restricted use), implementation of infection control measures (e.g., hand washing, screening and isolation) are the strategies aimed at prevention of emergence and spread of antibiotic resistance.     

Antimicrobial resistance

Antimicrobial resistance is not a new concept. For over half a century, health care providers have been faced with this problem. The overuse and misuse of antimicrobial therapy by health care providers has contributed largely to the problem, but several other factors have also been associated with antimicrobial resistance. This article reviews current literature regarding antimicrobial resistance in an effort to educate health care providers to make judicious decisions in the treatment of bacterial infections and stem the rise of antibiotic resistance by carefully scrutinizing prescribing practices. Contributing factors to antimicrobial resistance and recommendations for the control of antimicrobial resistance will be reviewed. Treatment recommendations for common health ailments (i.e., acute otitis media, rhinitis, sinusitis, and pharyngitis) are provided.     

Community-associated MRSA in the pediatric primary care setting

Community-associated methicillin-resistant (CA-MRSA) infections occur in children throughout the United States and worldwide. The most common are skin and soft tissue infections. However, life-threatening invasive disease and death can occur as a result of CA-MRSA. The rising prevalence of antimicrobial resistance associated with CA-MRSA further complicates antibiotic treatment therapy. This clinical paper elucidates the recent evolution in the epidemiology of CA-MRSA in otherwise healthy children within the community, and the rising antimicrobial resistance of this virulent pathogen. Furthermore, it will focus on the importance of timely diagnosis, treatment, and management of the most common presenting pediatric infections seen in the outpatient setting. The current Centers for Disease Control and Prevention (CDC) clinical management strategies identify the optimal prevention and treatment approach to be used by pediatric primary care providers.     

Bench-to-bedside review: Therapeutic options and issues in the management of ventilator-associated bacterial pneumonia

Despite progress in the diagnosis, prevention and therapy for hospital-acquired infections, ventilator-associated pneumonia (VAP) continues to complicate the course of a significant proportion of patients receiving mechanical ventilation. Mortality rates among patients with VAP have been reported to be as high as 72%, and the morbidity associated with VAP is also considerable, adding days to the hospital stay and increasing health care costs. Appropriate initial antimicrobial therapy for patients with VAP has been shown to reduce mortality rates and improve outcomes; therefore, rapid identification of infected patients and timely, accurate selection of effective antimicrobial agents are important clinical goals. The primary organisms responsible for VAP include Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. However, aetiologies differ considerably between intensive care units, and the increase in antibiotic resistance and nosocomial outbreaks worldwide have presented clinicians with a serious dilemma with respect to selecting appropriate empirical therapy. To date, no optimal antimicrobial regimen for the treatment of VAP has been identified, largely because none of the currently marketed antibiotics has a sufficiently extended spectrum of activity to cover all of the potential key pathogens. More active, less toxic antibacterial agents are still needed, in particular to combat problematic pathogens such as multiresistant Gram-negative bacilli and resistant Gram-positive organisms (e.g. methicillin-resistant S aureus).     

Duration of antimicrobial therapy for nosocomial pneumonia: possible strategies for minimizing antimicrobial use in intensive care units

OBJECTIVE: To review published data evaluating shorter courses of antibiotic therapy for nosocomial pneumonia and provide recommendations for minimizing antimicrobial use in intensive care units. DATA SOURCE: Literature was identified through MEDLINE (1966 through 6/2002) and a manual search of critical care, infectious disease, and pharmacy journals was conducted to identify relevant abstracts. DATA SYNTHESIS: Antibiotic use may be decreased by discontinuing therapy after 3 days in patients with low likelihood of nosocomial pneumonia. In addition, clinical guidelines or invasive diagnostic procedures may be effectively instituted to reduce duration of antibiotic therapy. CONCLUSION: Shorter-course antibiotic therapy may be beneficial in decreasing lengths of hospital and intensive care units stays, antimicrobial resistance, and total hospital costs. Further research is needed to determine the optimal duration of therapy in patients with nosocomial pneumonia.     

Toward understanding evidence uptake: semirecumbency for pneumonia prevention

OBJECTIVE: Randomized trials show that the semirecumbent position compared with the supine position is associated with less gastroesophageal aspiration and pneumonia in patients receiving mechanical ventilation. However, semirecumbency is inconsistently used in practice. The objective of this study was to understand the perspectives of intensive care unit clinicians regarding the determinants and consequences of semirecumbency. DESIGN: Qualitative study using semistructured interviews and focus groups. SETTING: Three university-affiliated intensive care units. PARTICIPANTS: A total of 93 intensive care unit clinicians, including bedside nurses, respiratory therapists, physiotherapists, nutritionists, residents, fellows, and intensivists. METHODS: We elicited perceptions about benefits and harms of semirecumbency, factors promoting and deterring use, and health systems changes to encourage semirecumbency. Interview and focus group notes were analyzed inductively to identify emerging themes. Validation methods involved triangulation by multidisciplinary analysis of several data sources collected through multiple methods and member checking. MEASUREMENTS AND MAIN RESULTS: Intensivists and nutritionists were familiar with semirecumbency as a potential pneumonia prevention strategy, whereas other clinicians were not. When made aware of the evidence, all participants endorsed semirecumbency. Nurses perceived that the main determinant of semirecumbency was physicians' orders, whereas intensivists perceived that the main determinant was nursing preference. Participants identified barriers to semirecumbency related to useful alternative positions (e.g., lateral position), contraindications (e.g., hemodynamic instability), risk of harm (e.g., decubitus ulcers), safety (e.g., sliding out of the bed), and resources (e.g., insufficient beds facilitating semirecumbency). Education, guidelines, reminders, audit and feedback, charting, and quality improvement initiatives were advocated to promote semirecumbency. CONCLUSIONS: Under-utilization of semirecumbency for pneumonia prevention is influenced by insufficient awareness of its benefit, real and perceived deterrents, poor agreement about implementation responsibility, and lack of enabling and reinforcing strategies. Cognitive, behavioral, and administrative approaches to enhancing evidence uptake may be needed in the complex, dynamic intensive care unit setting.     

How good is the evidence for the recommended empirical antimicrobial treatment of patients hospitalized because of community-acquired pneumonia? A systematic review

BACKGROUND: For years, monotherapy with a beta-lactam antibiotic (penicillin, amoxicillin or second-generation cephalosporin) was recommended as empirical therapy for patients with community-acquired pneumonia (CAP). A combination of a beta-lactam and a macrolide antibiotic was only recommended for patients with severe CAP needing intensive care treatment or when atypical pathogens, i.e. Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae, were strongly suspected. However, new guidelines recommend a combination of a beta-lactam antibiotic plus a macrolide or monotherapy with a fluoroquinolone for all patients hospitalized with CAP. We evaluated whether treatment with a beta-lactam plus macrolide or quinolone monotherapy is truly superior to beta-lactam treatment alone. METHODS: We systematically reviewed available studies, retrieved from MEDLINE and by hand-searching reference lists from recent reviews and guidelines on the effectiveness of recommended empirical antimicrobial treatment of patients hospitalized because of CAP. RESULTS: Eight relevant studies were selected. In six studies significant reductions in mortality were found, in one study a reduction in hospital length of stay was found and in one study no beneficial effects could be demonstrated for treatment regimens with fluoroquinolone monotherapy or combinations of beta-lactams and macrolides. The beneficial value of macrolides or fluoroquinolones might be the result of a large and mainly unrecognized role of atypical pathogens in the aetiology of CAP, anti-inflammatory effects of macrolides or resistance to beta-lactams of the most important pathogens. However, the studies supporting the recommended treatment regimen were designed as non-experimental cohort studies. As a consequence, the results may have been influenced by confounding by indication. In addition, the outcomes showed several inconsistencies. CONCLUSIONS: A randomized controlled trial is warranted to circumvent the methodological flaws in the designs of the currently available studies. Since the addition of macrolides or treatment with fluoroquinolones may lead to enhanced antibiotic resistance, increased side effects and healthcare-related costs, such a fundamental change in the treatment of CAP should be based on valid data.     

Administration of antibiotics via the respiratory tract for the prevention of ICU-acquired pneumonia: a meta-analysis of comparative trials

Introduction  

The administration of prophylactic antibiotics via the respiratory tract is one of several strategies for the prevention of intensive care unit (ICU)-acquired pneumonia. We systematically examined the available evidence regarding the effect of prophylactic antibiotics administered via the respiratory tract on the development of ICU-acquired pneumonia, mortality, colonization of the respiratory tract, emergence of antimicrobial resistance, and toxicity.     

Antimicrobial strategies in surgical critical care

There is clear evidence that early and appropriate empiric antimicrobial therapy for suspected nosocomial infections reduces the rate of adverse outcomes. This approach necessitates a liberal antimicrobial policy, whereas observational and experimental data also suggest that excessive antibiotic use promotes the emergence of antimicrobial resistance, creating a dilemma for the intensivists and begging the question as to whether minimization of antimicrobial resistance and maximization of individual patient outcomes are mutually exclusive. Contemporary strategies are outlined for the antimicrobial management of ventilator-associated pneumonia, the most common nosocomial infection in the intensive care unit, and the use of institution-specific guidelines, invasive diagnostic approaches, and other objective criteria to ensure adequate, yet not excessive use of antimicrobials are discussed. The focus is then on relative merits of routine antifungal prophylaxis as an example of an attempt to reduce the incidence and adverse consequences of late diagnoses of fungal sepsis. Finally, the advantages and disadvantages of antimicrobial cycling as a means of reducing antimicrobial resistance in the intensive care unit are outlined.     

Antimicrobial resistance in the intensive care unit: understanding the problem

Antimicrobial resistance is a problem that affects healthcare delivery around the globe. Factors associated with antimicrobial resistance include overuse or misuse of antimicrobial agents, immunosuppressed patients, and increased technology. Cellular mechanisms of antimicrobial resistance include the decreased uptake of a drug, efflux of the drug, enzymatic inactivation, and alterations in the antimicrobial target site. New treatment options are currently available for resistant organisms. Therapeutic strategies such as antibiotic control policies and antibiotic "cycling" have been proposed as methods for minimizing the emergence of more resistant organisms. Little evidence is available to indicate that these strategies are effective in limiting the emergence of resistance. Clinicians are urged to be judicious in their use and choice of antimicrobials.     

Mechanisms of resistance among respiratory tract pathogens

Antimicrobial resistance among respiratory tract pathogens represents a significant health care threat. Identifying the antimicrobial agents that remain effective in the presence of resistance, and knowing why, requires a thorough understanding of the mechanisms of action of the various agents as well as the mechanisms of resistance demonstrated among respiratory tract pathogens. The primary goal of antimicrobial therapy is to eradicate the pathogen, via killing or inhibiting bacteria, from the site of infection; the defenses of the body are required for killing any remaining bacteria. Targeting a cellular process or function specific to bacteria and not to the host limits the toxicity to patients. Currently, there are four general cellular targets to which antimicrobials are targeted: cell wall formation and maintenance, protein synthesis, DNA replication, and folic acid metabolism. Resistance mechanisms among respiratory tract pathogens have been demonstrated for all four targets. In general, the mechanisms of resistance used by these pathogens fall into one of three categories: enzymatic inactivation of the antimicrobial, prevention of intracellular accumulation, and modification of the target site to which agents bind to exert an antimicrobial effect. Resistance to some agents can be overcome by modifying the dosage regimens (e.g., using high-dose therapy) or inhibiting the resistance mechanism (e.g., b-lactamase inhibitors), whereas other mechanisms of resistance can only be overcome by using an agent from a different class. Understanding the mechanisms of action of the various agents and the mechanisms of resistance used by respiratory tract pathogens can help clinicians identify the agents that will increase the likelihood of achieving optimal outcomes.     

Accurate diagnosis and appropriate treatment of acute bacterial rhinosinusitis: minimizing bacterial resistance

BACKGROUND: Antimicrobial resistance in respiratory pathogens has become a common clinical problem that has serious public health implications. Inappropriate use of antibiotics for the treatment of viral upper respiratory tract infections (URTIs) has contributed to the development of resistant microorganisms. Health care providers can help control the spread of resistance by limiting the use of antimicrobial agents to infections that meet clinical guidelines for a bacterial cause. OBJECTIVE: This article examines the means of accurately diagnosing and appropriately treating acute bacterial rhinosinusitis (ABRS) in an effort to control increasing levels of resistance. METHODS: This article discusses current treatment guidelines that provide the evidenced-based rationale for choosing the most appropriate antimicrobial agents for suspected ABRS in adults and children. An evidence-based approach can help minimize the public health threat posed by the continuing increase in microbial resistance. RESULTS: Although definitive clinical criteria that differentiate between ABRS and viral URTI are lacking, careful evaluation of the duration and severity of symptoms provides a rational basis for diagnosing ABRS in primary care settings. CONCLUSIONS: Once a diagnosis of ABRS has been made, empiric antibiotic therapy may be justified. When it is, the first-line agent should be the narrowest spectrum antibiotic that would be expected to eradicate the most common causative organisms. The antibiotic selection process should take into account prevailing patterns of resistance and the presence of risk factors for infection with resistant pathogens, as well as published evidence-based guidelines.     

Prevention of infection in the intensive care unit

PURPOSE OF REVIEW: Infections remain an important threat for critically ill patients, and the emergence of antibiotic resistance is increasingly hampering successful treatment. In this review, new aspects of the diagnosis and prevention of ventilator-associated pneumonia and of strategies of antibiotic use to limit the development and spread of resistance are described. RECENT FINDINGS: Prevention of ventilator-associated pneumonia is cost effective, but the most optimal preventive measure (or set of measures) remains controversial. There is growing evidence that antibiotic prophylaxis reduces the occurrence of ventilator-associated pneumonia and improves patient outcome. Moreover, antibiotic use can be reduced by increasing the specificity of diagnosing ventilator-associated pneumonia and by limiting the duration of antibiotic treatment. SUMMARY: Recent developments in diagnosis, treatment, and prevention of ventilator-associated pneumonia and strategies to reduce emergence of antibiotic resistance have been reviewed. Whether changes in antibiotic policy will reduce the emergence of antibiotic resistance remains to be determined. In this area, methodologic problems that have been overlooked in many studies have been addressed recently. These issues must be clarified to provide reliable data on the effects of interventions in hospital settings.     

Non-phenotypic tests to detect and characterize antibiotic resistance mechanisms in Enterobacteriaceae

In the past 2 decades, we have observed a rapid increase of infections due to multidrug-resistant Enterobacteriaceae. Regrettably, these isolates possess genes encoding for extended-spectrum β-lactamases (e.g., bla_CTX-M, bla_TEM, bla_SHV) or plasmid-mediated AmpCs (e.g., bla_CMY) that confer resistance to last-generation cephalosporins. Furthermore, other resistance traits against quinolones (e.g., mutations in gyrA and parC, qnr elements) and aminoglycosides (e.g., aminoglycosides modifying enzymes and 16S rRNA methylases) are also frequently co-associated. Even more concerning is the rapid increase of Enterobacteriaceae carrying genes conferring resistance to carbapenems (e.g., bla_KPC, bla_NDM). Therefore, the spread of these pathogens puts in peril our antibiotic options. Unfortunately, standard microbiological procedures require several days to isolate the responsible pathogen and to provide correct antimicrobial susceptibility test results. This delay impacts the rapid implementation of adequate antimicrobial treatment and infection control countermeasures. Thus, there is emerging interest in the early and more sensitive detection of resistance mechanisms. Modern non-phenotypic tests are promising in this respect, and hence, can influence both clinical outcome and healthcare costs. In this review, we present a summary of the most advanced methods (e.g., next-generation DNA sequencing, multiplex PCRs, real-time PCRs, microarrays, MALDI-TOF MS, and PCR/ESI MS) presently available for the rapid detection of antibiotic resistance genes in Enterobacteriaceae. Taking into account speed, manageability, accuracy, versatility, and costs, the possible settings of application (research, clinic, and epidemiology) of these methods and their superiority against standard phenotypic methods are discussed.     

Antibiotic stewardship programmes in intensive care units:Why,how,and where are they leading us

Antibiotic usage and increasing antimicrobial resistance(AMR) mount significant challenges to patient safety and management of the critically ill on intensive care units(ICU). Antibiotic stewardship programmes(ASPs) aim to optimise appropriate antibiotic treatment whilst minimising antibiotic resistance. Different models of ASP in intensive care setting, include "standard" control of antibiotic prescribing such as "de-escalation strategies"through to interventional approaches utilising biomarkerguided antibiotic prescribing. A systematic review of outcomes related studies for ASPs in an ICU setting was conducted. Forty three studies were identified from MEDLINE between 1996 and 2014. Of 34 nonprotocolised studies, [1 randomised control trial(RCT), 22 observational and 11 case series], 29(85%) were positive with respect to one or more outcome: These were the key outcome of reduced antibiotic use, or ICU length of stay, antibiotic resistance, or prescribing cost burden. Limitations of non-standard antibiotic initiation triggers, patient and antibiotic selection bias or baseline demographic variance were identified. All 9 protocolised studies were RCTs, of which 8 were procalcitonin(PCT) guided antibiotic stop/start interventions. Five studies addressed antibiotic escalation, 3 de-escalation and 1 addressed both. Six studies reported positive outcomes for reduced antibiotic use, ICU length of stay or antibiotic resistance. PCT based ASPs are effective as antibiotic-stop(de-escalation) triggers, but not as an escalation trigger alone. PCT has also been effective in reducing antibiotic usage without worsening morbidity or mortality in ventilator associated pulmonary infection. No study has demonstrated survival benefit of ASP. Ongoing challenges to infectious disease management, reported by the World Health Organisation global report 2014, are high AMR to newer antibiotics, and regional knowledge gaps in AMR surveillance. Improved AMR surveillance data, identifying core aspects of successful ASPs that are transferable, and further well-conducted trials will be necessary if ASPs are to be an effective platform for delivering desired patient outcomes and safety through best antibiotic policy.     

Benchmarking antimicrobial drug use in hospitals

Measuring and monitoring antibiotic use in hospitals is believed to be an important component of the strategies available to antimicrobial stewardship programs to address acquired antimicrobial resistance. Recent efforts to organize large numbers of hospitals into networks allow for interhospital comparisons of a variety of healthcare processes and outcomes, a process often called 'benchmarking'. For comparisons of antimicrobial use to be valid, usage figures must be risk-adjusted to account for differences in patient mix and hospital characteristics. The purpose of this review is to describe recent methods to benchmark antimicrobial drug use and to critically assess the potential advantages and the remaining challenges. While many methodological challenges remain, and the clinical outcomes resulting from benchmarking programs have yet to be determined, recent developments suggest that benchmarking antimicrobial drug use will become an important component of antimicrobial stewardship program activities.     

Significance of genomic DNA group delineation in comparative studies of antimicrobial susceptibility of Acinetobacter spp

There were significant differences in antimicrobial susceptibilities in isolates of genomic DNA groups 2 (Acinetobacter baumannii), 3, and 13TU collected from the same sources, e.g., patients in intensive care units and general wards, and in isolates of the same group collected from different sources. The delineation of genomic groups is important in comparative surveillance studies of antimicrobial susceptibilities.