Preventing the spread of antimicrobial resistance among bacterial respiratory pathogens in industrialized countries: the case for judicious antimicrobial use.

The spread of antimicrobial resistance is an important emerging health threat in developed countries. Widespread outpatient antimicrobial use leads to the spread of resistance among community-acquired pathogens such as Streptococcus pneumoniae. The Centers for Disease Control and Prevention and partner organizations have initiated a national campaign promoting more judicious antimicrobial use to decrease the spread of resistance. The initial focus is to improve management of respiratory tract infections, which account for most outpatient antimicrobial use. Survey and focus group results indicate that patient pressure and suboptimal diagnosis and treatment contribute to antibiotic overuse. To educate physicians, a series of "principles of judicious antibiotic use" have been developed that identify optimal approaches to management of common respiratory infections. Patient education materials and strategies to improve doctor-patient communication also have been developed. Several studies currently under way will evaluate the impact of intervention on antibiotic use practices and resistant carriage or infection.     

Extended-spectrum beta-lactamases

Extended-spectrum beta-lactamases, most commonly found in Klebsiella pneumoniae and Escherichia coli, have increased markedly in the past decade, particularly in the intensive care unit setting. The problem has been significant in the United States but is even more prevalent in parts of Latin America and Asia. These plasmid-mediated beta-lactamases confer resistance to broad-spectrum beta-lactam antibiotics, including third- and fourth-generation cephalosporins, aztreonam, and extended-spectrum penicillins. Other resistances, such as aminoglycoside resistance and trimethoprim/sulfamethoxazole resistance, are often cotransferred on the same plasmid. Fluoroquinolone resistance is often associated, resulting in an organism that is resistant to most of the usual antimicrobial options. Although carbapenems are currently considered the drugs of choice for these pathogens, widespread use of these agents may lead to other resistance problems. Due to limited therapeutic options, prevention and control measures are important. Traditional infection control measures, such as contact precautions, are recommended to prevent spread in intensive care units. In addition, because this type of antimicrobial resistance appears to be particularly influenced by antibiotic utilization, antibiotic control measures may also be a very important intervention in limiting the spread of extended-spectrum beta-lactamases.     

Pathogens resistant to antimicrobial agents. Epidemiology, molecular mechanisms, and clinical management

The emergence of resistance to antimicrobial agents continues to be a major problem in the nosocomial setting and now in nursing homes and the community as well. Bacteria use a variety of strategies to avoid the inhibitory effects of antibiotic agents and have evolved highly efficient means for the dissemination of resistance traits. Control of antibiotic-resistant pathogens provides a major challenge for both the medical community and society in general. To control the emergence of resistant pathogens, CDC and infection control guidelines must be adhered to, and antibiotics must be used more judiciously.     

Enterococcus: an emerging pathogen in hospitals

Enterococci remain an important cause of nosocomial infection, particularly among the critically ill. Nationwide, the incidence of enterococcal infections is rising, with an increasing proportion caused by resistant organisms. The spread of vancomycin-resistant enterococci (VRE) within hospitals has been well studied and helps to explain the proliferation of enterococcal disease. After hospital admission of an individual carrying VRE, persistent colonization contributes to the development of a reservoir of colonized inpatients. VRE is usually spread patient to patient by health care workers caring for colonized individuals. To interrupt this phenomenon, infection control efforts including improved hand hygiene, use of gloves and cover gowns, and antibiotic control measures have been promoted. Prospective data concerning the relative benefit of each intervention are limited, and no consensus has emerged regarding the optimal strategy for limiting the dissemination of VRE. Appropriate treatment of an individual patient infected with VRE depends upon successful interpretation of the antibiotic susceptibility profile of the infecting strain. For the critically ill patient, an aggressive approach to diagnosis and therapy is essential. However, even the newest agents available to treat resistant enterococci are limited because of emerging resistance and toxicity.     

The prevention of antibiotic resistance during treatment

Prevention of emergence of antibiotic resistance during treatment is an important goal when prescribing antimicrobials. Antibiotic resistant bacteria can emerge in three main ways--by acquisition of new genes via transposons or horizontal gene transfer, by selection of resistant variants and by selection of naturally resistant strains. In order to minimize emergence of antibiotic resistance during therapy it is important to try and avoid antibiotics which encourage the transfer of resistance genes, to avoid selection of resistant variants from susceptible pathogens and to avoid ablation of antibiotic susceptible normal flora. However, implementing these objectives is not always easy. This paper discusses possible ways of limiting the emergence of resistant bacteria during treatment. It does not consider how to prevent the spread of these strains from person to person. The prevalence of antibiotic-resistant bacteria depends upon the selection of antibiotic-resistant strains and spread of these strains from person to person. Prevention therefore consists of two parts--the prevention of acquisition of resistance/selection of antibiotic-resistant variants and interrupting the mechanisms by which person-to-person spread can occur. This paper considers only the first of these two influences on prevalence of resistance.     

Staphylococcal infections in the intensive care unit

Staphylococcus aureus and coagulase-negative staphylococci are among the most common causes of nosocomial infections in the intensive care unit (ICU). The clinical presentation of staphylococcal device-related infections, pneumonias, or surgical wound infections is not unique. However, treatment of these infections is increasingly problematic because of the resistance of clinical isolates to a widening number of antimicrobial agents.The confluence of critically ill patients and the need for multiple invasive procedures, as well as the use of broad-spectrum antimicrobial agents in the ICU, set the stage for the emergence of these multidrug-resistant staphylococci. In the past 10 years, there has been a progressive increase in the overall resistance of staphylococci to antimicrobial agents. Conventional infection control measures, such as handwashing and isolation precautions, to prevent the spread of staphylococcal infections in the ICU setting remain of critical importance. New approaches, including the prophylactic use of topical antistaphylococcal agents to eliminate nasal colonization in high-risk ICU patients and the development of antistaphylococcal vaccines, are currently being investigated.     

Drug resistance in intensive care units

Intensive care units (ICUs) are generally considered epicenters of antibiotic resistance and the principal sources of outbreaks of multi-resistant bacteria. The most important risk factors are obvious, such as excessive consumption of antibiotics exerting selective pressure on bacteria, the frequent use of invasive devices and relative density of a susceptible patient population with severe underlying diseases. Infections due to antibiotic-resistant bacteria have a major impact on morbidity and health-care costs. Increased mortality is not uniformly shown for all of these organisms: Methicillin-resistant Staphylococcus aureus (MRSA) seems to cause significantly higher mortality, in contrast to vancomycin-resistant enterococci (VRE). Therefore it is essential to diminish these potential risk factors, especially by providing locally adapted guidelines for the prudent use of antibiotic therapy. A quality control of antimicrobial therapy within a hospital, and especially within the ICU, might help to minimize the selection of multidrug-resistant bacteria. The restricted use of antimicrobial agents in prophylaxis and therapy has also been shown to have at least temporal effects on local resistance patterns. New approaches to the problem of drug resistance in ICUs are badly needed.     

Ecological theory suggests that antimicrobial cycling will not reduce antimicrobial resistance in hospitals

Hospital-acquired infections caused by antibiotic-resistant bacteria pose a grave and growing threat to public health. Antimicrobial cycling, in which two or more antibiotic classes are alternated on a time scale of months to years, seems to be a leading candidate in the search for treatment strategies that can slow the evolution and spread of antibiotic resistance in hospitals. We develop a mathematical model of antimicrobial cycling in a hospital setting and use this model to explore the efficacy of cycling programs. We find that cycling is unlikely to reduce either the evolution or the spread of antibiotic resistance. Alternative drug-use strategies such as mixing, in which each treated patient receives one of several drug classes used simultaneously in the hospital, are predicted to be more effective. A simple ecological explanation underlies these results. Heterogeneous antibiotic use slows the spread of resistance. However, at the scale relevant to bacterial populations, mixing imposes greater heterogeneity than does cycling. As a consequence, cycling is unlikely to be effective and may even hinder resistance control. These results may explain the limited success reported thus far from clinical trials of antimicrobial cycling.     

Ventilator-associated pneumonia complicating the acute respiratory distress syndrome

Pulmonary infections span a wide spectrum, ranging from self-limited processes (e.g., tracheobronchitis) to life-threatening infections including both community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). Together, pneumonia and influenza rank as the sixth leading cause of death in the United States and lead all other infectious diseases in this respect. Pneumonia is the second-most-common hospital-acquired infection in the United States, accounting for 17.8% of all hospital-acquired infections and 40,000 to 70,000 deaths per year. HAP is the most common nosocomial infection occurring in patients requiring mechanical ventilation, developing in 6.5% of patients after 10 days and in 28% of patients after 30 days of ventilatory support. Patients acquiring HAP have a greater risk of mortality than comparably ill ventilated patients who do not develop pneumonia. Ventilator-associated pneumonia (VAP) specifically refers to a bacterial pneumonia developing in patients with acute respiratory failure who have been receiving mechanical ventilation for at least 48 hours. The etiologic bacteriologic agents associated with VAP typically differ based on the timing of the occurrence of the infection relative to the start of mechanical ventilation. VAP occurring within 96 hours of the onset of mechanical ventilation is usually due to antibiotic-sensitive bacteria that colonize the patient prior to hospital admission (e.g., Streptococcus pneumoniae, Haemophilus influenza, oxacillin-sensitive Staphylococcus aureus). VAP developing after 96 hours of ventilatory support is more often associated with antibiotic-resistant bacteria including oxacillin-resistant Staphylococcus aureus, Acinetobacter species and Pseudomonas aeruginosa. However, more recent data suggest that hospitalization and exposure to antibiotics prior to the start of mechanical ventilation are important risk factors for the occurrence of VAP attributed to antibiotic-resistant bacteria. Therefore, these risk factors should be considered when deciding on an appropriate empiric antibiotic regimen regardless of the onset of VAP. VAP and catheter-associated bloodstream infections are the leading causes of infection acquired in the intensive care unit (ICU) setting. Patients in the ICU have rates of HAP that are as much as five to ten times higher than the rates in general hospital wards. Additionally, like nosocomial bloodstream infections, VAP is associated with an attributable mortality beyond that accounted for by patients' severity of illness. The attributable mortality associated with VAP appears to be greatest for "high-risk' antibiotic-resistant bacteria including Pseudomonas aeruginosa and oxacillin-resistant Staphylococcus aureus. The greater hospital mortality associated with these "high-risk' pathogens has been attributed to the virulence of these bacteria and the increased occurrence of inadequate initial antibiotic treatment of VAP due to the presence of antibiotic resistance. This review provides an overview of the clinical importance of VAP. We then describe how this nosocomial infection influences the management and outcomes of patients with the acute respiratory distress syndrome (ARDS).     

Diagnosis and treatment of bacterial diarrhea

Diarrheal illness caused by bacterial pathogens is a global health problem and remains one of the most common complaints prompting patients to seek medical care. Strategies to increase the yield of stool culture and new rapid diagnostic tests can improve diagnostic ability. Emerging antimicrobial resistance among the common bacterial causes of diarrhea has made treatment more challenging. Emerging fluoroquinolone resistance is a particular concern. Recent studies of rifaximin, a nonabsorbed antibiotic for the treatment of bacterial diarrhea, have shown favorable results. Rifaximin may represent a muchneeded addition to the armamentarium against bacterial agents.     

Antibiotic utilization strategies to limit antimicrobial resistance

Antimicrobial resistance is now being recognized as a major factor determining morbidity, mortality, and cost in the intensive care unit (ICU). Various strategies to limit its spread have evolved with our understanding and are based on four basic principles: infection prevention, infection eradication, containment of resistant species, and optimization of antibiotic utilization. The optimization of antibiotic utilization, at its most basic level, is the appropriate use of antibiotics and the limitation of unnecessary antibiotic administration/exposure consisting of appropriate diagnosis, acquiring appropriate culture and sensitivity data, implementing the most appropriate treatment, selecting appropriate antibiotics, and dosing appropriately. In addition various antibiotic utilization strategies including antibiotic utilization guidelines, formulary restriction, and antibiotic cycling or rotation have evolved from our understanding of the impact of changes in antibiotic utilization on subsequent antibiotic susceptibility patterns. These strategies can be utilized as a part of a multidisciplinary approach to limit the appearance and dissemination of antimicrobial resistance in our ICUs.     

Infection in the intensive care unit: prevention strategies

PURPOSE OF THE REVIEW: Nosocomial infections remain among the most common treatment complications, particularly in intensive care unit patients. In many countries antibiotic resistance is increasingly hampering treatment of these infections. Preventive strategies have therefore become more important and have been directed both against the development of specific infections and against the spread of antibiotic-resistant pathogens. The present review addresses recent data on the latter issue. In particular, we discuss the first approaches to use mathematical modelling as a tool to analyse and guide strategies to prevent infection, and the effects of antibiotic cycling. RECENT FINDINGS: Several mathematical models to address the dynamics of pathogen transmission in hospital settings have been developed. One of the models may allow quantification of the effects of different strategies to prevent infection in intensive care units, and another may be used to determine the relative importance of different colonization routes, without the need for expensive genotyping methods. The results of the first prospective studies on antibiotic cycling are inconclusive, and again mathematical modelling may help to provide testable hypotheses for such interventions. Finally, recent studies have shown that alcohol-based hand rubs are better than hand washing with soap and water for most hand disinfection purposes. SUMMARY: The first results of use of mathematical modelling to guide infection control strategies should be subjected to prospective, empirical testing in order to determine their clinical usefulness. More rigorously designed studies are needed to determine the benefits of antibiotic cycling strategies. Hands should be disinfected with alcohol-based hand rubs, which should be available at each bedside.     

Impact of antibiotic-resistant bacteria on the outcome of ventilator-associated pneumonia

Since antibiotic resistance has become a worldwide concern, there has been an ongoing debate as to whether infections caused by resistant bacteria are associated with higher mortality. Because resistant strains do not appear to be more virulent, differences in outcome may principally relate to patients' characteristics before or at the time of infection onset, and to high rates of inappropriate empirical antimicrobial treatment prescribed for antibiotic-resistant infections. In two large series of severe Staphylococcus aureus and Pseudomonas aeruginosa ventilator-associated pneumonia, we recently demonstrated that antibiotic resistance does not significantly affect intensive care unit mortality of patients receiving appropriate initial antibiotics. However, antibiotic resistance was consistently found to increase hospital length of stay. Early identification of patients with risk factors favoring antibiotic-resistant infections should prompt the initiation of an empirical antibiotic regimen covering these highly resistant bacteria, which can usually be deescalated 48 to 72 hours later when the results of microbiological samples culture become available.     

The role of the intestinal tract as a source for transmission of nosocomial pathogens

The intestinal tract provides an important source for transmission of many nosocomial pathogens, including Enterococcus species, Clostridium difficile, Candida species, Enterobacteriaceae, and other gram-negative bacilli. Recent data suggest that the intestinal tracts of hospitalized patients may also be an important reservoir of Staphylococcus aureus. Although the clinical manifestations of these pathogens are diverse, a common pathogenesis is involved in their colonization of and dissemination from the intestinal tract. Of particular importance is the role that antibiotic selective pressure plays in promotion of colonization by antibiotic-resistant pathogens. Strategies to limit the spread of these pathogens must include efforts to improve adherence to standard infection control practices and promotion of good antimicrobial stewardship. New strategies that include application of novel technologies to the problem of pathogen transmission are needed, and additional research is needed to clarify the potential utility of selective decontamination of the digestive tract.     

Infection control and quality health care in the new millennium

Health care-associated infection remains a major issue of patient safety. It complicates a significant proportion of patient care deliveries, adds to the burden of resource use, and contributes to unexpected deaths. Early infection control pioneers showed that surveillance and prevention programs can be successful and have set the scene for today's infection control activities. Parameters for success include those to recognize and explain health care-associated infections and implement interventions to decrease infection rates and limit antimicrobial resistance spread. Current major challenges facing infection control programs are reviewed with an emphasis on recent trends in health care delivery systems, together with some vision on future activities and interactions toward such changes. Benchmarking of infection rates is considered inevitable, and, thus, surveillance strategies, adapted to changing health care systems, should improve and emphasize intervention and standardization. Major challenges for the future include antimicrobial use and control of resistances, new materials, emerging pathogens, infection control issues related to transgenic therapy, massive and complete immunosuppression and xenotransplantation, prion diseases, use of fully computerized patient record and data-mining-derived epidemiology, development of evidence-based recommendations for infection control and prevention, addressing cost constraints and newly apparent health care system trends, and health care worker behavior modification.     

Extended-spectrum beta-lactamases

Resistance to broad-spectrum cephalosporins among Klebsiella pneumoniae has increased significantly, particularly in the intensive care unit setting, in the past decade.The problem has been noted not only in the United States, but around the world. A major mechanism responsible for this is the emergence of extended-spectrum beta-lactamases (ESBLs).These plasmid-mediated beta-lactamases confer resistance to broad-spectrum beta-lactam antibiotics, including third- and fourth-generation cephalosporins, aztreonam, and extended-spectrum penicillins. Other resistances, such as aminoglycoside and trimethoprim-sulfamethoxazole resistance, are often cotransferred on the same plasmid. Fluoroquinolone resistance is also frequently associated, resulting in an organism resistant to most broad-spectrum options. The carbapenems are currently considered the drug of choice for these pathogens. Prevention and control measures are important because of the multiresistant nature of these pathogens. Such traditional infection control measures as contact precautions are recommended. In addition, because this type of antimicrobial resistance appears to be particularly influenced by antibiotic use, antibiotic control measures may also be a very important intervention in controlling the spread of ESBLs.     

Resistente Erreger auf der Intensivstation

Antibiotic-resistant pathogens causing healthcare-associated infections pose an increasing public health challenge. Intensive care units represent a center for their generation, selection, and transmission due to the increased morbidity of patients, the increasing number of invasive procedures, inappropriate antibiotic usage, and non-compliance with standard infection control practices. This problem is made more complex because of varying levels of antibiotic resistance depending on the type of healthcare facility, the geographic area, differences between the individual resistant pathogens, and the difficulties associated with detecting some resistance mechanisms. While MRSA epidemics have leveled off in Germany, the rate of Gram-negative pathogens becoming resistant, especially those of the ESBL-phenotype, is steadily increasing. Since treatment options are limited, the establishment of improved antibiotic regimens as well as the implementation of cross-transmission prevention strategies is urgently needed. However, all attempts to meet this public health challenge will only work if this matter is prioritized and appropriate levels of resources are allocated and then used efficiently.     

Results of a Local Antibiotic Management Program on Antibiotic Use in a Tertiary Intensive Care Unit in Hungary

Background  Massive antibiotic use in intensive care units (ICU) is associated with increased microbial resistance. Therefore avoiding unneccesary antibiotic usage is essential. To achieve a more considered antibiotic prescribing practice, a new antibiotic policy was implemented at our ICU. In this paper, we evaluated the impact of this intervention, and described the aetiology and incidence of blood stream infections and selected antibiotic-resistant pathogens. Materials and Methods  In November 2002, a local antibiotic management program (LAMP) was implemented. This included a new infectious diseases specialist consultation service and restricted authorisation to prescribe antibiotics. The effect on ward-level antibiotic use was examined by segmented regression analysis. Patient, ICU and microbiology data were also recorded and compared before and after policy implementation. Results  The patient populations and the subsequent mortality rate were comparable before and after the implementation of the policy. Total antibiotic consumption was markedly reduced from 162.9 to 101.3 defined daily dose (DDD) per 100 patients, and per day (DDD per 100 patient-days). This was mainly accounted for a reduction in the use of quinolones, aminoglycosides, glycopeptides, metronidazol, carbepenems and third generation cephalosporins. Conclusion  This study has confirmed that establishing a targeted LAMP, based on close co-operation between intensive care physicians and infectious disease specialists together with a restricted prescribing authority, can reduce the use of antibiotics.