Healthcare‐associated infections (HAIs) are important causes of morbidity and mortality in the United States and other countries.13 Moreover, treatment of HAIs is frequently complicated by involvement of bacterial pathogens resistant to 1 or more antibiotics or antibiotic classes,4 and sometimes bacteria resistant to all or nearly all currently available agents.57 The rapid emergence of resistant bacteria both in and out of the hospital setting can affect empiric antimicrobial choices across all patients. The effort to avoid undertreating or not covering resistant bacteria can lead to overuse of wide‐spectrum antimicrobials. Antimicrobial useand especially antimicrobial overuse or misusehas been linked with increased antimicrobial resistance,817 leading to worsened clinical outcomes with increased length of hospital stay and healthcare costs. Table 1 defines the various lines of evidence supporting a causal relationship between antibiotic use and emergence of antimicrobial resistance.18, 19

Optimal management of patients with bacterial infections, both HAIs and those that originate in the community, involves a focus on treatment that maximizes clinical outcomes for the individual patient, while also inhibiting or slowing the development of antimicrobial resistance and its spread to other patients. Antimicrobial stewardship is a term describing the various clinical strategies that have been devised to maximize the benefits and minimize the costs of antimicrobial therapy through judicious use of these agents.18, 20, 21 This article examines the developing patterns of resistance among key bacterial pathogens in the hospital and associated healthcare settings, the costs associated with HAIs (specifically, those caused by resistant pathogens), and the various strategies or programs that have been developed by governmental agencies, individual healthcare institutions, and other organizations to optimize the use of antibiotics to improve patient outcomes and minimize healthcare costs. The value that the hospitalist can bring to the development and/or implementation of institutional antimicrobial stewardship programs is explored.

ANTIMICROBIAL RESISTANCE AND HAI TRENDS FOR KEY BACTERIAL PATHOGENS

Bacterial pathogens including Enterobacteriaceae (Klebsiella pneumoniae, Enterobacter spp, Escherichia coli, and Proteus spp, among others), Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecium22, 23 are increasingly prevalent in healthcare settings, and particularly troublesome to manage due to increasing resistance. Data from the Centers for Disease Control and Prevention's (CDC) National Healthcare Safety Network (NHSN) have shown that, in intensive care units (ICUs), 16% of HAIs are due to multidrug‐resistant (MDR) pathogens.4 These 16% have the highest mortality and length of hospital stay, and are associated with the highest healthcare costs.24, 25 Infections caused by MDR pathogens are more important than their actual numbers, because treatment decisions are driven by the intent to cover these MDR pathogens, even if that means providing excessively broad coverage for most patients. Moreover, the 16% mentioned above are only the tip of the iceberg, as many more HAIs will occur outside of the ICU, particularly catheter‐associated urinary tract infections (CAUTI) and surgical site infections, as these patients are often not sick enough to require ICU care. There is little information on the prevalence of HAIs outside of the ICU setting, the role of MDR bacteria in these infections, and the associated costs, mortality, and effects on length of stay.

K pneumoniae Carbapenemases and Community‐Acquired Methicillin‐Resistant Staphylococcus aureus

K pneumoniae carbapenemase (KPC) is a prime example of the emergence and rapid spread of a new resistance pattern that affects prescribing patterns. Emergence of KPC as the primary source of carbapenem resistance in Enterobacteriaceae26 is critically significant, as carbapenems are recommended first‐line therapy for serious infections caused by extended‐spectrum ‐lactamase (ESBL)‐producing K pneumoniae or other Enterobacteriaceae. One particularly remarkable fact about KPC‐producing bacteria is the speed at which they have spread since first emerging. Figure 1 from the CDC illustrates the rapid spread of KPC‐producing bacteria within the United States, from winter 2008 to May 2010. International spread has also been rapid and extensive. The first case of a KPC‐producing bacteria outside the United States was reported in France in February 2005, in an 80‐year‐old man who was admitted to a Parisian hospital 2 to 3 months after having a medical procedure performed in a New York City hospital, suggesting intercontinental transfer from the United States.27 Since then, KPC‐producing pathogenic bacteria have been identified in the Caribbean, South America, Europe, Israel, and China.2830 It is clear that once resistant bacteria emerge, they have the potential to spread very rapidly within and between countries, challenging currently available antimicrobial agents and complicating the treatment of serious infections.

Figure 1

Consideration of S aureus skin and skin‐structure infections highlights the fact that the barrier between hospital and community is now beginning to be crossed, further complicating prescribing decisions. The classic risk factors for resistance may no longer be reliable in determining best empiric treatment. In a landmark study, Moran et al. demonstrated the large percentages of outpatients in the United States with skin or soft‐tissue infections (SSTIs) involving community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA).31 S aureus was isolated from 76% (320/422) of adults presenting to 11 university‐affiliated emergency departments with acute, purulent SSTIs in August 2004, 59% of whom were infected with MRSA. More than half the patients in the study (57%) were initially treated with antibiotics to which MRSA isolates were not susceptible.31 In the hospital, it has been shown that most invasive MRSA infections now actually have their onset outside of the healthcare setting,32 and that increasing numbers of hospitalized patients are now developing infections associated with CA‐MRSA strains >72 hours after admission.3338 Thus, it is becoming increasingly difficult to determine whether an invasive S aureus infection encountered in either a healthcare facility or community setting involves a sensitive organism, healthcare‐associated MRSA, or a CA‐MRSA pathogen, directly impacting treatment choices across all patients we care for with skin and skin‐structure infections.

COSTS OF HAI_s AND ANTIMICROBIAL RESISTANCE

HAIs are an important and growing problem in the United States.56 Klevens et al. estimated that approximately 1.7 million individuals hospitalized in the United States in 2002 had HAI, leading to 98,987 deaths.1 Estimates of annual hospital costs in the United States related to HAIs range from $28 to $48 billion.57 Antimicrobial resistance is a major driver of mortality, increased length of hospital stay, and hospital costs associated with HAIs.24, 25 A recent review by Sipahi25 summarizes recent studies examining the impact of resistant and MDR bacterial infections (Figure 2).5866 It is dramatically clear that infections due to resistant and MDR bacteria more often result in death, are associated with longer hospital stays, and are considerably more expensive to treat.

Figure 2

A number of factors can lead to the increased hospital costs associated with infection with a resistant or MDR bacteria. These include the need to use more expensive antibiotics, increased length of hospital stay, delayed appropriate antibiotic therapy, increased treatment toxicity (and costs associated with managing these toxicities), and increased frequency of surgical interventions required to control infection.25, 67

The savings that could be realized through reduction in antimicrobial resistance was evaluated recently by Roberts et al.68 Using a sensitivity analysis for a sample of high‐risk adult patients hospitalized in an urban public teaching hospital in 2000, the authors determined that reducing the antimicrobial‐resistant infection rate by 3.5% (from 13.5% to 10.0%) would have saved the study hospital $910,812 (in 2008 US$), when using lowest cost and length of stay figures. The calculated societal savings, for reduced mortality and lost productivity associated with the reduced antimicrobial‐resistant rate, was $1.8 million. Hence, the analysis showed a minimum overall medical (hospital) and societal savings of $2.7 million for this single hospital with a cohort of 1391 patients. The projected savings would be dramatically higher if the reduced antimicrobial‐resistant rate was generalized to all hospitals throughout the United States.

ORGANIZATIONAL AND GOVERNMENTAL EFFORTS ADDRESSING ANTIMICROBIAL RESISTANCE AND HAI_s

Given the relationships between antimicrobial use and resistance, and between antimicrobial resistance and morbidity, mortality, length of hospital stay, and healthcare costs, it is not surprising that we have seen a variety of programs and initiatives begun by either government agencies or healthcare organizations aimed at reducing antimicrobial resistance and HAIs.

ANTIMICROBIAL STEWARDSHIP IN HOSPITALS AND THE HOSPITALIST'S ROLE

As recently defined, antimicrobial stewardship is a system of personnel, informatics, data collection, and policy/procedures that promote the optimal selection, dosing, and duration of therapy for antimicrobial agents throughout the course of their use.20 In simple words, the right antibiotic, at the right dose, at the right time, and for the right duration. The primary goals of antimicrobial stewardship are to reduce patient morbidity and mortality, prevent or slow the emergence of antimicrobial resistance, and reduce adverse drug effects, including secondary infections, such as C difficile‐associated diarrhea.18, 20 Secondary goals include a reduction in hospital length of stay and healthcare expenditures, without adversely impacting quality of care. These goals are entirely in line with those of the hospitalist, who can play a critical role in the prevention and successful management of these infections. Optimal effects are expected when antimicrobial stewardship is combined with implementation of effective infection control measures within the hospital setting.

CONCLUSIONS

Healthcare‐associated infections are increasingly a cause of morbidity and mortality in the United States and other countries, and the management of HAIs is increasingly complicated by involvement of MDR pathogens. Antimicrobial‐resistant pathogens are also increasingly involved in infections occurring outside the hospital setting. Infections caused by resistant or MDR pathogens are associated with increased mortality, longer length of hospital stay, and higher healthcare costs. The prevalence of these dangerous bacteria affects antimicrobial choices across a wider range of patients, particularly when choosing empiric therapy. Together with infection control, antimicrobial stewardship is an attractive solution to the challenges posed by antimicrobial resistance. Development and implementation of an effective institutional antimicrobial stewardship program can improve clinical outcome, reduce antimicrobial resistance and other unintended consequences of antimicrobial overuse/misuse, and lower healthcare costs.

At the forefront of inpatient care, hospitalists are positioned as excellent champions of the principles and practices of antimicrobial stewardship. By adhering to the principles of optimal antimicrobial therapy in their clinical practice, hospitalists can improve care and help reduce resistance on a patient‐by‐patient basis. At the same time, they may achieve other key hospitalist goals by reducing length of stay and decreasing costs and utilization. Moreover, they are well positioned to participate in, and at times lead, hospital‐based antimicrobial stewardship programs. As such, hospitalists are expected to play a critical role in helping to solve the problems of antimicrobial resistance and suboptimal inpatient care, as we move further into the 21st century.

Healthcare‐associated infections (HAIs) are important causes of morbidity and mortality in the United States and other countries.13 Moreover, treatment of HAIs is frequently complicated by involvement of bacterial pathogens resistant to 1 or more antibiotics or antibiotic classes,4 and sometimes bacteria resistant to all or nearly all currently available agents.57 The rapid emergence of resistant bacteria both in and out of the hospital setting can affect empiric antimicrobial choices across all patients. The effort to avoid undertreating or not covering resistant bacteria can lead to overuse of wide‐spectrum antimicrobials. Antimicrobial useand especially antimicrobial overuse or misusehas been linked with increased antimicrobial resistance,817 leading to worsened clinical outcomes with increased length of hospital stay and healthcare costs. Table 1 defines the various lines of evidence supporting a causal relationship between antibiotic use and emergence of antimicrobial resistance.18, 19

Optimal management of patients with bacterial infections, both HAIs and those that originate in the community, involves a focus on treatment that maximizes clinical outcomes for the individual patient, while also inhibiting or slowing the development of antimicrobial resistance and its spread to other patients. Antimicrobial stewardship is a term describing the various clinical strategies that have been devised to maximize the benefits and minimize the costs of antimicrobial therapy through judicious use of these agents.18, 20, 21 This article examines the developing patterns of resistance among key bacterial pathogens in the hospital and associated healthcare settings, the costs associated with HAIs (specifically, those caused by resistant pathogens), and the various strategies or programs that have been developed by governmental agencies, individual healthcare institutions, and other organizations to optimize the use of antibiotics to improve patient outcomes and minimize healthcare costs. The value that the hospitalist can bring to the development and/or implementation of institutional antimicrobial stewardship programs is explored.

ANTIMICROBIAL RESISTANCE AND HAI TRENDS FOR KEY BACTERIAL PATHOGENS

Bacterial pathogens including Enterobacteriaceae (Klebsiella pneumoniae, Enterobacter spp, Escherichia coli, and Proteus spp, among others), Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecium22, 23 are increasingly prevalent in healthcare settings, and particularly troublesome to manage due to increasing resistance. Data from the Centers for Disease Control and Prevention's (CDC) National Healthcare Safety Network (NHSN) have shown that, in intensive care units (ICUs), 16% of HAIs are due to multidrug‐resistant (MDR) pathogens.4 These 16% have the highest mortality and length of hospital stay, and are associated with the highest healthcare costs.24, 25 Infections caused by MDR pathogens are more important than their actual numbers, because treatment decisions are driven by the intent to cover these MDR pathogens, even if that means providing excessively broad coverage for most patients. Moreover, the 16% mentioned above are only the tip of the iceberg, as many more HAIs will occur outside of the ICU, particularly catheter‐associated urinary tract infections (CAUTI) and surgical site infections, as these patients are often not sick enough to require ICU care. There is little information on the prevalence of HAIs outside of the ICU setting, the role of MDR bacteria in these infections, and the associated costs, mortality, and effects on length of stay.

K pneumoniae Carbapenemases and Community‐Acquired Methicillin‐Resistant Staphylococcus aureus

K pneumoniae carbapenemase (KPC) is a prime example of the emergence and rapid spread of a new resistance pattern that affects prescribing patterns. Emergence of KPC as the primary source of carbapenem resistance in Enterobacteriaceae26 is critically significant, as carbapenems are recommended first‐line therapy for serious infections caused by extended‐spectrum ‐lactamase (ESBL)‐producing K pneumoniae or other Enterobacteriaceae. One particularly remarkable fact about KPC‐producing bacteria is the speed at which they have spread since first emerging. Figure 1 from the CDC illustrates the rapid spread of KPC‐producing bacteria within the United States, from winter 2008 to May 2010. International spread has also been rapid and extensive. The first case of a KPC‐producing bacteria outside the United States was reported in France in February 2005, in an 80‐year‐old man who was admitted to a Parisian hospital 2 to 3 months after having a medical procedure performed in a New York City hospital, suggesting intercontinental transfer from the United States.27 Since then, KPC‐producing pathogenic bacteria have been identified in the Caribbean, South America, Europe, Israel, and China.2830 It is clear that once resistant bacteria emerge, they have the potential to spread very rapidly within and between countries, challenging currently available antimicrobial agents and complicating the treatment of serious infections.

Figure 1

Consideration of S aureus skin and skin‐structure infections highlights the fact that the barrier between hospital and community is now beginning to be crossed, further complicating prescribing decisions. The classic risk factors for resistance may no longer be reliable in determining best empiric treatment. In a landmark study, Moran et al. demonstrated the large percentages of outpatients in the United States with skin or soft‐tissue infections (SSTIs) involving community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA).31 S aureus was isolated from 76% (320/422) of adults presenting to 11 university‐affiliated emergency departments with acute, purulent SSTIs in August 2004, 59% of whom were infected with MRSA. More than half the patients in the study (57%) were initially treated with antibiotics to which MRSA isolates were not susceptible.31 In the hospital, it has been shown that most invasive MRSA infections now actually have their onset outside of the healthcare setting,32 and that increasing numbers of hospitalized patients are now developing infections associated with CA‐MRSA strains >72 hours after admission.3338 Thus, it is becoming increasingly difficult to determine whether an invasive S aureus infection encountered in either a healthcare facility or community setting involves a sensitive organism, healthcare‐associated MRSA, or a CA‐MRSA pathogen, directly impacting treatment choices across all patients we care for with skin and skin‐structure infections.

COSTS OF HAI_s AND ANTIMICROBIAL RESISTANCE

HAIs are an important and growing problem in the United States.56 Klevens et al. estimated that approximately 1.7 million individuals hospitalized in the United States in 2002 had HAI, leading to 98,987 deaths.1 Estimates of annual hospital costs in the United States related to HAIs range from $28 to $48 billion.57 Antimicrobial resistance is a major driver of mortality, increased length of hospital stay, and hospital costs associated with HAIs.24, 25 A recent review by Sipahi25 summarizes recent studies examining the impact of resistant and MDR bacterial infections (Figure 2).5866 It is dramatically clear that infections due to resistant and MDR bacteria more often result in death, are associated with longer hospital stays, and are considerably more expensive to treat.

Figure 2

A number of factors can lead to the increased hospital costs associated with infection with a resistant or MDR bacteria. These include the need to use more expensive antibiotics, increased length of hospital stay, delayed appropriate antibiotic therapy, increased treatment toxicity (and costs associated with managing these toxicities), and increased frequency of surgical interventions required to control infection.25, 67

The savings that could be realized through reduction in antimicrobial resistance was evaluated recently by Roberts et al.68 Using a sensitivity analysis for a sample of high‐risk adult patients hospitalized in an urban public teaching hospital in 2000, the authors determined that reducing the antimicrobial‐resistant infection rate by 3.5% (from 13.5% to 10.0%) would have saved the study hospital $910,812 (in 2008 US$), when using lowest cost and length of stay figures. The calculated societal savings, for reduced mortality and lost productivity associated with the reduced antimicrobial‐resistant rate, was $1.8 million. Hence, the analysis showed a minimum overall medical (hospital) and societal savings of $2.7 million for this single hospital with a cohort of 1391 patients. The projected savings would be dramatically higher if the reduced antimicrobial‐resistant rate was generalized to all hospitals throughout the United States.

ORGANIZATIONAL AND GOVERNMENTAL EFFORTS ADDRESSING ANTIMICROBIAL RESISTANCE AND HAI_s

Given the relationships between antimicrobial use and resistance, and between antimicrobial resistance and morbidity, mortality, length of hospital stay, and healthcare costs, it is not surprising that we have seen a variety of programs and initiatives begun by either government agencies or healthcare organizations aimed at reducing antimicrobial resistance and HAIs.

ANTIMICROBIAL STEWARDSHIP IN HOSPITALS AND THE HOSPITALIST'S ROLE

As recently defined, antimicrobial stewardship is a system of personnel, informatics, data collection, and policy/procedures that promote the optimal selection, dosing, and duration of therapy for antimicrobial agents throughout the course of their use.20 In simple words, the right antibiotic, at the right dose, at the right time, and for the right duration. The primary goals of antimicrobial stewardship are to reduce patient morbidity and mortality, prevent or slow the emergence of antimicrobial resistance, and reduce adverse drug effects, including secondary infections, such as C difficile‐associated diarrhea.18, 20 Secondary goals include a reduction in hospital length of stay and healthcare expenditures, without adversely impacting quality of care. These goals are entirely in line with those of the hospitalist, who can play a critical role in the prevention and successful management of these infections. Optimal effects are expected when antimicrobial stewardship is combined with implementation of effective infection control measures within the hospital setting.

CONCLUSIONS

Healthcare‐associated infections are increasingly a cause of morbidity and mortality in the United States and other countries, and the management of HAIs is increasingly complicated by involvement of MDR pathogens. Antimicrobial‐resistant pathogens are also increasingly involved in infections occurring outside the hospital setting. Infections caused by resistant or MDR pathogens are associated with increased mortality, longer length of hospital stay, and higher healthcare costs. The prevalence of these dangerous bacteria affects antimicrobial choices across a wider range of patients, particularly when choosing empiric therapy. Together with infection control, antimicrobial stewardship is an attractive solution to the challenges posed by antimicrobial resistance. Development and implementation of an effective institutional antimicrobial stewardship program can improve clinical outcome, reduce antimicrobial resistance and other unintended consequences of antimicrobial overuse/misuse, and lower healthcare costs.

At the forefront of inpatient care, hospitalists are positioned as excellent champions of the principles and practices of antimicrobial stewardship. By adhering to the principles of optimal antimicrobial therapy in their clinical practice, hospitalists can improve care and help reduce resistance on a patient‐by‐patient basis. At the same time, they may achieve other key hospitalist goals by reducing length of stay and decreasing costs and utilization. Moreover, they are well positioned to participate in, and at times lead, hospital‐based antimicrobial stewardship programs. As such, hospitalists are expected to play a critical role in helping to solve the problems of antimicrobial resistance and suboptimal inpatient care, as we move further into the 21st century.

Healthcare‐associated infections (HAIs) are important causes of morbidity and mortality in the United States and other countries.13 Moreover, treatment of HAIs is frequently complicated by involvement of bacterial pathogens resistant to 1 or more antibiotics or antibiotic classes,4 and sometimes bacteria resistant to all or nearly all currently available agents.57 The rapid emergence of resistant bacteria both in and out of the hospital setting can affect empiric antimicrobial choices across all patients. The effort to avoid undertreating or not covering resistant bacteria can lead to overuse of wide‐spectrum antimicrobials. Antimicrobial useand especially antimicrobial overuse or misusehas been linked with increased antimicrobial resistance,817 leading to worsened clinical outcomes with increased length of hospital stay and healthcare costs. Table 1 defines the various lines of evidence supporting a causal relationship between antibiotic use and emergence of antimicrobial resistance.18, 19

Optimal management of patients with bacterial infections, both HAIs and those that originate in the community, involves a focus on treatment that maximizes clinical outcomes for the individual patient, while also inhibiting or slowing the development of antimicrobial resistance and its spread to other patients. Antimicrobial stewardship is a term describing the various clinical strategies that have been devised to maximize the benefits and minimize the costs of antimicrobial therapy through judicious use of these agents.18, 20, 21 This article examines the developing patterns of resistance among key bacterial pathogens in the hospital and associated healthcare settings, the costs associated with HAIs (specifically, those caused by resistant pathogens), and the various strategies or programs that have been developed by governmental agencies, individual healthcare institutions, and other organizations to optimize the use of antibiotics to improve patient outcomes and minimize healthcare costs. The value that the hospitalist can bring to the development and/or implementation of institutional antimicrobial stewardship programs is explored.

ANTIMICROBIAL RESISTANCE AND HAI TRENDS FOR KEY BACTERIAL PATHOGENS

Bacterial pathogens including Enterobacteriaceae (Klebsiella pneumoniae, Enterobacter spp, Escherichia coli, and Proteus spp, among others), Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecium22, 23 are increasingly prevalent in healthcare settings, and particularly troublesome to manage due to increasing resistance. Data from the Centers for Disease Control and Prevention's (CDC) National Healthcare Safety Network (NHSN) have shown that, in intensive care units (ICUs), 16% of HAIs are due to multidrug‐resistant (MDR) pathogens.4 These 16% have the highest mortality and length of hospital stay, and are associated with the highest healthcare costs.24, 25 Infections caused by MDR pathogens are more important than their actual numbers, because treatment decisions are driven by the intent to cover these MDR pathogens, even if that means providing excessively broad coverage for most patients. Moreover, the 16% mentioned above are only the tip of the iceberg, as many more HAIs will occur outside of the ICU, particularly catheter‐associated urinary tract infections (CAUTI) and surgical site infections, as these patients are often not sick enough to require ICU care. There is little information on the prevalence of HAIs outside of the ICU setting, the role of MDR bacteria in these infections, and the associated costs, mortality, and effects on length of stay.

K pneumoniae Carbapenemases and Community‐Acquired Methicillin‐Resistant Staphylococcus aureus

K pneumoniae carbapenemase (KPC) is a prime example of the emergence and rapid spread of a new resistance pattern that affects prescribing patterns. Emergence of KPC as the primary source of carbapenem resistance in Enterobacteriaceae26 is critically significant, as carbapenems are recommended first‐line therapy for serious infections caused by extended‐spectrum ‐lactamase (ESBL)‐producing K pneumoniae or other Enterobacteriaceae. One particularly remarkable fact about KPC‐producing bacteria is the speed at which they have spread since first emerging. Figure 1 from the CDC illustrates the rapid spread of KPC‐producing bacteria within the United States, from winter 2008 to May 2010. International spread has also been rapid and extensive. The first case of a KPC‐producing bacteria outside the United States was reported in France in February 2005, in an 80‐year‐old man who was admitted to a Parisian hospital 2 to 3 months after having a medical procedure performed in a New York City hospital, suggesting intercontinental transfer from the United States.27 Since then, KPC‐producing pathogenic bacteria have been identified in the Caribbean, South America, Europe, Israel, and China.2830 It is clear that once resistant bacteria emerge, they have the potential to spread very rapidly within and between countries, challenging currently available antimicrobial agents and complicating the treatment of serious infections.

Figure 1

Consideration of S aureus skin and skin‐structure infections highlights the fact that the barrier between hospital and community is now beginning to be crossed, further complicating prescribing decisions. The classic risk factors for resistance may no longer be reliable in determining best empiric treatment. In a landmark study, Moran et al. demonstrated the large percentages of outpatients in the United States with skin or soft‐tissue infections (SSTIs) involving community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA).31 S aureus was isolated from 76% (320/422) of adults presenting to 11 university‐affiliated emergency departments with acute, purulent SSTIs in August 2004, 59% of whom were infected with MRSA. More than half the patients in the study (57%) were initially treated with antibiotics to which MRSA isolates were not susceptible.31 In the hospital, it has been shown that most invasive MRSA infections now actually have their onset outside of the healthcare setting,32 and that increasing numbers of hospitalized patients are now developing infections associated with CA‐MRSA strains >72 hours after admission.3338 Thus, it is becoming increasingly difficult to determine whether an invasive S aureus infection encountered in either a healthcare facility or community setting involves a sensitive organism, healthcare‐associated MRSA, or a CA‐MRSA pathogen, directly impacting treatment choices across all patients we care for with skin and skin‐structure infections.

COSTS OF HAI_s AND ANTIMICROBIAL RESISTANCE

HAIs are an important and growing problem in the United States.56 Klevens et al. estimated that approximately 1.7 million individuals hospitalized in the United States in 2002 had HAI, leading to 98,987 deaths.1 Estimates of annual hospital costs in the United States related to HAIs range from $28 to $48 billion.57 Antimicrobial resistance is a major driver of mortality, increased length of hospital stay, and hospital costs associated with HAIs.24, 25 A recent review by Sipahi25 summarizes recent studies examining the impact of resistant and MDR bacterial infections (Figure 2).5866 It is dramatically clear that infections due to resistant and MDR bacteria more often result in death, are associated with longer hospital stays, and are considerably more expensive to treat.

Figure 2

A number of factors can lead to the increased hospital costs associated with infection with a resistant or MDR bacteria. These include the need to use more expensive antibiotics, increased length of hospital stay, delayed appropriate antibiotic therapy, increased treatment toxicity (and costs associated with managing these toxicities), and increased frequency of surgical interventions required to control infection.25, 67

The savings that could be realized through reduction in antimicrobial resistance was evaluated recently by Roberts et al.68 Using a sensitivity analysis for a sample of high‐risk adult patients hospitalized in an urban public teaching hospital in 2000, the authors determined that reducing the antimicrobial‐resistant infection rate by 3.5% (from 13.5% to 10.0%) would have saved the study hospital $910,812 (in 2008 US$), when using lowest cost and length of stay figures. The calculated societal savings, for reduced mortality and lost productivity associated with the reduced antimicrobial‐resistant rate, was $1.8 million. Hence, the analysis showed a minimum overall medical (hospital) and societal savings of $2.7 million for this single hospital with a cohort of 1391 patients. The projected savings would be dramatically higher if the reduced antimicrobial‐resistant rate was generalized to all hospitals throughout the United States.

ORGANIZATIONAL AND GOVERNMENTAL EFFORTS ADDRESSING ANTIMICROBIAL RESISTANCE AND HAI_s

Given the relationships between antimicrobial use and resistance, and between antimicrobial resistance and morbidity, mortality, length of hospital stay, and healthcare costs, it is not surprising that we have seen a variety of programs and initiatives begun by either government agencies or healthcare organizations aimed at reducing antimicrobial resistance and HAIs.

ANTIMICROBIAL STEWARDSHIP IN HOSPITALS AND THE HOSPITALIST'S ROLE

As recently defined, antimicrobial stewardship is a system of personnel, informatics, data collection, and policy/procedures that promote the optimal selection, dosing, and duration of therapy for antimicrobial agents throughout the course of their use.20 In simple words, the right antibiotic, at the right dose, at the right time, and for the right duration. The primary goals of antimicrobial stewardship are to reduce patient morbidity and mortality, prevent or slow the emergence of antimicrobial resistance, and reduce adverse drug effects, including secondary infections, such as C difficile‐associated diarrhea.18, 20 Secondary goals include a reduction in hospital length of stay and healthcare expenditures, without adversely impacting quality of care. These goals are entirely in line with those of the hospitalist, who can play a critical role in the prevention and successful management of these infections. Optimal effects are expected when antimicrobial stewardship is combined with implementation of effective infection control measures within the hospital setting.

CONCLUSIONS

Healthcare‐associated infections are increasingly a cause of morbidity and mortality in the United States and other countries, and the management of HAIs is increasingly complicated by involvement of MDR pathogens. Antimicrobial‐resistant pathogens are also increasingly involved in infections occurring outside the hospital setting. Infections caused by resistant or MDR pathogens are associated with increased mortality, longer length of hospital stay, and higher healthcare costs. The prevalence of these dangerous bacteria affects antimicrobial choices across a wider range of patients, particularly when choosing empiric therapy. Together with infection control, antimicrobial stewardship is an attractive solution to the challenges posed by antimicrobial resistance. Development and implementation of an effective institutional antimicrobial stewardship program can improve clinical outcome, reduce antimicrobial resistance and other unintended consequences of antimicrobial overuse/misuse, and lower healthcare costs.

At the forefront of inpatient care, hospitalists are positioned as excellent champions of the principles and practices of antimicrobial stewardship. By adhering to the principles of optimal antimicrobial therapy in their clinical practice, hospitalists can improve care and help reduce resistance on a patient‐by‐patient basis. At the same time, they may achieve other key hospitalist goals by reducing length of stay and decreasing costs and utilization. Moreover, they are well positioned to participate in, and at times lead, hospital‐based antimicrobial stewardship programs. As such, hospitalists are expected to play a critical role in helping to solve the problems of antimicrobial resistance and suboptimal inpatient care, as we move further into the 21st century.

Two conflicting aims collide when choosing initial empiric therapy for patients with a potential life‐threatening infection. On the one hand, the clinical picture and seriousness of the suspected infectionsometimes with a multi‐drug resistant (MDR) pathogenpoint to the need for immediate empiric therapy with a broad‐spectrum regimen covering the most likely pathogens. This getting it right the first time approach1 is clearly a reasonable one given the significant negative impact of inappropriate or inadequate initial therapy on patient outcomes and costs,24 and the apparent inability to remedy the initial error by subsequent antimicrobial regimen adjustment.57 On the other hand, use of a broad‐spectrum regimen increases the risk of emergent antimicrobial‐resistant pathogens, with potential harm for the immediate patient and all subsequent patients who become exposed and infected with the resistant pathogen. Hence, the aim of optimizing initial empiric therapy comes into conflict with an important aim of antimicrobial stewardship, namely, to use antimicrobials in a manner that does not excessively promote development or selection of antimicrobial‐resistant pathogens.

The de‐escalation strategy is an approach that attempts to balance these conflicting aims by providing optimal initial patient management without inordinately promoting development of antimicrobial resistance. As discussed more fully in the corresponding supplement article by Dr Syndman, the first part of this strategy involves collecting cultures from suitable patients prior to initiating broad‐spectrum empiric antimicrobial therapy designed to cover the most likely pathogenic microorganisms, based on local patterns of prevalence and susceptibility, and the presence of risk factors for infection with drug‐resistant species.810 The second critical step involves modification of initial empiric therapy (when warranted) based on clinical status and when culture results are available.810 In this manner, the initial broad‐spectrum regimen can often be streamlined or de‐escalated to a more narrow‐spectrum regimen or, in some cases, terminated when negative cultures suggest no infection. Frequently, initial combination therapy can be replaced by monotherapy targeting the pathogenic organism identified in culture. Sometimes culture results indicate that initial empiric therapy was inappropriate/emnadequate and requires replacement or other modification. Thus, by modifying empiric antimicrobial therapy on the basis of culture results and clinical criteria, the de‐escalation strategy enables more effective targeting of the causative pathogen(s), elimination of redundant therapy, a decrease in antimicrobial pressure for emergence of resistance, and cost savings.10, 11 Decreasing the number of antimicrobial agents and/or the spectrum of coverage is also expected to decrease the risk of adverse events, drugdrug interactions, and Clostridium difficile‐associated disease.12, 13 A number of studies have demonstrated that de‐escalation of initially appropriate therapy can be successfully accomplished with either improved outcomes14, 15 or with comparable effectiveness as continued initial therapy,1618 but with reduced antimicrobial exposure and costs.19

The timing of streamlining or other modification of initial empiric therapy typically occurs when microbiological culture results become available. Assuming blood or other relevant tissue cultures were obtained prior to initiating empiric therapy, this means de‐escalation or other modifications of initial therapy generally occurs 24 days after hospitalization and/or the beginning of empiric therapy. If rapid diagnostic tests are used to identify or rule out particular pathogens, then de‐escalation may occur slightly sooner. In addition to culture results, observation of the patient in the hospital setting and improved clarity as to his or her clinical status also affect the decision about whether and how to modify the initial empiric antimicrobial regimen. The clinical scenario of the patient and his or her response to initial antimicrobial therapy is also typically clearer by day 3 of antibiotic therapy. If, for some reason, cultures were not obtained prior to beginning empiric therapy, then observations of clinical status and consideration of patient risk factors for resistant pathogens become predominant in the decision‐making process. With respect to the timing of culture attainment, this should occur prior to beginning antimicrobial therapy, because therapy may reduce culture yield and result in false negative or other misleading findings.20, 21

CASE 1: HEALTHCARE‐ASSOCIATED PNEUMONIA

Case 1 is a 72‐year‐old woman admitted with findings consistent with healthcare‐associated pneumonia (HCAP). Empiric therapy was initiated with vancomycin and piperacillin/tazobactam. Figure 1 provides the laboratory (white blood cell [WBC] counts) and body temperature data for the patient since she entered the hospital and began empiric antibiotic therapy 3 days earlier. The WBC counts suggest the patient is responding to the antibiotic regimen, as demonstrated by a progressive reduction over the time period. However, her counts were still elevated above normal at last measurement, suggesting an incompletely resolved infection at this time. In addition, the patient is still coughing, but has less sputum production, and has some energy to get up and move around. Crackles are apparent at the right lung base. The patient's fever curve has trended down, but still shows notable fever spikes, with a temperature maximum of 101.4F for the past 24 hours. Her blood pressure (135/84 mmHg), pulse (74 bpm), and respiratory rate (14 breaths per minute) are normal, with slightly decreased oxygen saturation (94%) on room air, although improved from initial examination 3 days earlier (92%). The blood culture shows no growth; the sputum culture simply shows oropharyngeal flora. In other words, the culture results have not isolated a causative pathogen. In addition to vancomycin and piperacillin/tazobactam, the patient continues to receive her usual medications for a past history of myocardial infarction (low‐dose aspirin, metoprolol) and hypertension (enalapril, furosemide).

Figure 1

HCAP is a common infection often requiring initial empiric therapy with a broad‐spectrum regimen that covers possible involvement of resistant bacteria. As such, HCAP frequently provides excellent opportunities for de‐escalation. Figure 2 presents the general strategy from the 2005 American Thoracic Society and Infectious Diseases Society of America (ATS/IDSA) guidelines for the management of HCAP, hospital‐acquired pneumonia (HAP), or ventilator‐associated pneumonia (VAP).22 According to the guidelines, HCAP, HAP, and VAP should be similarly managed. Broad‐spectrum initial empiric antibiotic therapy is recommended for patients with late‐onset disease or those with risk factors for MDR pathogens (including high prevalence of resistance based on local antibiograms), while limited‐spectrum antibiotic therapy is recommended for all other patients. Note that consideration of de‐escalation or streamlining of initial therapy begins 2‐3 days after initiation of therapy. Data that should be reviewed prior to instituting de‐escalation include blood cultures and respiratory cultures, as well as the clinical status of the patient. The adequacy of respiratory samples used for culturing should factor into the decision‐making process. For example, in patients who are not intubated or mechanically ventilated, it can be challenging to obtain a quality respiratory specimen for culture. If clinicians are uncertain as to the quality of the respiratory specimen that was cultured, then de‐escalation decisions should be based more on the clinical status of the patient.

Figure 2

The clinical status of the patient, 2 days after beginning treatment, and culture results are critical in guiding the de‐escalation process.9, 22 The ATS/IDSA guidelines recommend serial assessments of clinical parameters to define the response to initial empiric therapy. If the therapy regimen is effective, an improvement in clinical response should be apparent within 2‐3 days of its initiation.22 Hence, no change in antimicrobial therapy should be undertaken before 3 days, unless there is evidence of rapid deterioration in clinical status or infectious diseases experts recommend a change. With respect to culture results, failure to isolate a group of MDR pathogens for which initial broad‐spectrum empiric therapy was selected affords an opportunity to now streamline therapy or treat with a more narrow‐spectrum regimen.9 Similarly, isolation of a particular pathogen can guide treatment modifications (when necessary), while a negative culture raises the possibility of terminating antimicrobial therapy, provided the culture was collected before initiating therapy. Confidence in this latter decision is bolstered when the patient exhibits rapid improvement in clinical status that is backed by radiographic resolution of lung abnormalities, or an alternative diagnosis has been established for which antimicrobial therapy is not indicated.9

At this stage in the process3 days after initiating empiric therapy, and with culture results in hand and evidence of clinical improvementthe first decision or question is whether antimicrobial therapy can be stopped altogether, ie, do the current data suggest a noninfectious diagnosis (eg, pulmonary embolism, atelectasis) or that bacterial pneumonia is unlikely or has resolved. A 2000 study by Singh et al. highlighted the feasibility of using operational criteria in the form of clinical pulmonary infection score (CPIS) to decide whether to terminate or shorten the duration of initial empiric antibiotic therapy for suspected VAP.23 More specifically, patients with pulmonary infiltrates but a low likelihood of pneumonia (CPIS 6) were randomized to receive either standard antibiotic therapy or ciprofloxacin monotherapy. The situation was re‐evaluated at 3 days, and ciprofloxacin therapy was discontinued if the CPIS remained 6. Results showed no difference in mortality between the ciprofloxacin and standard therapy groups, despite shorter duration of therapy for the former, together with lower antimicrobial exposure and costs for the ciprofloxacin group. (Use of the CPIS to shorten the duration of empiric therapy and limit antimicrobial exposure is discussed in greater detail in the corresponding article in this supplement by Dr File.) Having said that, the case study before us describes a patient with pneumonia by clinical criteria who has responded to broad‐spectrum therapy. Alternative noninfectious diagnoses are not apparent, and even though cultures have returned without significant growth, the patient should continue to receive antimicrobial treatment. The question now is whether to de‐escalate/streamline to a more narrow‐spectrum regimen, or continue the current one.

De‐escalation often targets antimicrobials that provide unnecessarily broad coverage, eg, those with antipseudomonal activity (particularly antipseudomonal carbapenems) and/or agents with activity against methicillin‐resistant Staphylococcus aureus (MRSA). In the absence of definitive culture results isolating a particular pathogen(s), decisions regarding which antibiotics to stop or change often depends, in large part, on patient characteristics (eg, history of prior infection with resistant pathogens, as well as drug allergies or renal insufficiency) and local antibiograms indicating the prevalence and antimicrobial susceptibility of different pneumonia pathogens in the hospital at large or particular wards within the hospital. However, negative culture results can also be useful in guiding subsequent therapy decisions or modifications. In the present case, MRSA was not grown from any cultures, and there was no evidence of Gram‐positive cocci clusters with Gram staining. This suggests that vancomycin should be stopped, and antimicrobial therapy continued with a single antibiotic or antibiotic product that does include MRSA coverage. The question then is whether to continue piperacillin/tazobactam or replace it with another antibiotic.

Because Pseudomonas aeruginosa was not isolated, the clinician might consider streamlining piperacillin/tazobactam to an antibiotic with less pseudomonal and anaerobic coverage, possibly a nonpseudomonal third‐generation cephalosporin or nonpseudomonal carbapenem, such as ertapenem. Given the activity of piperacillin/tazobactam against aerobic Gram‐positive and Gram‐negative pathogens, continuing piperacillin‐tazobactam as single‐agent therapy would also be a viable alternative. However, in the spirit of stewardship and lack of need for pseudomonal coverage, a decision was made to replace piperacillin/tazobactam with ceftriaxone. Ceftriaxone is a nonpseudomonal third‐generation cephalosporin with activity against most other Gram‐negative bacteria. Note that in this case, only oropharyngeal flora grew from the respiratory culture, and the blood culture was negative. However, if a pathogen had grown from either respiratory or blood cultures, then single‐agent therapy could have been used to target that specific pathogen. For example, if Klebsiella spp susceptible to ceftriaxone was isolated from the respiratory culture, then ceftriaxone would have been the obvious choice. If MRSA was isolated, then vancomycin (or another appropriate active agent, such as linezolid or clindamycin) could be administered as a single agent.

CASE 2: INTRA‐ABDOMINAL INFECTION (DIVERTICULITIS)

Case 2 is a 56‐year‐old woman who presents with a diverticular abscess and walled off perforation. Interventional radiology inserts a drain, and the patient is treated with ciprofloxacin plus metronidazole. This regimen is consistent with guidelines from the Surgical Infection Society and IDSA for initial empiric treatment of complicated intra‐abdominal infection of mild‐to‐moderate severity.24 On day 3 following hospital admission and initiation of empiric therapy, the patient seems to show treatment response, as evidenced by downward trends in body temperature and WBC count (Figure 3). However, although the body temperature measures are trending in the right direction, there is still concern about continuing fever spikes and fever at last measure (100.9F). In addition, the WBC count is still elevated, though improving. The patient's blood pressure has normalized (112/72 mmHg vs 84/58 mmHg at admission), and oxygen saturation (98%) measures are normal. The patient's lungs are clear, and her abdominal examination results are improving, though there is still some diffuse tenderness. Microbiological data show blood cultures with no growth, and isolation of Gram‐negative rods from cultures of the abdominal abscess.

Figure 3

We now have preliminary microbiological data for a patient who remains febrile and has continuing abdominal tenderness, but who is otherwise clinically stable. Can her antimicrobial regimen be de‐escalated at this point, based on what is currently known? When managing a patient after the first 3 or 4 days of empiric treatment, it is important to realize that the patient's condition with regards to infection might reflect issues unrelated to inadequate antimicrobial coverage. If the patient's clinical status has not improved, or if he or she remains febrile even 3 or 4 days into therapy, the clinician should not automatically assume the lack of improvement is due to antibiotic failure. At this point, it is important to consider possible nonantibiotic causes of persistent clinical abnormalities and fever, and for the case here, one possibility is inadequate abscess drainage. The patient should be evaluated with abdominal imaging to ascertain whether the abscess is being adequately drained. With respect to antimicrobial therapy, the patient's blood pressure has stabilized, and her fever is trending downward. In many cases, a lingering fever such as the one observed here, in the context of improving WBC counts and clinical stabilization, may reflect inadequate mechanical drainage of the abscess. Certainly the antimicrobial therapy should not be broadened at this time, and consideration should be given to de‐escalation based on the available microbiological data.

If a type of pathogenic organism is preliminarily identified from culture, but the exact identification of the organism is pending, adjustments of therapy can still be made. Adjustments can also be made based on what is not growing. In this case, the abscess culture has grown Gram‐negative rods, but no Gram‐positive organisms. Hence, continued coverage of Gram‐negative organisms is warranted. In addition, anaerobes often will not readily grow in clinical cultures, and because anaerobes are frequent co‐pathogens, it is appropriate to continue to provide anaerobic coverage. Based on this information, continuation of both ciprofloxacin (for aerobic Gram‐negative coverage) and metronidazole (to cover for anaerobic bacteria) is appropriate in the present case. In other words, the initial empiric therapy should be continued until subsequent culture identifies a particular pathogen, at which time the therapy can be streamlined.

Now, 1 day later (day 4 of hospital admission and empiric therapy), the patient's clinical status is essentially unchangedexcept for a spike in fever to 103.2F. The WBC count is unchanged. Moreover, additional abscess culture data are available, showing definitive identification of an extended‐spectrum ‐lactamase (ESBL)‐producing Escherichia coli organism. The blood culture is still negative. The first observation is that ESBL‐producing E coli is a relatively unusual pathogen in a community‐based infection. However, the patient here did have risk factors for antibiotic‐resistant pathogens, notably prior antimicrobial therapy as an outpatient. It is also important to recognize that community‐acquired infections with ESBL‐producing bacteria (mostly isolated from the urinary tract) have been reported in many parts of the world, and even in some parts of the United States.25

Based on these additional microbiological data, the patient was switched to treatment with ertapenem, a nonpseudomonal carbapenem with activity against ESBL‐producing Enterobacteriaceae.26 In addition, ertapenem, and other carbapenems, have excellent activity against anaerobes,26 and it is prudent to continue coverage for anaerobes even though anaerobes were not grown in the culture. As mentioned above, these organisms are difficult to grow in clinical culture, and they are common pathogens or co‐pathogens in intra‐abdominal infections. Carbapenems are widely regarded as the antimicrobials of choice for treatment of serious, invasive infections with ESBL‐producing bacteria.27 Furthermore, by choosing a nonpseudomonal carbapenem, compared with an antipseudomonal carbapenem, the new antibiotic regimen provides coverage of the isolated ESBL‐producing E coli organismas well as covering possible anaerobe involvementwithout exposing host bacteria to unnecessarily broad antipseudomonal activity. Cephalosporins, monobactams, and fluoroquinolones are generally not active against ESBL‐producing Enterobacteriaceae, and ‐lactam/‐lactamase inhibitor combinations (eg, ampicillin/sulbactam, piperacillin/tazobactam) do not have reliable activity in serious, high inoculum infections caused by ESBL‐producing Enterobacteriaceae.27

CASE 3: CENTRAL LINE‐ASSOCIATED BLOODSTREAM INFECTION

Case 3 is a 56‐year‐old man who presented to the hospital emergency department with status epilepticus. He was intubated, had a central line placed in the internal jugular vein, and was admitted to the intensive care unit (ICU). The seizure was successfully broken by aggressive treatment with repeated intravenous dosing of lorazepam and loading with fosphenytoin. Empiric antibiotic therapy was initiated with vancomycin and piperacillin/tazobactam on day 5, after spiking a fever of 103.4F. No clear source of the fever was identified. While in the ICU with a central line in place, 2 sets of blood cultures were drawn. Now on hospital day 6, the patient is still spiking fever, although the fever trend appears to be decreasing. The patient is hemodynamically stable, with no other abnormal findings (besides persistent fever) on physical examination. WBC count remains elevated, and both sets of blood cultures are notable for growth of Gram‐positive cocci.

Bloodstream infection is a serious condition in hospitalized patients that is associated with significant morbidity and mortality.28 Patients with suspected bloodstream infection typically receive empiric broad‐spectrum antimicrobial therapy, and are thus good candidates for de‐escalation based on subsequent clinical status and blood culture results. Because of the seriousness of bloodstream infection, healthcare workers are sometimes hesitant to de‐escalate initial empiric therapy, even when cultures isolate a pathogen susceptible to narrower‐spectrum agents, particularly if the patient appears to be improving on such therapy. This is true for various serious hospital or healthcare‐associated infections,16, 29 but particularly for bloodstream infections. Moreover, when central line‐associated bloodstream infection (CLABSI) is suspected, the most important initial intervention is to remove the infected central venous catheter. For a patient with a short‐term catheter and a CLABSI due to Gram‐negative bacilli, S aureus (which appears to be a likely pathogen for the case patient here), enterococci, fungi, or mycobacteria, the 2009 IDSA guidelines for management of intravascular catheter‐related infections recommend catheter removal.30 Catheter removal is even more important than antibiotic coverage; this point cannot be stressed enough. In some extreme cases, when the line cannot be removed for clinical reasons, antibiotic lock therapy can be used to supplement systemic antimicrobial therapy.30 This involves instilling a high antibiotic solution into the catheter lumen for a period of time in order to sterilize the lumen and prevent biofilm formation.31

The first step taken for the patient here was to remove the central venous catheter. Then, turning to the preliminary culture data, there is evidence for Gram‐positive cocci in the patient's blood. The blood culture did not grow any Gram‐negative organisms. Gram‐positive cocci (coagulase‐negative staphylococci, S aureus [methicillin‐susceptible or MRSA]) are the most common causes of CLABSI.32 Can the physician de‐escalate antibiotic therapy in this patient with CLABSI based on the preliminary information? Yes. The information is solid enough to suggest removal of the catheter which was providing coverage for Gram‐negative bacteria (piperacillin/tazobactam), while continuing vancomycin for coverage of possible MRSA, pending further review, ie, until the Gram‐positive cocci are speciated. Rapid diagnostic methods, including polymerase chain reaction (PCR) and nucleic acid probes, can be used to provide more information about certain pathogens (such as MRSA33, 34) before final culture and susceptibility results are available, but these are not routinely available in many clinical microbiology laboratories. Furthermore, these newer technologies remain fairly expensive.

Revisiting the patient 1 day later (hospital day 7), after narrowing the initial combination antibiotic regimen to vancomycin monotherapy, the physical examination indicates the patient is clinically stable, with continued improvement in fever and WBC count (Figure 4). Blood culture analysis now isolates methicillin‐susceptible S aureus (MSSA). Methicillin resistance mediates resistance to all ‐lactams, including carbapenems, greatly limiting treatment options. Vancomycin is the most commonly utilized antibiotic for the treatment of MRSA, and the recent clinical practice guidelines from the IDSA recommend either vancomycin or daptomycin for management of MRSA bacteremia in adult patients.35 However, antistaphylococcal penicillins and first‐generation cephalosporins are the antibiotics of choice for MSSA infections, and particularly for MSSA bloodstream infections.

Figure 4

The activity provided by vancomycin (or daptomycin) is overly broad if MSSA is involved, and importantly, it is not as effective as treatment with an antistaphylococcal penicillin or first‐generation cephalosporin. A recent study by Stryjewski et al., of hemodialysis patients with MSSA bacteremia, reported a higher proportion of treatment failure with vancomycin versus first‐generation cephalosporin therapy (31% vs 13%; P = 0.02).36 Furthermore, multivariate analysis identified vancomycin (vs first‐generation cephalosporin) use as a significant independent predictor of treatment failure (odds ratio [OR], 3.53; 95% confidence interval [CI], 1.1513.45; P = 0.04). Similarly, Chang et al. reported nafcillin, an antistaphylococcal penicillin, was superior to vancomycin in preventing bacteriologic failure (persistent failure and/or relapse) in patients with MSSA bacteremia (0% vs 19%; P = 0.058), and used multivariate analysis to identify vancomycin as a significant independent predictor of relapse (OR, 6.5; 95% CI, 1.052.8; P 0.05).37 Another recent study by Lodise et al. reported that initial empiric therapy with vancomycin for endocarditis caused by MSSA was associated with a higher infection‐related mortality rate than initial empiric therapy with a ‐lactam‐containing regimen (39% vs 11%; P = 0.005).38 The negative impact of initial treatment with vancomycin persisted even in patients switched to a ‐lactam therapy after culture results became available.

Hence, if a patient is being treated with vancomycin for a bloodstream (or other) infection due to MSSA, the therapy is suboptimal. In such a scenariowhich corresponds to that for the case patient herevancomycin should be discontinued and replaced with an antistaphylococcal penicillin or first‐generation cephalosporin. Many times, clinicians are resistant to terminating vancomycin and de‐escalating to antistaphylococcal penicillin/first‐generation cephalosporin therapy in a patient with bacteremia who is apparently responding to vancomycin. However, as the studies just reviewed make clear, not only is vancomycin treatment overly broad for the circumstance, it is also suboptimal and does not represent best clinical practice or patient care. Furthermore, continuing vancomycin in this situation unnecessarily exposes the patient to possible renal toxicity, particularly when aggressive dosing or prolonged vancomycin treatment is involved.39 Because of these issues and concerns, case 3 was de‐escalated from vancomycin to cefazolin, a first‐generation cephalosporin. One word of caution, however, is that there is some controversy over using cefazolin in patients with S aureus native valve endocarditis, given the possibility of a Type A ‐lactamase‐producing species causing cefazolin degradation.40 As a result, the clinician should first rule out endocarditis in the patient here before proceeding with cefazolin therapy. Another alternative would be to use an antistaphylococcal penicillin, such as nafcillin.

Finally, when dealing with bacteremia, and particularly when dealing with a possible CLABSI, the issue of potential culture contamination needs to be seriously considered and answered. Treating an actual infection, not what appears to be an infection because of culture contamination, is particularly important when dealing with possible CLABSI, because coagulase‐negative staphylococci (CoNS) are the most common cause of these types of infections,32 and CoNS are also frequent blood‐culture contaminants.41 Therefore, one needs to determine whether a blood culture growing a CoNS represents true bacteremia or simply contaminationwhich will obviously impact de‐escalation decisions.

In addition, when determining whether a blood culture is truly positive and clinically significant, it is important to consider whether the isolated pathogens are unlikely to be contaminants, likely to be contaminants, or the situation is unclear. A 2000 study by Kim et al.42 suggested that, among patients with 2 positive blood cultures for CoNS, routine identification of CoNS species and genotyping selected isolates using pulsed‐field gel electrophoresis may improve the process of discriminating contaminants from pathogens. Various additional factors need to be weighed when trying to interpret CoNS blood culture results, including patient risk factors, presence of prosthetic devices, number of blood cultures and number positive, and the antimicrobial sensitivity patterns of different isolates. For example, if the sensitivity patterns of 2 CoNS strains isolated from a patient are the same, the likelihood is increased that they represent true pathogens rather than contaminants. Figure 5 presents a schematic of this general approach.42

Figure 5

CONCLUSIONS

De‐escalation is a critical component of antimicrobial stewardship. As the prevalence of antimicrobial resistance grows in the hospital and community, de‐escalation will have an increasingly important role in limiting the further emergence of antimicrobial resistance. Pneumonia, intra‐abdominal infection, and bloodstream infection are commonly managed in the hospital setting. Each of these infection types presents excellent opportunities for de‐escalation, and each presents unique challenges and caveats. Concerted efforts must be made by clinicians and stewardship personnel to de‐escalate as soon as possible, based on culture results and clinical status. Although not discussed here, successful de‐escalation programs utilize structured process, guidelines, and algorithms to consistently implement de‐escalation efforts. These tools of implementation are more fully discussed in the corresponding article in this supplement by Dr Rosenberg.

Two conflicting aims collide when choosing initial empiric therapy for patients with a potential life‐threatening infection. On the one hand, the clinical picture and seriousness of the suspected infectionsometimes with a multi‐drug resistant (MDR) pathogenpoint to the need for immediate empiric therapy with a broad‐spectrum regimen covering the most likely pathogens. This getting it right the first time approach1 is clearly a reasonable one given the significant negative impact of inappropriate or inadequate initial therapy on patient outcomes and costs,24 and the apparent inability to remedy the initial error by subsequent antimicrobial regimen adjustment.57 On the other hand, use of a broad‐spectrum regimen increases the risk of emergent antimicrobial‐resistant pathogens, with potential harm for the immediate patient and all subsequent patients who become exposed and infected with the resistant pathogen. Hence, the aim of optimizing initial empiric therapy comes into conflict with an important aim of antimicrobial stewardship, namely, to use antimicrobials in a manner that does not excessively promote development or selection of antimicrobial‐resistant pathogens.

The de‐escalation strategy is an approach that attempts to balance these conflicting aims by providing optimal initial patient management without inordinately promoting development of antimicrobial resistance. As discussed more fully in the corresponding supplement article by Dr Syndman, the first part of this strategy involves collecting cultures from suitable patients prior to initiating broad‐spectrum empiric antimicrobial therapy designed to cover the most likely pathogenic microorganisms, based on local patterns of prevalence and susceptibility, and the presence of risk factors for infection with drug‐resistant species.810 The second critical step involves modification of initial empiric therapy (when warranted) based on clinical status and when culture results are available.810 In this manner, the initial broad‐spectrum regimen can often be streamlined or de‐escalated to a more narrow‐spectrum regimen or, in some cases, terminated when negative cultures suggest no infection. Frequently, initial combination therapy can be replaced by monotherapy targeting the pathogenic organism identified in culture. Sometimes culture results indicate that initial empiric therapy was inappropriate/emnadequate and requires replacement or other modification. Thus, by modifying empiric antimicrobial therapy on the basis of culture results and clinical criteria, the de‐escalation strategy enables more effective targeting of the causative pathogen(s), elimination of redundant therapy, a decrease in antimicrobial pressure for emergence of resistance, and cost savings.10, 11 Decreasing the number of antimicrobial agents and/or the spectrum of coverage is also expected to decrease the risk of adverse events, drugdrug interactions, and Clostridium difficile‐associated disease.12, 13 A number of studies have demonstrated that de‐escalation of initially appropriate therapy can be successfully accomplished with either improved outcomes14, 15 or with comparable effectiveness as continued initial therapy,1618 but with reduced antimicrobial exposure and costs.19

The timing of streamlining or other modification of initial empiric therapy typically occurs when microbiological culture results become available. Assuming blood or other relevant tissue cultures were obtained prior to initiating empiric therapy, this means de‐escalation or other modifications of initial therapy generally occurs 24 days after hospitalization and/or the beginning of empiric therapy. If rapid diagnostic tests are used to identify or rule out particular pathogens, then de‐escalation may occur slightly sooner. In addition to culture results, observation of the patient in the hospital setting and improved clarity as to his or her clinical status also affect the decision about whether and how to modify the initial empiric antimicrobial regimen. The clinical scenario of the patient and his or her response to initial antimicrobial therapy is also typically clearer by day 3 of antibiotic therapy. If, for some reason, cultures were not obtained prior to beginning empiric therapy, then observations of clinical status and consideration of patient risk factors for resistant pathogens become predominant in the decision‐making process. With respect to the timing of culture attainment, this should occur prior to beginning antimicrobial therapy, because therapy may reduce culture yield and result in false negative or other misleading findings.20, 21

CASE 1: HEALTHCARE‐ASSOCIATED PNEUMONIA

Case 1 is a 72‐year‐old woman admitted with findings consistent with healthcare‐associated pneumonia (HCAP). Empiric therapy was initiated with vancomycin and piperacillin/tazobactam. Figure 1 provides the laboratory (white blood cell [WBC] counts) and body temperature data for the patient since she entered the hospital and began empiric antibiotic therapy 3 days earlier. The WBC counts suggest the patient is responding to the antibiotic regimen, as demonstrated by a progressive reduction over the time period. However, her counts were still elevated above normal at last measurement, suggesting an incompletely resolved infection at this time. In addition, the patient is still coughing, but has less sputum production, and has some energy to get up and move around. Crackles are apparent at the right lung base. The patient's fever curve has trended down, but still shows notable fever spikes, with a temperature maximum of 101.4F for the past 24 hours. Her blood pressure (135/84 mmHg), pulse (74 bpm), and respiratory rate (14 breaths per minute) are normal, with slightly decreased oxygen saturation (94%) on room air, although improved from initial examination 3 days earlier (92%). The blood culture shows no growth; the sputum culture simply shows oropharyngeal flora. In other words, the culture results have not isolated a causative pathogen. In addition to vancomycin and piperacillin/tazobactam, the patient continues to receive her usual medications for a past history of myocardial infarction (low‐dose aspirin, metoprolol) and hypertension (enalapril, furosemide).

Figure 1

HCAP is a common infection often requiring initial empiric therapy with a broad‐spectrum regimen that covers possible involvement of resistant bacteria. As such, HCAP frequently provides excellent opportunities for de‐escalation. Figure 2 presents the general strategy from the 2005 American Thoracic Society and Infectious Diseases Society of America (ATS/IDSA) guidelines for the management of HCAP, hospital‐acquired pneumonia (HAP), or ventilator‐associated pneumonia (VAP).22 According to the guidelines, HCAP, HAP, and VAP should be similarly managed. Broad‐spectrum initial empiric antibiotic therapy is recommended for patients with late‐onset disease or those with risk factors for MDR pathogens (including high prevalence of resistance based on local antibiograms), while limited‐spectrum antibiotic therapy is recommended for all other patients. Note that consideration of de‐escalation or streamlining of initial therapy begins 2‐3 days after initiation of therapy. Data that should be reviewed prior to instituting de‐escalation include blood cultures and respiratory cultures, as well as the clinical status of the patient. The adequacy of respiratory samples used for culturing should factor into the decision‐making process. For example, in patients who are not intubated or mechanically ventilated, it can be challenging to obtain a quality respiratory specimen for culture. If clinicians are uncertain as to the quality of the respiratory specimen that was cultured, then de‐escalation decisions should be based more on the clinical status of the patient.

Figure 2

The clinical status of the patient, 2 days after beginning treatment, and culture results are critical in guiding the de‐escalation process.9, 22 The ATS/IDSA guidelines recommend serial assessments of clinical parameters to define the response to initial empiric therapy. If the therapy regimen is effective, an improvement in clinical response should be apparent within 2‐3 days of its initiation.22 Hence, no change in antimicrobial therapy should be undertaken before 3 days, unless there is evidence of rapid deterioration in clinical status or infectious diseases experts recommend a change. With respect to culture results, failure to isolate a group of MDR pathogens for which initial broad‐spectrum empiric therapy was selected affords an opportunity to now streamline therapy or treat with a more narrow‐spectrum regimen.9 Similarly, isolation of a particular pathogen can guide treatment modifications (when necessary), while a negative culture raises the possibility of terminating antimicrobial therapy, provided the culture was collected before initiating therapy. Confidence in this latter decision is bolstered when the patient exhibits rapid improvement in clinical status that is backed by radiographic resolution of lung abnormalities, or an alternative diagnosis has been established for which antimicrobial therapy is not indicated.9

At this stage in the process3 days after initiating empiric therapy, and with culture results in hand and evidence of clinical improvementthe first decision or question is whether antimicrobial therapy can be stopped altogether, ie, do the current data suggest a noninfectious diagnosis (eg, pulmonary embolism, atelectasis) or that bacterial pneumonia is unlikely or has resolved. A 2000 study by Singh et al. highlighted the feasibility of using operational criteria in the form of clinical pulmonary infection score (CPIS) to decide whether to terminate or shorten the duration of initial empiric antibiotic therapy for suspected VAP.23 More specifically, patients with pulmonary infiltrates but a low likelihood of pneumonia (CPIS 6) were randomized to receive either standard antibiotic therapy or ciprofloxacin monotherapy. The situation was re‐evaluated at 3 days, and ciprofloxacin therapy was discontinued if the CPIS remained 6. Results showed no difference in mortality between the ciprofloxacin and standard therapy groups, despite shorter duration of therapy for the former, together with lower antimicrobial exposure and costs for the ciprofloxacin group. (Use of the CPIS to shorten the duration of empiric therapy and limit antimicrobial exposure is discussed in greater detail in the corresponding article in this supplement by Dr File.) Having said that, the case study before us describes a patient with pneumonia by clinical criteria who has responded to broad‐spectrum therapy. Alternative noninfectious diagnoses are not apparent, and even though cultures have returned without significant growth, the patient should continue to receive antimicrobial treatment. The question now is whether to de‐escalate/streamline to a more narrow‐spectrum regimen, or continue the current one.

De‐escalation often targets antimicrobials that provide unnecessarily broad coverage, eg, those with antipseudomonal activity (particularly antipseudomonal carbapenems) and/or agents with activity against methicillin‐resistant Staphylococcus aureus (MRSA). In the absence of definitive culture results isolating a particular pathogen(s), decisions regarding which antibiotics to stop or change often depends, in large part, on patient characteristics (eg, history of prior infection with resistant pathogens, as well as drug allergies or renal insufficiency) and local antibiograms indicating the prevalence and antimicrobial susceptibility of different pneumonia pathogens in the hospital at large or particular wards within the hospital. However, negative culture results can also be useful in guiding subsequent therapy decisions or modifications. In the present case, MRSA was not grown from any cultures, and there was no evidence of Gram‐positive cocci clusters with Gram staining. This suggests that vancomycin should be stopped, and antimicrobial therapy continued with a single antibiotic or antibiotic product that does include MRSA coverage. The question then is whether to continue piperacillin/tazobactam or replace it with another antibiotic.

Because Pseudomonas aeruginosa was not isolated, the clinician might consider streamlining piperacillin/tazobactam to an antibiotic with less pseudomonal and anaerobic coverage, possibly a nonpseudomonal third‐generation cephalosporin or nonpseudomonal carbapenem, such as ertapenem. Given the activity of piperacillin/tazobactam against aerobic Gram‐positive and Gram‐negative pathogens, continuing piperacillin‐tazobactam as single‐agent therapy would also be a viable alternative. However, in the spirit of stewardship and lack of need for pseudomonal coverage, a decision was made to replace piperacillin/tazobactam with ceftriaxone. Ceftriaxone is a nonpseudomonal third‐generation cephalosporin with activity against most other Gram‐negative bacteria. Note that in this case, only oropharyngeal flora grew from the respiratory culture, and the blood culture was negative. However, if a pathogen had grown from either respiratory or blood cultures, then single‐agent therapy could have been used to target that specific pathogen. For example, if Klebsiella spp susceptible to ceftriaxone was isolated from the respiratory culture, then ceftriaxone would have been the obvious choice. If MRSA was isolated, then vancomycin (or another appropriate active agent, such as linezolid or clindamycin) could be administered as a single agent.

CASE 2: INTRA‐ABDOMINAL INFECTION (DIVERTICULITIS)

Case 2 is a 56‐year‐old woman who presents with a diverticular abscess and walled off perforation. Interventional radiology inserts a drain, and the patient is treated with ciprofloxacin plus metronidazole. This regimen is consistent with guidelines from the Surgical Infection Society and IDSA for initial empiric treatment of complicated intra‐abdominal infection of mild‐to‐moderate severity.24 On day 3 following hospital admission and initiation of empiric therapy, the patient seems to show treatment response, as evidenced by downward trends in body temperature and WBC count (Figure 3). However, although the body temperature measures are trending in the right direction, there is still concern about continuing fever spikes and fever at last measure (100.9F). In addition, the WBC count is still elevated, though improving. The patient's blood pressure has normalized (112/72 mmHg vs 84/58 mmHg at admission), and oxygen saturation (98%) measures are normal. The patient's lungs are clear, and her abdominal examination results are improving, though there is still some diffuse tenderness. Microbiological data show blood cultures with no growth, and isolation of Gram‐negative rods from cultures of the abdominal abscess.

Figure 3

We now have preliminary microbiological data for a patient who remains febrile and has continuing abdominal tenderness, but who is otherwise clinically stable. Can her antimicrobial regimen be de‐escalated at this point, based on what is currently known? When managing a patient after the first 3 or 4 days of empiric treatment, it is important to realize that the patient's condition with regards to infection might reflect issues unrelated to inadequate antimicrobial coverage. If the patient's clinical status has not improved, or if he or she remains febrile even 3 or 4 days into therapy, the clinician should not automatically assume the lack of improvement is due to antibiotic failure. At this point, it is important to consider possible nonantibiotic causes of persistent clinical abnormalities and fever, and for the case here, one possibility is inadequate abscess drainage. The patient should be evaluated with abdominal imaging to ascertain whether the abscess is being adequately drained. With respect to antimicrobial therapy, the patient's blood pressure has stabilized, and her fever is trending downward. In many cases, a lingering fever such as the one observed here, in the context of improving WBC counts and clinical stabilization, may reflect inadequate mechanical drainage of the abscess. Certainly the antimicrobial therapy should not be broadened at this time, and consideration should be given to de‐escalation based on the available microbiological data.

If a type of pathogenic organism is preliminarily identified from culture, but the exact identification of the organism is pending, adjustments of therapy can still be made. Adjustments can also be made based on what is not growing. In this case, the abscess culture has grown Gram‐negative rods, but no Gram‐positive organisms. Hence, continued coverage of Gram‐negative organisms is warranted. In addition, anaerobes often will not readily grow in clinical cultures, and because anaerobes are frequent co‐pathogens, it is appropriate to continue to provide anaerobic coverage. Based on this information, continuation of both ciprofloxacin (for aerobic Gram‐negative coverage) and metronidazole (to cover for anaerobic bacteria) is appropriate in the present case. In other words, the initial empiric therapy should be continued until subsequent culture identifies a particular pathogen, at which time the therapy can be streamlined.

Now, 1 day later (day 4 of hospital admission and empiric therapy), the patient's clinical status is essentially unchangedexcept for a spike in fever to 103.2F. The WBC count is unchanged. Moreover, additional abscess culture data are available, showing definitive identification of an extended‐spectrum ‐lactamase (ESBL)‐producing Escherichia coli organism. The blood culture is still negative. The first observation is that ESBL‐producing E coli is a relatively unusual pathogen in a community‐based infection. However, the patient here did have risk factors for antibiotic‐resistant pathogens, notably prior antimicrobial therapy as an outpatient. It is also important to recognize that community‐acquired infections with ESBL‐producing bacteria (mostly isolated from the urinary tract) have been reported in many parts of the world, and even in some parts of the United States.25

Based on these additional microbiological data, the patient was switched to treatment with ertapenem, a nonpseudomonal carbapenem with activity against ESBL‐producing Enterobacteriaceae.26 In addition, ertapenem, and other carbapenems, have excellent activity against anaerobes,26 and it is prudent to continue coverage for anaerobes even though anaerobes were not grown in the culture. As mentioned above, these organisms are difficult to grow in clinical culture, and they are common pathogens or co‐pathogens in intra‐abdominal infections. Carbapenems are widely regarded as the antimicrobials of choice for treatment of serious, invasive infections with ESBL‐producing bacteria.27 Furthermore, by choosing a nonpseudomonal carbapenem, compared with an antipseudomonal carbapenem, the new antibiotic regimen provides coverage of the isolated ESBL‐producing E coli organismas well as covering possible anaerobe involvementwithout exposing host bacteria to unnecessarily broad antipseudomonal activity. Cephalosporins, monobactams, and fluoroquinolones are generally not active against ESBL‐producing Enterobacteriaceae, and ‐lactam/‐lactamase inhibitor combinations (eg, ampicillin/sulbactam, piperacillin/tazobactam) do not have reliable activity in serious, high inoculum infections caused by ESBL‐producing Enterobacteriaceae.27

CASE 3: CENTRAL LINE‐ASSOCIATED BLOODSTREAM INFECTION

Case 3 is a 56‐year‐old man who presented to the hospital emergency department with status epilepticus. He was intubated, had a central line placed in the internal jugular vein, and was admitted to the intensive care unit (ICU). The seizure was successfully broken by aggressive treatment with repeated intravenous dosing of lorazepam and loading with fosphenytoin. Empiric antibiotic therapy was initiated with vancomycin and piperacillin/tazobactam on day 5, after spiking a fever of 103.4F. No clear source of the fever was identified. While in the ICU with a central line in place, 2 sets of blood cultures were drawn. Now on hospital day 6, the patient is still spiking fever, although the fever trend appears to be decreasing. The patient is hemodynamically stable, with no other abnormal findings (besides persistent fever) on physical examination. WBC count remains elevated, and both sets of blood cultures are notable for growth of Gram‐positive cocci.

Bloodstream infection is a serious condition in hospitalized patients that is associated with significant morbidity and mortality.28 Patients with suspected bloodstream infection typically receive empiric broad‐spectrum antimicrobial therapy, and are thus good candidates for de‐escalation based on subsequent clinical status and blood culture results. Because of the seriousness of bloodstream infection, healthcare workers are sometimes hesitant to de‐escalate initial empiric therapy, even when cultures isolate a pathogen susceptible to narrower‐spectrum agents, particularly if the patient appears to be improving on such therapy. This is true for various serious hospital or healthcare‐associated infections,16, 29 but particularly for bloodstream infections. Moreover, when central line‐associated bloodstream infection (CLABSI) is suspected, the most important initial intervention is to remove the infected central venous catheter. For a patient with a short‐term catheter and a CLABSI due to Gram‐negative bacilli, S aureus (which appears to be a likely pathogen for the case patient here), enterococci, fungi, or mycobacteria, the 2009 IDSA guidelines for management of intravascular catheter‐related infections recommend catheter removal.30 Catheter removal is even more important than antibiotic coverage; this point cannot be stressed enough. In some extreme cases, when the line cannot be removed for clinical reasons, antibiotic lock therapy can be used to supplement systemic antimicrobial therapy.30 This involves instilling a high antibiotic solution into the catheter lumen for a period of time in order to sterilize the lumen and prevent biofilm formation.31

The first step taken for the patient here was to remove the central venous catheter. Then, turning to the preliminary culture data, there is evidence for Gram‐positive cocci in the patient's blood. The blood culture did not grow any Gram‐negative organisms. Gram‐positive cocci (coagulase‐negative staphylococci, S aureus [methicillin‐susceptible or MRSA]) are the most common causes of CLABSI.32 Can the physician de‐escalate antibiotic therapy in this patient with CLABSI based on the preliminary information? Yes. The information is solid enough to suggest removal of the catheter which was providing coverage for Gram‐negative bacteria (piperacillin/tazobactam), while continuing vancomycin for coverage of possible MRSA, pending further review, ie, until the Gram‐positive cocci are speciated. Rapid diagnostic methods, including polymerase chain reaction (PCR) and nucleic acid probes, can be used to provide more information about certain pathogens (such as MRSA33, 34) before final culture and susceptibility results are available, but these are not routinely available in many clinical microbiology laboratories. Furthermore, these newer technologies remain fairly expensive.

Revisiting the patient 1 day later (hospital day 7), after narrowing the initial combination antibiotic regimen to vancomycin monotherapy, the physical examination indicates the patient is clinically stable, with continued improvement in fever and WBC count (Figure 4). Blood culture analysis now isolates methicillin‐susceptible S aureus (MSSA). Methicillin resistance mediates resistance to all ‐lactams, including carbapenems, greatly limiting treatment options. Vancomycin is the most commonly utilized antibiotic for the treatment of MRSA, and the recent clinical practice guidelines from the IDSA recommend either vancomycin or daptomycin for management of MRSA bacteremia in adult patients.35 However, antistaphylococcal penicillins and first‐generation cephalosporins are the antibiotics of choice for MSSA infections, and particularly for MSSA bloodstream infections.

Figure 4

The activity provided by vancomycin (or daptomycin) is overly broad if MSSA is involved, and importantly, it is not as effective as treatment with an antistaphylococcal penicillin or first‐generation cephalosporin. A recent study by Stryjewski et al., of hemodialysis patients with MSSA bacteremia, reported a higher proportion of treatment failure with vancomycin versus first‐generation cephalosporin therapy (31% vs 13%; P = 0.02).36 Furthermore, multivariate analysis identified vancomycin (vs first‐generation cephalosporin) use as a significant independent predictor of treatment failure (odds ratio [OR], 3.53; 95% confidence interval [CI], 1.1513.45; P = 0.04). Similarly, Chang et al. reported nafcillin, an antistaphylococcal penicillin, was superior to vancomycin in preventing bacteriologic failure (persistent failure and/or relapse) in patients with MSSA bacteremia (0% vs 19%; P = 0.058), and used multivariate analysis to identify vancomycin as a significant independent predictor of relapse (OR, 6.5; 95% CI, 1.052.8; P 0.05).37 Another recent study by Lodise et al. reported that initial empiric therapy with vancomycin for endocarditis caused by MSSA was associated with a higher infection‐related mortality rate than initial empiric therapy with a ‐lactam‐containing regimen (39% vs 11%; P = 0.005).38 The negative impact of initial treatment with vancomycin persisted even in patients switched to a ‐lactam therapy after culture results became available.

Hence, if a patient is being treated with vancomycin for a bloodstream (or other) infection due to MSSA, the therapy is suboptimal. In such a scenariowhich corresponds to that for the case patient herevancomycin should be discontinued and replaced with an antistaphylococcal penicillin or first‐generation cephalosporin. Many times, clinicians are resistant to terminating vancomycin and de‐escalating to antistaphylococcal penicillin/first‐generation cephalosporin therapy in a patient with bacteremia who is apparently responding to vancomycin. However, as the studies just reviewed make clear, not only is vancomycin treatment overly broad for the circumstance, it is also suboptimal and does not represent best clinical practice or patient care. Furthermore, continuing vancomycin in this situation unnecessarily exposes the patient to possible renal toxicity, particularly when aggressive dosing or prolonged vancomycin treatment is involved.39 Because of these issues and concerns, case 3 was de‐escalated from vancomycin to cefazolin, a first‐generation cephalosporin. One word of caution, however, is that there is some controversy over using cefazolin in patients with S aureus native valve endocarditis, given the possibility of a Type A ‐lactamase‐producing species causing cefazolin degradation.40 As a result, the clinician should first rule out endocarditis in the patient here before proceeding with cefazolin therapy. Another alternative would be to use an antistaphylococcal penicillin, such as nafcillin.

Finally, when dealing with bacteremia, and particularly when dealing with a possible CLABSI, the issue of potential culture contamination needs to be seriously considered and answered. Treating an actual infection, not what appears to be an infection because of culture contamination, is particularly important when dealing with possible CLABSI, because coagulase‐negative staphylococci (CoNS) are the most common cause of these types of infections,32 and CoNS are also frequent blood‐culture contaminants.41 Therefore, one needs to determine whether a blood culture growing a CoNS represents true bacteremia or simply contaminationwhich will obviously impact de‐escalation decisions.

In addition, when determining whether a blood culture is truly positive and clinically significant, it is important to consider whether the isolated pathogens are unlikely to be contaminants, likely to be contaminants, or the situation is unclear. A 2000 study by Kim et al.42 suggested that, among patients with 2 positive blood cultures for CoNS, routine identification of CoNS species and genotyping selected isolates using pulsed‐field gel electrophoresis may improve the process of discriminating contaminants from pathogens. Various additional factors need to be weighed when trying to interpret CoNS blood culture results, including patient risk factors, presence of prosthetic devices, number of blood cultures and number positive, and the antimicrobial sensitivity patterns of different isolates. For example, if the sensitivity patterns of 2 CoNS strains isolated from a patient are the same, the likelihood is increased that they represent true pathogens rather than contaminants. Figure 5 presents a schematic of this general approach.42

Figure 5

CONCLUSIONS

De‐escalation is a critical component of antimicrobial stewardship. As the prevalence of antimicrobial resistance grows in the hospital and community, de‐escalation will have an increasingly important role in limiting the further emergence of antimicrobial resistance. Pneumonia, intra‐abdominal infection, and bloodstream infection are commonly managed in the hospital setting. Each of these infection types presents excellent opportunities for de‐escalation, and each presents unique challenges and caveats. Concerted efforts must be made by clinicians and stewardship personnel to de‐escalate as soon as possible, based on culture results and clinical status. Although not discussed here, successful de‐escalation programs utilize structured process, guidelines, and algorithms to consistently implement de‐escalation efforts. These tools of implementation are more fully discussed in the corresponding article in this supplement by Dr Rosenberg.

Two conflicting aims collide when choosing initial empiric therapy for patients with a potential life‐threatening infection. On the one hand, the clinical picture and seriousness of the suspected infectionsometimes with a multi‐drug resistant (MDR) pathogenpoint to the need for immediate empiric therapy with a broad‐spectrum regimen covering the most likely pathogens. This getting it right the first time approach1 is clearly a reasonable one given the significant negative impact of inappropriate or inadequate initial therapy on patient outcomes and costs,24 and the apparent inability to remedy the initial error by subsequent antimicrobial regimen adjustment.57 On the other hand, use of a broad‐spectrum regimen increases the risk of emergent antimicrobial‐resistant pathogens, with potential harm for the immediate patient and all subsequent patients who become exposed and infected with the resistant pathogen. Hence, the aim of optimizing initial empiric therapy comes into conflict with an important aim of antimicrobial stewardship, namely, to use antimicrobials in a manner that does not excessively promote development or selection of antimicrobial‐resistant pathogens.

The de‐escalation strategy is an approach that attempts to balance these conflicting aims by providing optimal initial patient management without inordinately promoting development of antimicrobial resistance. As discussed more fully in the corresponding supplement article by Dr Syndman, the first part of this strategy involves collecting cultures from suitable patients prior to initiating broad‐spectrum empiric antimicrobial therapy designed to cover the most likely pathogenic microorganisms, based on local patterns of prevalence and susceptibility, and the presence of risk factors for infection with drug‐resistant species.810 The second critical step involves modification of initial empiric therapy (when warranted) based on clinical status and when culture results are available.810 In this manner, the initial broad‐spectrum regimen can often be streamlined or de‐escalated to a more narrow‐spectrum regimen or, in some cases, terminated when negative cultures suggest no infection. Frequently, initial combination therapy can be replaced by monotherapy targeting the pathogenic organism identified in culture. Sometimes culture results indicate that initial empiric therapy was inappropriate/emnadequate and requires replacement or other modification. Thus, by modifying empiric antimicrobial therapy on the basis of culture results and clinical criteria, the de‐escalation strategy enables more effective targeting of the causative pathogen(s), elimination of redundant therapy, a decrease in antimicrobial pressure for emergence of resistance, and cost savings.10, 11 Decreasing the number of antimicrobial agents and/or the spectrum of coverage is also expected to decrease the risk of adverse events, drugdrug interactions, and Clostridium difficile‐associated disease.12, 13 A number of studies have demonstrated that de‐escalation of initially appropriate therapy can be successfully accomplished with either improved outcomes14, 15 or with comparable effectiveness as continued initial therapy,1618 but with reduced antimicrobial exposure and costs.19

The timing of streamlining or other modification of initial empiric therapy typically occurs when microbiological culture results become available. Assuming blood or other relevant tissue cultures were obtained prior to initiating empiric therapy, this means de‐escalation or other modifications of initial therapy generally occurs 24 days after hospitalization and/or the beginning of empiric therapy. If rapid diagnostic tests are used to identify or rule out particular pathogens, then de‐escalation may occur slightly sooner. In addition to culture results, observation of the patient in the hospital setting and improved clarity as to his or her clinical status also affect the decision about whether and how to modify the initial empiric antimicrobial regimen. The clinical scenario of the patient and his or her response to initial antimicrobial therapy is also typically clearer by day 3 of antibiotic therapy. If, for some reason, cultures were not obtained prior to beginning empiric therapy, then observations of clinical status and consideration of patient risk factors for resistant pathogens become predominant in the decision‐making process. With respect to the timing of culture attainment, this should occur prior to beginning antimicrobial therapy, because therapy may reduce culture yield and result in false negative or other misleading findings.20, 21

CASE 1: HEALTHCARE‐ASSOCIATED PNEUMONIA

Case 1 is a 72‐year‐old woman admitted with findings consistent with healthcare‐associated pneumonia (HCAP). Empiric therapy was initiated with vancomycin and piperacillin/tazobactam. Figure 1 provides the laboratory (white blood cell [WBC] counts) and body temperature data for the patient since she entered the hospital and began empiric antibiotic therapy 3 days earlier. The WBC counts suggest the patient is responding to the antibiotic regimen, as demonstrated by a progressive reduction over the time period. However, her counts were still elevated above normal at last measurement, suggesting an incompletely resolved infection at this time. In addition, the patient is still coughing, but has less sputum production, and has some energy to get up and move around. Crackles are apparent at the right lung base. The patient's fever curve has trended down, but still shows notable fever spikes, with a temperature maximum of 101.4F for the past 24 hours. Her blood pressure (135/84 mmHg), pulse (74 bpm), and respiratory rate (14 breaths per minute) are normal, with slightly decreased oxygen saturation (94%) on room air, although improved from initial examination 3 days earlier (92%). The blood culture shows no growth; the sputum culture simply shows oropharyngeal flora. In other words, the culture results have not isolated a causative pathogen. In addition to vancomycin and piperacillin/tazobactam, the patient continues to receive her usual medications for a past history of myocardial infarction (low‐dose aspirin, metoprolol) and hypertension (enalapril, furosemide).

Figure 1

HCAP is a common infection often requiring initial empiric therapy with a broad‐spectrum regimen that covers possible involvement of resistant bacteria. As such, HCAP frequently provides excellent opportunities for de‐escalation. Figure 2 presents the general strategy from the 2005 American Thoracic Society and Infectious Diseases Society of America (ATS/IDSA) guidelines for the management of HCAP, hospital‐acquired pneumonia (HAP), or ventilator‐associated pneumonia (VAP).22 According to the guidelines, HCAP, HAP, and VAP should be similarly managed. Broad‐spectrum initial empiric antibiotic therapy is recommended for patients with late‐onset disease or those with risk factors for MDR pathogens (including high prevalence of resistance based on local antibiograms), while limited‐spectrum antibiotic therapy is recommended for all other patients. Note that consideration of de‐escalation or streamlining of initial therapy begins 2‐3 days after initiation of therapy. Data that should be reviewed prior to instituting de‐escalation include blood cultures and respiratory cultures, as well as the clinical status of the patient. The adequacy of respiratory samples used for culturing should factor into the decision‐making process. For example, in patients who are not intubated or mechanically ventilated, it can be challenging to obtain a quality respiratory specimen for culture. If clinicians are uncertain as to the quality of the respiratory specimen that was cultured, then de‐escalation decisions should be based more on the clinical status of the patient.

Figure 2

The clinical status of the patient, 2 days after beginning treatment, and culture results are critical in guiding the de‐escalation process.9, 22 The ATS/IDSA guidelines recommend serial assessments of clinical parameters to define the response to initial empiric therapy. If the therapy regimen is effective, an improvement in clinical response should be apparent within 2‐3 days of its initiation.22 Hence, no change in antimicrobial therapy should be undertaken before 3 days, unless there is evidence of rapid deterioration in clinical status or infectious diseases experts recommend a change. With respect to culture results, failure to isolate a group of MDR pathogens for which initial broad‐spectrum empiric therapy was selected affords an opportunity to now streamline therapy or treat with a more narrow‐spectrum regimen.9 Similarly, isolation of a particular pathogen can guide treatment modifications (when necessary), while a negative culture raises the possibility of terminating antimicrobial therapy, provided the culture was collected before initiating therapy. Confidence in this latter decision is bolstered when the patient exhibits rapid improvement in clinical status that is backed by radiographic resolution of lung abnormalities, or an alternative diagnosis has been established for which antimicrobial therapy is not indicated.9

At this stage in the process3 days after initiating empiric therapy, and with culture results in hand and evidence of clinical improvementthe first decision or question is whether antimicrobial therapy can be stopped altogether, ie, do the current data suggest a noninfectious diagnosis (eg, pulmonary embolism, atelectasis) or that bacterial pneumonia is unlikely or has resolved. A 2000 study by Singh et al. highlighted the feasibility of using operational criteria in the form of clinical pulmonary infection score (CPIS) to decide whether to terminate or shorten the duration of initial empiric antibiotic therapy for suspected VAP.23 More specifically, patients with pulmonary infiltrates but a low likelihood of pneumonia (CPIS 6) were randomized to receive either standard antibiotic therapy or ciprofloxacin monotherapy. The situation was re‐evaluated at 3 days, and ciprofloxacin therapy was discontinued if the CPIS remained 6. Results showed no difference in mortality between the ciprofloxacin and standard therapy groups, despite shorter duration of therapy for the former, together with lower antimicrobial exposure and costs for the ciprofloxacin group. (Use of the CPIS to shorten the duration of empiric therapy and limit antimicrobial exposure is discussed in greater detail in the corresponding article in this supplement by Dr File.) Having said that, the case study before us describes a patient with pneumonia by clinical criteria who has responded to broad‐spectrum therapy. Alternative noninfectious diagnoses are not apparent, and even though cultures have returned without significant growth, the patient should continue to receive antimicrobial treatment. The question now is whether to de‐escalate/streamline to a more narrow‐spectrum regimen, or continue the current one.

De‐escalation often targets antimicrobials that provide unnecessarily broad coverage, eg, those with antipseudomonal activity (particularly antipseudomonal carbapenems) and/or agents with activity against methicillin‐resistant Staphylococcus aureus (MRSA). In the absence of definitive culture results isolating a particular pathogen(s), decisions regarding which antibiotics to stop or change often depends, in large part, on patient characteristics (eg, history of prior infection with resistant pathogens, as well as drug allergies or renal insufficiency) and local antibiograms indicating the prevalence and antimicrobial susceptibility of different pneumonia pathogens in the hospital at large or particular wards within the hospital. However, negative culture results can also be useful in guiding subsequent therapy decisions or modifications. In the present case, MRSA was not grown from any cultures, and there was no evidence of Gram‐positive cocci clusters with Gram staining. This suggests that vancomycin should be stopped, and antimicrobial therapy continued with a single antibiotic or antibiotic product that does include MRSA coverage. The question then is whether to continue piperacillin/tazobactam or replace it with another antibiotic.

Because Pseudomonas aeruginosa was not isolated, the clinician might consider streamlining piperacillin/tazobactam to an antibiotic with less pseudomonal and anaerobic coverage, possibly a nonpseudomonal third‐generation cephalosporin or nonpseudomonal carbapenem, such as ertapenem. Given the activity of piperacillin/tazobactam against aerobic Gram‐positive and Gram‐negative pathogens, continuing piperacillin‐tazobactam as single‐agent therapy would also be a viable alternative. However, in the spirit of stewardship and lack of need for pseudomonal coverage, a decision was made to replace piperacillin/tazobactam with ceftriaxone. Ceftriaxone is a nonpseudomonal third‐generation cephalosporin with activity against most other Gram‐negative bacteria. Note that in this case, only oropharyngeal flora grew from the respiratory culture, and the blood culture was negative. However, if a pathogen had grown from either respiratory or blood cultures, then single‐agent therapy could have been used to target that specific pathogen. For example, if Klebsiella spp susceptible to ceftriaxone was isolated from the respiratory culture, then ceftriaxone would have been the obvious choice. If MRSA was isolated, then vancomycin (or another appropriate active agent, such as linezolid or clindamycin) could be administered as a single agent.

CASE 2: INTRA‐ABDOMINAL INFECTION (DIVERTICULITIS)

Case 2 is a 56‐year‐old woman who presents with a diverticular abscess and walled off perforation. Interventional radiology inserts a drain, and the patient is treated with ciprofloxacin plus metronidazole. This regimen is consistent with guidelines from the Surgical Infection Society and IDSA for initial empiric treatment of complicated intra‐abdominal infection of mild‐to‐moderate severity.24 On day 3 following hospital admission and initiation of empiric therapy, the patient seems to show treatment response, as evidenced by downward trends in body temperature and WBC count (Figure 3). However, although the body temperature measures are trending in the right direction, there is still concern about continuing fever spikes and fever at last measure (100.9F). In addition, the WBC count is still elevated, though improving. The patient's blood pressure has normalized (112/72 mmHg vs 84/58 mmHg at admission), and oxygen saturation (98%) measures are normal. The patient's lungs are clear, and her abdominal examination results are improving, though there is still some diffuse tenderness. Microbiological data show blood cultures with no growth, and isolation of Gram‐negative rods from cultures of the abdominal abscess.

Figure 3

We now have preliminary microbiological data for a patient who remains febrile and has continuing abdominal tenderness, but who is otherwise clinically stable. Can her antimicrobial regimen be de‐escalated at this point, based on what is currently known? When managing a patient after the first 3 or 4 days of empiric treatment, it is important to realize that the patient's condition with regards to infection might reflect issues unrelated to inadequate antimicrobial coverage. If the patient's clinical status has not improved, or if he or she remains febrile even 3 or 4 days into therapy, the clinician should not automatically assume the lack of improvement is due to antibiotic failure. At this point, it is important to consider possible nonantibiotic causes of persistent clinical abnormalities and fever, and for the case here, one possibility is inadequate abscess drainage. The patient should be evaluated with abdominal imaging to ascertain whether the abscess is being adequately drained. With respect to antimicrobial therapy, the patient's blood pressure has stabilized, and her fever is trending downward. In many cases, a lingering fever such as the one observed here, in the context of improving WBC counts and clinical stabilization, may reflect inadequate mechanical drainage of the abscess. Certainly the antimicrobial therapy should not be broadened at this time, and consideration should be given to de‐escalation based on the available microbiological data.

If a type of pathogenic organism is preliminarily identified from culture, but the exact identification of the organism is pending, adjustments of therapy can still be made. Adjustments can also be made based on what is not growing. In this case, the abscess culture has grown Gram‐negative rods, but no Gram‐positive organisms. Hence, continued coverage of Gram‐negative organisms is warranted. In addition, anaerobes often will not readily grow in clinical cultures, and because anaerobes are frequent co‐pathogens, it is appropriate to continue to provide anaerobic coverage. Based on this information, continuation of both ciprofloxacin (for aerobic Gram‐negative coverage) and metronidazole (to cover for anaerobic bacteria) is appropriate in the present case. In other words, the initial empiric therapy should be continued until subsequent culture identifies a particular pathogen, at which time the therapy can be streamlined.

Now, 1 day later (day 4 of hospital admission and empiric therapy), the patient's clinical status is essentially unchangedexcept for a spike in fever to 103.2F. The WBC count is unchanged. Moreover, additional abscess culture data are available, showing definitive identification of an extended‐spectrum ‐lactamase (ESBL)‐producing Escherichia coli organism. The blood culture is still negative. The first observation is that ESBL‐producing E coli is a relatively unusual pathogen in a community‐based infection. However, the patient here did have risk factors for antibiotic‐resistant pathogens, notably prior antimicrobial therapy as an outpatient. It is also important to recognize that community‐acquired infections with ESBL‐producing bacteria (mostly isolated from the urinary tract) have been reported in many parts of the world, and even in some parts of the United States.25

Based on these additional microbiological data, the patient was switched to treatment with ertapenem, a nonpseudomonal carbapenem with activity against ESBL‐producing Enterobacteriaceae.26 In addition, ertapenem, and other carbapenems, have excellent activity against anaerobes,26 and it is prudent to continue coverage for anaerobes even though anaerobes were not grown in the culture. As mentioned above, these organisms are difficult to grow in clinical culture, and they are common pathogens or co‐pathogens in intra‐abdominal infections. Carbapenems are widely regarded as the antimicrobials of choice for treatment of serious, invasive infections with ESBL‐producing bacteria.27 Furthermore, by choosing a nonpseudomonal carbapenem, compared with an antipseudomonal carbapenem, the new antibiotic regimen provides coverage of the isolated ESBL‐producing E coli organismas well as covering possible anaerobe involvementwithout exposing host bacteria to unnecessarily broad antipseudomonal activity. Cephalosporins, monobactams, and fluoroquinolones are generally not active against ESBL‐producing Enterobacteriaceae, and ‐lactam/‐lactamase inhibitor combinations (eg, ampicillin/sulbactam, piperacillin/tazobactam) do not have reliable activity in serious, high inoculum infections caused by ESBL‐producing Enterobacteriaceae.27

CASE 3: CENTRAL LINE‐ASSOCIATED BLOODSTREAM INFECTION

Case 3 is a 56‐year‐old man who presented to the hospital emergency department with status epilepticus. He was intubated, had a central line placed in the internal jugular vein, and was admitted to the intensive care unit (ICU). The seizure was successfully broken by aggressive treatment with repeated intravenous dosing of lorazepam and loading with fosphenytoin. Empiric antibiotic therapy was initiated with vancomycin and piperacillin/tazobactam on day 5, after spiking a fever of 103.4F. No clear source of the fever was identified. While in the ICU with a central line in place, 2 sets of blood cultures were drawn. Now on hospital day 6, the patient is still spiking fever, although the fever trend appears to be decreasing. The patient is hemodynamically stable, with no other abnormal findings (besides persistent fever) on physical examination. WBC count remains elevated, and both sets of blood cultures are notable for growth of Gram‐positive cocci.

Bloodstream infection is a serious condition in hospitalized patients that is associated with significant morbidity and mortality.28 Patients with suspected bloodstream infection typically receive empiric broad‐spectrum antimicrobial therapy, and are thus good candidates for de‐escalation based on subsequent clinical status and blood culture results. Because of the seriousness of bloodstream infection, healthcare workers are sometimes hesitant to de‐escalate initial empiric therapy, even when cultures isolate a pathogen susceptible to narrower‐spectrum agents, particularly if the patient appears to be improving on such therapy. This is true for various serious hospital or healthcare‐associated infections,16, 29 but particularly for bloodstream infections. Moreover, when central line‐associated bloodstream infection (CLABSI) is suspected, the most important initial intervention is to remove the infected central venous catheter. For a patient with a short‐term catheter and a CLABSI due to Gram‐negative bacilli, S aureus (which appears to be a likely pathogen for the case patient here), enterococci, fungi, or mycobacteria, the 2009 IDSA guidelines for management of intravascular catheter‐related infections recommend catheter removal.30 Catheter removal is even more important than antibiotic coverage; this point cannot be stressed enough. In some extreme cases, when the line cannot be removed for clinical reasons, antibiotic lock therapy can be used to supplement systemic antimicrobial therapy.30 This involves instilling a high antibiotic solution into the catheter lumen for a period of time in order to sterilize the lumen and prevent biofilm formation.31

The first step taken for the patient here was to remove the central venous catheter. Then, turning to the preliminary culture data, there is evidence for Gram‐positive cocci in the patient's blood. The blood culture did not grow any Gram‐negative organisms. Gram‐positive cocci (coagulase‐negative staphylococci, S aureus [methicillin‐susceptible or MRSA]) are the most common causes of CLABSI.32 Can the physician de‐escalate antibiotic therapy in this patient with CLABSI based on the preliminary information? Yes. The information is solid enough to suggest removal of the catheter which was providing coverage for Gram‐negative bacteria (piperacillin/tazobactam), while continuing vancomycin for coverage of possible MRSA, pending further review, ie, until the Gram‐positive cocci are speciated. Rapid diagnostic methods, including polymerase chain reaction (PCR) and nucleic acid probes, can be used to provide more information about certain pathogens (such as MRSA33, 34) before final culture and susceptibility results are available, but these are not routinely available in many clinical microbiology laboratories. Furthermore, these newer technologies remain fairly expensive.

Revisiting the patient 1 day later (hospital day 7), after narrowing the initial combination antibiotic regimen to vancomycin monotherapy, the physical examination indicates the patient is clinically stable, with continued improvement in fever and WBC count (Figure 4). Blood culture analysis now isolates methicillin‐susceptible S aureus (MSSA). Methicillin resistance mediates resistance to all ‐lactams, including carbapenems, greatly limiting treatment options. Vancomycin is the most commonly utilized antibiotic for the treatment of MRSA, and the recent clinical practice guidelines from the IDSA recommend either vancomycin or daptomycin for management of MRSA bacteremia in adult patients.35 However, antistaphylococcal penicillins and first‐generation cephalosporins are the antibiotics of choice for MSSA infections, and particularly for MSSA bloodstream infections.

Figure 4

The activity provided by vancomycin (or daptomycin) is overly broad if MSSA is involved, and importantly, it is not as effective as treatment with an antistaphylococcal penicillin or first‐generation cephalosporin. A recent study by Stryjewski et al., of hemodialysis patients with MSSA bacteremia, reported a higher proportion of treatment failure with vancomycin versus first‐generation cephalosporin therapy (31% vs 13%; P = 0.02).36 Furthermore, multivariate analysis identified vancomycin (vs first‐generation cephalosporin) use as a significant independent predictor of treatment failure (odds ratio [OR], 3.53; 95% confidence interval [CI], 1.1513.45; P = 0.04). Similarly, Chang et al. reported nafcillin, an antistaphylococcal penicillin, was superior to vancomycin in preventing bacteriologic failure (persistent failure and/or relapse) in patients with MSSA bacteremia (0% vs 19%; P = 0.058), and used multivariate analysis to identify vancomycin as a significant independent predictor of relapse (OR, 6.5; 95% CI, 1.052.8; P 0.05).37 Another recent study by Lodise et al. reported that initial empiric therapy with vancomycin for endocarditis caused by MSSA was associated with a higher infection‐related mortality rate than initial empiric therapy with a ‐lactam‐containing regimen (39% vs 11%; P = 0.005).38 The negative impact of initial treatment with vancomycin persisted even in patients switched to a ‐lactam therapy after culture results became available.

Hence, if a patient is being treated with vancomycin for a bloodstream (or other) infection due to MSSA, the therapy is suboptimal. In such a scenariowhich corresponds to that for the case patient herevancomycin should be discontinued and replaced with an antistaphylococcal penicillin or first‐generation cephalosporin. Many times, clinicians are resistant to terminating vancomycin and de‐escalating to antistaphylococcal penicillin/first‐generation cephalosporin therapy in a patient with bacteremia who is apparently responding to vancomycin. However, as the studies just reviewed make clear, not only is vancomycin treatment overly broad for the circumstance, it is also suboptimal and does not represent best clinical practice or patient care. Furthermore, continuing vancomycin in this situation unnecessarily exposes the patient to possible renal toxicity, particularly when aggressive dosing or prolonged vancomycin treatment is involved.39 Because of these issues and concerns, case 3 was de‐escalated from vancomycin to cefazolin, a first‐generation cephalosporin. One word of caution, however, is that there is some controversy over using cefazolin in patients with S aureus native valve endocarditis, given the possibility of a Type A ‐lactamase‐producing species causing cefazolin degradation.40 As a result, the clinician should first rule out endocarditis in the patient here before proceeding with cefazolin therapy. Another alternative would be to use an antistaphylococcal penicillin, such as nafcillin.

Finally, when dealing with bacteremia, and particularly when dealing with a possible CLABSI, the issue of potential culture contamination needs to be seriously considered and answered. Treating an actual infection, not what appears to be an infection because of culture contamination, is particularly important when dealing with possible CLABSI, because coagulase‐negative staphylococci (CoNS) are the most common cause of these types of infections,32 and CoNS are also frequent blood‐culture contaminants.41 Therefore, one needs to determine whether a blood culture growing a CoNS represents true bacteremia or simply contaminationwhich will obviously impact de‐escalation decisions.

In addition, when determining whether a blood culture is truly positive and clinically significant, it is important to consider whether the isolated pathogens are unlikely to be contaminants, likely to be contaminants, or the situation is unclear. A 2000 study by Kim et al.42 suggested that, among patients with 2 positive blood cultures for CoNS, routine identification of CoNS species and genotyping selected isolates using pulsed‐field gel electrophoresis may improve the process of discriminating contaminants from pathogens. Various additional factors need to be weighed when trying to interpret CoNS blood culture results, including patient risk factors, presence of prosthetic devices, number of blood cultures and number positive, and the antimicrobial sensitivity patterns of different isolates. For example, if the sensitivity patterns of 2 CoNS strains isolated from a patient are the same, the likelihood is increased that they represent true pathogens rather than contaminants. Figure 5 presents a schematic of this general approach.42

Figure 5

CONCLUSIONS

De‐escalation is a critical component of antimicrobial stewardship. As the prevalence of antimicrobial resistance grows in the hospital and community, de‐escalation will have an increasingly important role in limiting the further emergence of antimicrobial resistance. Pneumonia, intra‐abdominal infection, and bloodstream infection are commonly managed in the hospital setting. Each of these infection types presents excellent opportunities for de‐escalation, and each presents unique challenges and caveats. Concerted efforts must be made by clinicians and stewardship personnel to de‐escalate as soon as possible, based on culture results and clinical status. Although not discussed here, successful de‐escalation programs utilize structured process, guidelines, and algorithms to consistently implement de‐escalation efforts. These tools of implementation are more fully discussed in the corresponding article in this supplement by Dr Rosenberg.

The appropriate duration of antimicrobial therapy for serious infections such as hospital‐ or healthcare‐associated pneumonia, complicated intra‐abdominal infection, and bacteremia has not been well studied. To the extent that guidelines for treatment duration exist, they are largely based on observational studies, clinical experience, and consensus, rather than data from well‐designed clinical studiesalthough such studies and data are beginning to emerge, more so in some areas (pneumonia) than others (intra‐abdominal infections and catheter‐related bacteremia). Additional studies supporting treatment durations for these and other important infections are encouraged, given the widely recognized relationships between antimicrobial use and development of antimicrobial resistance, and between antimicrobial resistance and increased morbidity, mortality, and healthcare costs.13 Duration is a component of antimicrobial exposure, and together with optimal dosing, has been linked with antimicrobial resistance and other adverse or unintended consequences of antimicrobial therapy. The general idea is to eradicate (kill) the pathogen as soon as possible, and then stop therapy, since dead bugs don't mutate.

An overwhelming body of work has established a link between antimicrobial use and emergence of antimicrobial‐resistant bacteria. This relationship holds for most, if not all, antimicrobial,47 but appears to be particularly strong for broader‐spectrum agents like fluoroquinolones,814 extended‐spectrum cephalosporins,1518 and carbapenems.4, 1822 Using an antimicrobial from a particular drug class typically promotes development of resistance to all members of the class, but can also lead to more broad‐based resistance including other drug classes, depending on the mechanisms of resistance. Emergence of resistance is expected to be especially high when a suboptimal antimicrobial regimen is administered for a prolonged time or duration,7, 23 as these conditions optimize pressure for selection of preexistent resistant strains or development of new ones.

Optimal efficacy and safety of antimicrobial therapy depends, first, on avoiding antimicrobials when they are not indicated, and second, when they are used, focusing on the 4 Ds of optimal antimicrobial therapy: right Drug, right Dose, De‐escalation to pathogen‐directed therapy, and right Duration of therapy.24 Corresponding articles in this supplement have focused on the first 3 Ds: Dr Syndman on selection of the right drug and dose, and Dr Kaye on de‐escalation of initial empiric therapy, when circumstances warrant it. The current article examines the rationale for reducing the duration of antimicrobial therapy (when possible), and current evidence or guidelines supporting the use of shorter courses of antimicrobial therapy for such infections as pneumonia (community‐, hospital‐, or healthcare‐acquired/associated), complicated intra‐abdominal infection, and bacteremia or sepsis. Key points will be illustrated through 3 case studies dealing with each of these general infection categories.

ADJUSTING DURATION TO OPTIMIZE ANTIMICROBIAL THERAPY

The ultimate goals of short‐course antimicrobial therapy are to rapidly eradicate pathogenic microorganisms and reduce selective pressure for emergence of resistance. The primary potential advantages of shorter duration antimicrobial therapy include lower cost, less toxicity, better adherence, reduced antimicrobial resistance, and reduced disruption of endogenous flora and risk of superinfections, such as Clostridium difficile‐associated disease.23 Other potential benefits of shorter antimicrobial durations include a shorter length of hospital stay and (perhaps) earlier removal of an intravenous catheter, which would be expected to reduce risk of iatrogenic complications and facilitate early mobility and earlier return to full health. Effective short‐course antimicrobial therapy also appears to better meet patient expectations of therapy than longer courses.25

Rapid or early eradication of pathogens depends not only on selecting an agent or combination of agents with activity against the causative pathogen, but also administering the agent in a manner that enables it to achieve its pharmacodynamic (PD) target for pathogen eradication in a rapid fashion.23, 26 The PD parameter that best predicts efficacy will vary for different antimicrobial classes, but the general idea is to use a dose, dosing schedule, and route of administration that rapidly achieves adequate tissue penetration and drug concentration at the infection site for a sufficient length of time for maximum efficacy. In brief, the general concept for short‐course antimicrobial therapy is to hit hard and fast then leave as soon as possible.23

The World Health Organization (WHO) 2000 report on overcoming antimicrobial resistance also recognizes that ideal antimicrobial usage includes using the correct drug, administered by the best route, in the right amount, at optimal intervals, for the appropriate period, after an accurate diagnosis.27 Administering antimicrobials for the wrong period of time (ie, duration) increases risk of resistance. In essence, the WHO report is another call to treat aggressively with shorter courses to help reduce antimicrobial resistance, and to avoid antimicrobial therapy when it is not warranted.

However, while there is general agreement about the utility of using as short an antimicrobial course as is consistent with efficacy, there has been a general dearth of information about exactly what the optimal duration is for particular agents (or drug classes) used to treat particular infections. This is especially the case for most infections occurring in critically ill patients in the hospital setting. Appropriate duration of therapy has been established for some infections, notably group A streptococcus pharyngitis, urinary tract infections, and some sexually transmitted diseases,2831 but treatment duration has not been firmly established for most serious infections. Furthermore, clinicians are often reluctant to shorten the duration of antimicrobial therapy in patients with serious infections for fear of incompletely eradicating the pathogen, thereby leading to relapses and significant morbidity or mortality.

Nevertheless, several studies have now been published that point to the effectiveness of shorter‐course antimicrobial therapy for community‐acquired pneumonia (CAP)3235 and hospital‐acquired pneumonia (HAP) or ventilator‐associated pneumonia (VAP),3645 and a more limited number pointing to the effectiveness of shorter‐course therapy for intra‐abdominal infections38, 46, 47 or bacteremia.4851 In addition, clinical practice guidelines recommend shorter‐course antimicrobial therapy for most patients with CAP,52 uncomplicated healthcare‐associated pneumonia (HCAP) or HAP/VAP,53 and complicated intra‐abdominal infections54and clinical practice guidelines for the management of intravascular catheter‐related infection, including bacteremia, specify a standard duration of therapy and conditions under which a shorter (or longer) course may be considered.55 Shorter‐course therapy can be best implemented based on clinical parameters (eg, resolution of fever, reduction of leukocytosis) along with clinical judgment of the well‐informed clinician with guidance from evidenced‐based guidelines.

The remainder of this section will examine some of the preclinical and clinical evidence supporting shorter‐course therapy for CAP. Subsequent sections of the article utilize 3 case studies to discuss current guidelines and supportive evidence for use of shorter‐course antimicrobial therapy in patients with HCAP or HAP/VAP, complicated intra‐abdominal infections, and bacteremia. The discussion of CAP is intended as an introduction that lays down some general concepts concerning shorter‐duration therapy before delving into the serious hospital‐ or healthcare‐related infections outlined above. Because there is more clinical research on duration of treatment for patients with HAP/VAP than for complicated intra‐abdominal infections or bacteremia, the section on HCAP/HAP/VAP is much longer and detailed than the ones for complicated intra‐abdominal infections or bacteremia.

CAP is defined as pneumonia developing in individuals who are not residents in a nursing home or extended‐care facility, and who have not recently been hospitalized or had significant exposure to the healthcare setting. Pneumonia developing after 48 hours of hospital admission, and that was not incubating at the time of admission, is known as HAP,53, 56 and VAP is a subset of HAP, more precisely defined as HAP that arises after endotracheal intubation.53 HCAP includes patients characterized by residence in a nursing home or extended‐care facility or hospitalization for 2 days in the preceding 90 days or other significant exposure to the healthcare setting.53, 57, 58

DURATION OF THERAPY FOR CAP

A number of studies have reported similar efficacy with shortened versus longer durations of antimicrobial therapy for CAP.33, 5964 Consistent with this, 2 recent meta‐analyses of studies comparing shorter‐ versus longer‐course therapy for mild‐to‐moderate CAP (22 randomized controlled trials and >8000 patients between them) reported similar efficacy and safety with shorter‐course therapy.65, 66 In addition, other studies have reported an association between longer durations of antimicrobial therapy and development of resistance by community respiratory pathogens, especially when lower doses have been used.67, 68 These findings are consistent with the belief that prolonged treatment with a suboptimal antimicrobial regimen creates particularly fertile conditions for selection or development of antimicrobial‐resistant strains.65, 66

Data from preclinical studies provide a basis for understanding the effectiveness of shorter‐dosing regimens of adequate antimicrobial therapy for CAP or other forms of pneumonia. In particular, in vitro time‐kill studies6974 and animal models of infection7577 have demonstrated that Streptococcus pneumoniae can be rapidly eradicated without use of long‐term therapy when appropriate antimicrobials are used. Consistent with these preclinical data, various clinical studies have also shown that S pneumoniae and other respiratory pathogens are rapidly eradicated from lower respiratory tract secretions after initiation of appropriate antimicrobial treatment. For example, Montravers et al. reported that 94% of respiratory pathogens were eradicated from the lungs of 76 patients with VAP after just 3 days of antimicrobial therapy.78

Based on the available data, the 2007 Infectious Diseases Society of America (IDSA)/America Thoracic Society (ATS) guidelines for CAP management recommend a minimum of 5 days of antimicrobial treatment, while noting that most patients become clinically stable within 3‐7 days of treatment onset and rarely require longer durations.52 The guidelines further recommend that CAP patients should be afebrile for 4872 hours and should have no more than 1 CAP‐associated sign of clinical instability before discontinuation of therapy. Although the general movement is toward use of shorter‐duration treatment courses than the traditional 710 days or longer, the IDSA/ATS guidelines acknowledge that longer durations may be needed in certain situations.79

CASE 1: HEALTHCARE‐ASSOCIATED PNEUMONIA

Case 1 is a 72‐year‐old woman admitted with findings consistent with HCAP who was initiated on an empiric therapy regimen of vancomycin and piperacillin‐tazobactam. Results from blood and sputum cultures obtained prior to treatment initiation came back on day 3, and were negative for pathogenic bacteria. White blood cell (WBC) counts were trending downward, and the patient appeared to be stabilizing. She still had an elevated WBC count, slight fever (temperature maximum of 101.4F for the past 24 hours), and lung crackles at the right lung base. Because Gram stain failed to identify Gram‐positive cocci clusters, and there was no culture evidence of methicillin‐resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa, vancomycin treatment was terminated and the patient was switched to single‐agent therapy with intravenous ceftriaxone, a nonpseudomonal third‐generation cephalosporin. On hospital day 5, there was continuing evidence of response to antimicrobial therapy. The patient reported feeling better and she was breathing comfortably. Her cough was much improved, sputum production was markedly decreased, and her fever had resolved. Now, on day 7, the patient is still afebrile, her WBC count is normal, and she has 96% oxygen saturation on room air.

The question before the clinician is whether to terminate or continue antimicrobial therapy, and if continued, with what regimen and for how long? In addition, if a decision is made to continue antimicrobial therapy, there is a possibility of switching from an intravenous to oral treatment regimen. An examination of the literature and current treatment guidelines for HCAP/HAP/VAP should enable a more informed decision, one that optimally benefits not only this patient, but all subsequent ones who might be exposed and infected with a resistant pathogen that develops when treatment is continued longer than necessary.

Clinical Trial to Support Shortened Duration of HCAP/HAP/VAP Therapy

A French study published in JAMA in 2003 provides more direct support that approximately 1 week of antimicrobial therapy produces effectiveness comparable to more traditional 23‐week therapy for most patients with VAP.37 In this prospective, multicenter, randomized, double‐blind (until day 8) clinical trial, 401 patients with microbiologically proven VAP were randomly assigned to receive either 8 days (n = 197) or 15 days (n = 204) of initial empiric antimicrobial therapy selected by the treating physician. No significant differences were observed between the 8‐day and 15‐day treatment groups for the 2 primary efficacy endpoints of death from any cause (18.8% vs 17.2%) and microbiologically documented pulmonary infection recurrence (28.9% vs 26.0%). There were also no differences between the groups for number of mechanical ventilation‐free days (8.7 vs 9.1 days), number of organ‐failure‐free days (8.7 vs 8.9 days), length of ICU stay (30.0 vs 27.5 days), unfavorable outcome (death, pulmonary infection recurrence, or prescription of a new antimicrobial) (46.2% vs 43.6%), mortality rate on day 60 (25.4% vs 27.9%), or in‐hospital mortality (32% vs 29.9%).

Conversely, patients in the 8‐day treatment group had significantly more antimicrobial‐free days (13.1 vs 8.7 days, P 0.001), and among patients who developed recurrent infections, multidrug‐resistant pathogens emerged more frequently in patients in the 15‐day versus 8‐day treatment group (62.0% vs 42.1%, P = 0.04). However, there was an apparent exception to the general comparable efficacy of the 8‐ and 15‐day treatment regimens for infections caused by nonfermenting Gram‐negative bacilli, including P aeruginosa. For primary infections caused by nonfermenting Gram‐negative bacilli, the 8‐day versus 15‐day regimen was associated with higher rates of pulmonary recurrence (40.6% vs 25.4%). Interestingly, the 8‐day regimen was not associated with more adverse outcomes here, just a higher recurrence rate. With respect to primary infections caused by MRSA, no differences were observed between the 2 treatment regimens for death for all causes (23.4% vs 30.2%) or pulmonary infection recurrence (33.3% vs 42.9%). Figure 1 presents the probability of survival data for the 8‐day and 15‐day treatment groups.

Figure 1

Hence, the data from the Chastre et al. study37 support use of an 8‐day (or shortened) regimen as standard antimicrobial therapy for most patients with VAP, with some possible exceptions. Additional studies provide further support for this general conclusion. For example, a prospective, randomized, controlled trial by Micek et al. evaluated the impact of using an antimicrobial discontinuation policy based on clinical criteria (discontinuation group; n = 150)versus the decision of treating physicians (conventional group, n = 140)to determine the duration of antimicrobial therapy for VAP, and observed a statistically shorter treatment duration in the discontinuation versus conventional management group (6.0 vs 8.0 days, P = 0.001), but no difference between the groups for hospital mortality (32.0% vs 37.1%), ICU length of stay (6.8 vs 7.0 days), or VAP recurrence (17.3% vs 19.3%).42 A prior study by the same group reported a shorter duration of antimicrobial therapy for VAP following implementation of an antimicrobial guideline (vs prior to implementation) (8.6 vs 14.8 days, P 0.001), and a lower rate of VAP recurrence among patients in the after period (7.7% vs 24.0%, P = 0.03). However, interpretation of the results was complicated by the fact that initial empiric therapy was more often appropriate during the after versus before guideline implementation period (94.2% vs 48.0%, P 0.001).40

A limited number of studies have focused further on shortened duration of therapy for patients with VAP caused by Gram‐negative bacteria, and particularly by nonfermenting Gram‐negative bacilli. A retrospective study by Hedrick et al. analyzed the relationship between antimicrobial duration and outcomes of 452 episodes of VAP in the ICU, 154 caused by nonfermenting Gram‐negative bacilli.39 In the study, 127 patients infected with a nonfermenting Gram‐negative bacillus received 9 days (mean 17.1 0.7 days) of antimicrobial therapy, while 27 received 3‐8 days (mean 6.4 0.3 days) of therapy. No significant differences were observed between the shorter‐ and longer‐duration groups for mortality (22% vs 14%, P = 0.38) or VAP recurrence (22% vs 34%, P = 0.27) for these patient populations. Table 2 provides the results for all 452 VAP episodes based on 8 days or 9 days of antimicrobial therapy.

Table 2.VAP in All Patients According to Treatment Duration

Patient Characteristic	8 Days (n = 98)	9 Days (n = 354)	P Value
NOTE: Adapted from Hedrick et al.39 Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; VAP, ventilator‐associated pneumonia.
Mean antimicrobial days	6.2	16.8	0.0001
Mean APACHE II	18	20	0.0009
% Trauma	71	68	0.63
Mean time to onset, days	17.7	17.8	0.97
Recurrence	11%	25%	0.004
Death	13%	11%	0.59
Nonfermenting Gram‐negative bacilli recurrence	22% (n = 27)	34% (n = 127)	0.27
Staphylococcus aureus recurrence	20% (n = 10)	38% (n = 47)	0.47

The retrospective nature of the study limits the ability to more confidently interpret the results, but the data appear to be consistent with the conclusion that short‐duration therapy does not necessarily increase recurrence or worsen other outcomes in patients with VAP caused by nonfermenting Gram‐negative bacilli. The most common Gram‐negative bacilli associated with VAP in the study were P aeruginosa (18% of all infections), Enterobacter cloacae (11%), Acinetobacter spp (11%), Klebsiella pneumoniae (7%), Stenotrophomonas maltophilia (7%), Serratia spp (7%), H influenzae (6%), and Escherichia coli (4%). In addition, the study results suggest that short‐duration therapy is at least as effective as longer‐duration therapy for the overall VAP population, with potential benefits in terms of reduced antimicrobial use and lower rate of recurrence.

Another recent retrospective analysis examining an even shorter course of antimicrobial therapy (5 days) for patients with HAP associated with Gram‐negative bacteria reported a low overall recurrence rate (14%) and a critical care mortality rate (34.2%) in line with prior studies of short‐term therapy for VAP/HAP.44 However, the HAP relapse rate was significantly higher in patients with HAP caused by nonfermenting Gram‐negative bacilli versus other Gram‐negative species (17% vs 2%, P = 0.03).

A recent US pilot study explored the use of repeat bronchoalveolar lavage (BAL) to guide antimicrobial duration in 52 patients with VAP, and compared the results with a matched control group of 52 VAP patients treated before institution of the BAL pathway.43 Antimicrobial therapy in the pathway patients was discontinued if pathogen growth was 10,000 colony forming units/mL on the repeat BAL performed on day 4 of therapy. One objective was to determine whether a repeat BAL strategy, such as the one here, might be able to identify patients with VAP due to nonfermenting Gram‐negative bacilli or other microorganisms who could be safely and effectively treated with shorter‐duration therapy.

Results showed that the antimicrobial duration was significantly shorter for patients in the pathway group than the matched control group (9.8 vs 3.8 days, P 0.001), including the subset of patients with VAP associated with nonfermenting Gram‐negative bacilli (10.7 vs 14.4 days, P 0.001). No significant differences were observed between the overall treatment populations for VAP recurrence, mechanical ventilator‐free ICU days, ICU‐free hospital days, or mortality. Repeat BAL showed most VAP isolates in the study group (83%) responded to initial therapy with a mean duration of 8.8 days. Nonresponders without concomitant infections received significantly longer treatment than pure responding isolates (14.4 vs 7.3 days, P 0.001), and the most common nonresponding microorganisms were P aeruginosa (41% response rate) and S maltophilia (50% response rate), 2 nonfermenting Gram‐negative bacilli.

Most nonfermenting Gram‐negative bacilli‐associated VAP isolates in the study group did respond on repeat BAL (59%). These responders were treated for a mean duration of 8.2 days, and exhibited a similar recurrence rate versus that observed for the matched control group (12.0% vs 17.9%, P = 0.71). These pilot study results suggest that repeat BAL might be used to identify patients likely to benefit from short‐duration therapy, including patients infected with nonfermenting Gram‐negative bacilli. Further study on this is needed.

ATS/IDSA Guidelines for Duration of HCAP/HAP/VAP Therapy

Based largely on the studies by Dennesen et al.80 and Luna et al.83 indicating most VAP patients who respond to appropriate antimicrobial therapy do so within the first 6 days, and those by Chastre et al.37 and Singh et al.45 pointing to the efficacy and safety of shorter‐duration VAP therapy, the 2005 ATS/IDSA guidelines recommend the use of shorter‐duration antimicrobial therapy for most patients with HCAP or HAP/VAP.53 More specifically, the guidelines state, If patients receive an initially appropriate antimicrobial regimen, efforts should be made to shorten the duration of therapy from the traditional 14 to 21 days to periods as short as 7 days, provided that the etiologic pathogen is not P. aeruginosa, and that the patient has a good clinical response with resolution of clinical features of infection.53 Figure 2 presents an overview of the ATS/IDSA guidelines for HCAP/HAP/VAP management 48 to 72 hours after initiation of empiric antimicrobial therapy.53

Figure 2

Note that the clinician should consider terminating antimicrobial therapy in patients with clinical improvement and negative cultures or other evidence suggestive of a noninfectious cause. CPIS can also be helpful when deciding whether to terminate initial empiric therapy in a patient with clinical improvement after 23 days of therapy and negative cultures. If cultures are positive, the clinician should consider whether antimicrobial de‐escalation is possible (as discussed by Dr Kaye in the corresponding supplement article), and aim to treat selected patients with an antimicrobial course lasting 78 days. After 78 days, patients should be reassessed for treatment termination or other appropriate actions.

The ATS/IDSA guidelines also provide recommendations for route of drug administration, and if and when to switch from an intravenous to oral agent. In particular, the guidelines state that all patients with HCAP, HAP, or VAP should initially receive therapy intravenously, but conversion to oral/enteral therapy may be possible in certain responding patients, ie, those with a good clinical response and a functioning intestinal tract.53 Fluoroquinolones and linezolid have oral formulations with bioavailability equivalent to the intravenous form, meaning the oral formulations are capable of achieving high levels at the site of infection. This may facilitate conversion to oral therapy in select patients. Early step‐down is safe and effective with fluoroquinolones.84, 85

Based on the information just reviewed, the antimicrobial can be terminated on day 7 for case 1. She is afebrile, and her WBC and oxygenation are normal. In fact, since her records show she was responding at day 5, consideration could have been given to switching from intravenous to oral therapy at that time, and perhaps even discharging her to the rehabilitation center.

CASE 2: INTRA‐ABDOMINAL INFECTION (DIVERTICULITIS)

Case 2 is a 56‐year‐old woman who presents with sepsis and diverticular abscess with walled‐off perforation. Upon hospital arrival, Interventional Radiology inserted a drain, and the patient was initiated on ciprofloxacin and metronidazole therapy. Day 3 examination showed improvement in WBC count and normal vital signs, but the patient still had a low‐grade fever (100.9F). Abdominal examination results were improved, but with some diffuse tenderness. Initial cultures of the abdominal abscess isolated Gram‐negative rods, and the patient was continued on ciprofloxacin/metronidazole. Further cultures on day 4 identified an extended‐spectrum ‐lactamase (ESBL)‐producing E coli organism as the causative pathogen. The patient was switched from ciprofloxacin/metronidazole to ertapenem. It is now hospital day 8, and the patient continues to show good response to treatment. She is afebrile and WBC count is normal. The abscess catheter is no longer draining. Her abdominal pain is improved, and she is complaining that she is hungry. A repeat computed tomography scan shows resolution of the abscess and no evidence of bowel perforation. Should antimicrobial therapy be continued in this patient, and if so, with what agent and for how long?

Guidelines from the Surgical Infection Society and IDSA state that antimicrobial therapy of established or complicated intra‐abdominal infection in adults should be limited to 47 days, unless it is difficult to achieve adequate source control.54 This is because extended antimicrobial exposure increases antimicrobial cost and risk of resistance, superinfection, C difficile‐associated colitis, or other untoward and unintended consequences of antimicrobial therapy, and there is no evidence that longer treatment durations improve outcomes.46, 47, 54, 86 Runyon et al. randomized 90 patients with spontaneous bacterial peritonitis or culture‐negative neutrocytic ascites to receive 5 days or 10 days of cefotaxime monotherapy, and reported similar rates of infection‐related mortality (0% vs 4.3%), hospitalization mortality (33% vs 43%), bacteriologic cure (93% vs 92%), and recurrence of ascitic fluid infection (12% vs 13%).46 Furthermore, shorter‐course therapy was associated with significantly lower antimicrobial administration and costs. Similarly, a recent prospective, randomized, double‐blind trial comparing 3 versus 5 days of ertapenem therapy in 111 patients with community‐acquired intra‐abdominal infection reported similar cure (93% vs 90%) and eradication rates (95% vs 94%).86 However, it should be noted that the mean duration of antimicrobial therapy in the longer‐duration group was still relatively short (5.7 days, range of 5‐10 days).

Studies also indicate there is a very low risk of infection recurrence or treatment failure when antimicrobial therapy is terminated in a patient diagnosed with a complicated intra‐abdominal infection who no longer shows signs of continuing infection.38, 87 Lennard et al. compared postoperative outcomes in 65 patients with or without leukocytosis and fever at the conclusion of antimicrobial therapy for intra‐abdominal sepsis, and reported development of intra‐abdominal infection in 7 of 21 (33%) with persistent leukocytosis.87 None of the 30 patients with normal WBC counts at the end of therapy developed an intra‐abdominal infection postoperatively. Furthermore, intra‐abdominal infection occurred postoperatively in 11 of 14 patients (79%) who responded to treatment but were still febrile at the time of antimicrobial discontinuation.

Similar results were obtained in a much larger, more recent study that retrospectively analyzed the relationship between duration of antimicrobial therapy and infectious complications for patients with intra‐abdominal infections.38 In the study, 929 patients with intra‐abdominal infections associated with either fever or leukocytosis were organized into 4 quartiles based on total duration of antimicrobial therapy (quartile 1: 07 days, n = 218; quartile 2: 812 days, n = 217; quartile 3: 1317 days, n = 246; and quartile 4: >17 days, n = 248) or antimicrobial duration after resolution of leukocytosis (quartile 1: 05 days, n = 130; quartile 2: 610 days, n = 127; quartile 3: 1115 days, n = 124; and quartile 4: >15 days, n = 118). Based on either total duration of antimicrobial therapy or duration after leukocytosis resolution, risk of recurrence was significantly higher for patients in quartiles 3 or 4 versus those in quartile 1, and there was no difference between quartiles 1 and 2.

Taken together, these results suggest that antimicrobial therapy for intra‐abdominal sepsis can be shortened in patients exhibiting a clinical response to treatment, if there are no signs of persistent leukocytosis or fever. Hence, clinicians should use the resolution of clinical signs of infection as a guide to determine when during the 47‐day window antimicrobial therapy should be terminated.54 In practical terms, this usually means treatment can be terminated when the patient is afebrile, has normal WBC counts, and is able to tolerate an oral diet.

Based on the clinical status of case 2 after 8 days of antimicrobial therapy (afebrile with normal WBC counts and requesting oral diet), the ertapenem regimen should be stopped. There is no reason to consider further outpatient antimicrobial therapy for this particular patient, but the Surgical Infection Society and IDSA guidelines discuss the type of patient who should be considered for oral or outpatient antimicrobial therapy. According to the guidelines, the patient convalescing from a complicated intra‐abdominal infection may receive oral antimicrobial therapy, but that therapy should only be included as a component within the brief treatment duration already mentioned, ie, in total, it should rarely exceed 7 days.54 Such therapy is rarely indicated for patients who are afebrile, with normal peripheral WBC/leukocyte counts, and with return of bowel function. These recommendations make it clear that no further antimicrobial therapy is warranted for case 2.

However, for appropriate patients who are recovering from a complicated intra‐abdominal infection and are able to tolerate an oral diet, an oral antimicrobial regimen selected on the basis of identified primary isolates may be used for completion of therapy.54 In the absence of cultures, an oral regimen that covers commonly isolated pathogens (eg, E coli, streptococci, and Bacteroides fragilis) should be considered. Common regimens include an oral cephalosporin or fluoroquinolone with metronidazole, or amoxicillin‐clavulanic acid, assuming susceptibility studies do not demonstrate resistance. Given the identification of an ESBL‐producing E coli for case 2a pathogen relatively resistant to oral antimicrobialan oral regimen probably would not have been viable for this patient even earlier in the treatment course. Lastly, a repeat computed tomography scan was used for the case here. It should be noted that there are currently no well‐established criteria for determining when repeat imaging is needed to confirm resolution of fluid collections. This should be a clinical decision. A general practice is that the catheter is left in place until there is minimal drainage (eg, 10 mL/day); catheter sinograms can also be helpful in determining the status of the abscess.

CASE 3: CENTRAL LINE‐ASSOCIATED BACTEREMIA

Case 3 is a 56‐year‐old man with status epilepticus, intubation, and ICU stay. He was initially treated with vancomycin and piperacillin‐tazobactam for a fever of 103.4F on day 5 of hospitalization. Blood cultures grew Gram‐positive cocci. The central venous catheter was removed, and the initial antimicrobial regimen was de‐escalated to vancomycin monotherapy, which was associated with continued improvement in fever and WBC count, and clinical stability on hospital day 7. At that time, further blood culture analyses isolated methicillin‐susceptible S aureus (MSSA), and the antimicrobial regimen was switched/de‐escalated from vancomycin to cefazolin. It is now hospital day 9 (day 3 of cefazolin) and the patient continues to respond and is afebrile. Repeat blood cultures show no bacterial growth, and a transesophageal echocardiograph (TEE) was performed and revealed normal heart valves. Should the antimicrobial therapy be continued for this patient, and if so, with what agent and for how long?

The IDSA guidelines for management of intravascular catheter‐related infections recommend catheter removal and 46 weeks of antimicrobial therapy for patients with S aureus catheter‐related bloodstream infection (CRBSI), unless the patient has exceptions allowing consideration of shorter‐duration therapy (minimum of 14 days, with day 1 being the first day of negative blood culture results).55 These exceptions include absence of diabetes; immunocompetence (no immunosuppression); removal of the infected catheter; no prosthetic intravascular device (eg, pacemaker or recently placed vascular graft); no evidence of endocarditis or suppurative thrombophlebitis on TEE and ultrasound, respectively; fever and bacteremia resolved within 72 hours after initiation of appropriate antimicrobial therapy; and no evidence of metastatic infection on physical examination and sign‐ or symptom‐directed diagnostic tests.

Short‐duration (10‐16 day) antimicrobial therapy has been reported to yield similarly low recurrence or relapse rates as longer courses of therapy in patients with uncomplicated catheter‐associated S aureus bacteremia.50, 51, 88, 89 A small 1989 study by Ehni and Reller prospectively followed 13 patients with S aureus CRBSI who had received short‐course therapy (17 days), and reported only 1 case of relapse with endocarditis (8% relapse rate).50 A subsequent study by Malanoski et al. retrospectively analyzed the data from 55 patients with S aureus CRBSI.51 Excluding the 8 patients with early complications, the authors observed similar rates of relapse in patients treated for 1015 days and those receiving longer courses of antimicrobial therapy (0% vs 4.7%). The clinical characteristics of the 2 treatment duration groups were similar, and delayed catheter removal was linked with persistence of bacteremia (P = 0.01).

A more recent multicenter, prospective observational study by Chang et al. examined recurrence and the impact of antimicrobial treatment in 505 consecutive patients with S aureus bacteremia, and determined that duration of antimicrobial therapy was not a factor associated with relapse.88 This was true both for patients with bacteremia resulting from endocarditis, bacteremia with no apparent source, or bacteremia due to a focus that could not be cured or removed (28 days therapy after defervescence, 28 days therapy, or 28 days therapy), or those with bacteremia resulting from a source amenable to definitive cure, such as an intravascular device that could be removed, an abscess that could be incised and drained, or an infected bone that could be resected (>14 days, 1014 days, or 10 days therapy). Similarly, a 2005 prospective study by Thomas and Morris determined there was no relationship between treatment duration (7 vs 8 days, 10 vs 10 days, or 14 vs 15 days; P = 0.62, 0.87, and 0.16, respectively) and rate of relapse for 276 patients with cannula‐associated S aureus bacteremia.89 Longer‐duration antimicrobial therapy is warranted in patients with CRBSI and an early complicated course, eg, fever and/or bacteremia persisting for >3 days after catheter removal.90

According to the IDSA guidelines, a TEE should be obtained for all patients with CRBSI involving S aureus who are being considered for a shorter duration of therapy, and the TEE should be performed at least 57 days after onset of bacteremia to minimize risk of false‐negative results.55 High rates of infective endocarditis are observed in patients with S aureus bacteremia,89, 9193 with higher rates in patients with MSSA versus MRSA bacteremia (43.4% vs 19.6%, P 0.009).91 TEE is essential to diagnose endocarditis and detect other complications of bacteremia.92, 93 This recommendation for use of TEE does not necessarily apply to all patients with CRBSI when S aureus is not involved.

Figure 3 summarizes the general recommendations from the IDSA guidelines for the management of CRBSI in patients with a short‐term catheter.55 The figure illustrates the varied recommendations for treatment duration depending on whether the infection is complicated or uncomplicated, and based on the pathogenic microorganism. Returning to case 3, the patient meets the general criteria for shorter duration of antimicrobial therapy: he is not diabetic or immunosuppressed, his catheter has been removed, he does not have any prosthetic intravascular devices, his fever and bacteremia (based on blood cultures) resolved within 3 days of initiating cefazolin therapy, and there is no evidence of endocarditis or other complications of bacteremia. Hence, he is an excellent example of a patient with uncomplicated MSSA CRBSI who meets the criteria for consideration of shortened antimicrobial therapy. Based on the clinical practice guidelines, the patient should continue on intravenous cefazolin for a 14‐day course of therapy, at which time he can be re‐evaluated. A recent review of bloodstream infections caused by various pathogens similarly concluded that the minimum treatment duration for low‐risk patients with S aureus CRBSI is 14 days.48 As a final point, it is also important to note that there is no role for oral therapy in patients with CRBSI, so whether shortened or not, the chosen regimen should be administered intravenously.

Figure 3

CONCLUSIONS

Shortening the duration of appropriate and adequate antimicrobial therapy represents one strategy for reducing pressure for selection or development of resistant pathogenic microorganisms. Other potential benefits of shorter courses of antimicrobial therapy include reduced risk of antimicrobial‐associated infections (superinfection, C difficile‐associated diarrhea) and other antimicrobial‐related adverse events, improved compliance, and reduced antimicrobial costs. Clinicians are sometimes concerned that reducing antimicrobial courses for patients with serious infections, such as HCAP/HAP/VAP, complicated intra‐abdominal infection, and CRBSI, will lead to incomplete eradication of pathogenic microorganisms, leading to disease recurrence and increased morbidity and mortality. When managing patients with these serious infections, clinicians often turn to the literature and recommendations from professional organizations for guidance. Available data from randomized controlled and nonrandomized clinical trials indicate that shorter‐course therapy is effective and safe for patients with CAP, HCAP/HAP/VAP, complicated intra‐abdominal infections, and CRBSI. Based on these data, and consensus/expert opinion, clinical practice guidelines have been developed that recommend specific durations of antimicrobial therapy for each of these infections.

Although greater study of antimicrobial therapy duration is needed, the current and developing literature and current treatment guidelines should enable clinicians to recognize patients who would benefit from shortened courses of antimicrobial therapy. In doing so, they would help to lower antimicrobial costs and reduce the growing problem of antimicrobial resistance, with its wide‐ranging, negative consequences for current and future patients, and the clinicians who treat them.

The appropriate duration of antimicrobial therapy for serious infections such as hospital‐ or healthcare‐associated pneumonia, complicated intra‐abdominal infection, and bacteremia has not been well studied. To the extent that guidelines for treatment duration exist, they are largely based on observational studies, clinical experience, and consensus, rather than data from well‐designed clinical studiesalthough such studies and data are beginning to emerge, more so in some areas (pneumonia) than others (intra‐abdominal infections and catheter‐related bacteremia). Additional studies supporting treatment durations for these and other important infections are encouraged, given the widely recognized relationships between antimicrobial use and development of antimicrobial resistance, and between antimicrobial resistance and increased morbidity, mortality, and healthcare costs.13 Duration is a component of antimicrobial exposure, and together with optimal dosing, has been linked with antimicrobial resistance and other adverse or unintended consequences of antimicrobial therapy. The general idea is to eradicate (kill) the pathogen as soon as possible, and then stop therapy, since dead bugs don't mutate.

An overwhelming body of work has established a link between antimicrobial use and emergence of antimicrobial‐resistant bacteria. This relationship holds for most, if not all, antimicrobial,47 but appears to be particularly strong for broader‐spectrum agents like fluoroquinolones,814 extended‐spectrum cephalosporins,1518 and carbapenems.4, 1822 Using an antimicrobial from a particular drug class typically promotes development of resistance to all members of the class, but can also lead to more broad‐based resistance including other drug classes, depending on the mechanisms of resistance. Emergence of resistance is expected to be especially high when a suboptimal antimicrobial regimen is administered for a prolonged time or duration,7, 23 as these conditions optimize pressure for selection of preexistent resistant strains or development of new ones.

Optimal efficacy and safety of antimicrobial therapy depends, first, on avoiding antimicrobials when they are not indicated, and second, when they are used, focusing on the 4 Ds of optimal antimicrobial therapy: right Drug, right Dose, De‐escalation to pathogen‐directed therapy, and right Duration of therapy.24 Corresponding articles in this supplement have focused on the first 3 Ds: Dr Syndman on selection of the right drug and dose, and Dr Kaye on de‐escalation of initial empiric therapy, when circumstances warrant it. The current article examines the rationale for reducing the duration of antimicrobial therapy (when possible), and current evidence or guidelines supporting the use of shorter courses of antimicrobial therapy for such infections as pneumonia (community‐, hospital‐, or healthcare‐acquired/associated), complicated intra‐abdominal infection, and bacteremia or sepsis. Key points will be illustrated through 3 case studies dealing with each of these general infection categories.

ADJUSTING DURATION TO OPTIMIZE ANTIMICROBIAL THERAPY

The ultimate goals of short‐course antimicrobial therapy are to rapidly eradicate pathogenic microorganisms and reduce selective pressure for emergence of resistance. The primary potential advantages of shorter duration antimicrobial therapy include lower cost, less toxicity, better adherence, reduced antimicrobial resistance, and reduced disruption of endogenous flora and risk of superinfections, such as Clostridium difficile‐associated disease.23 Other potential benefits of shorter antimicrobial durations include a shorter length of hospital stay and (perhaps) earlier removal of an intravenous catheter, which would be expected to reduce risk of iatrogenic complications and facilitate early mobility and earlier return to full health. Effective short‐course antimicrobial therapy also appears to better meet patient expectations of therapy than longer courses.25

Rapid or early eradication of pathogens depends not only on selecting an agent or combination of agents with activity against the causative pathogen, but also administering the agent in a manner that enables it to achieve its pharmacodynamic (PD) target for pathogen eradication in a rapid fashion.23, 26 The PD parameter that best predicts efficacy will vary for different antimicrobial classes, but the general idea is to use a dose, dosing schedule, and route of administration that rapidly achieves adequate tissue penetration and drug concentration at the infection site for a sufficient length of time for maximum efficacy. In brief, the general concept for short‐course antimicrobial therapy is to hit hard and fast then leave as soon as possible.23

The World Health Organization (WHO) 2000 report on overcoming antimicrobial resistance also recognizes that ideal antimicrobial usage includes using the correct drug, administered by the best route, in the right amount, at optimal intervals, for the appropriate period, after an accurate diagnosis.27 Administering antimicrobials for the wrong period of time (ie, duration) increases risk of resistance. In essence, the WHO report is another call to treat aggressively with shorter courses to help reduce antimicrobial resistance, and to avoid antimicrobial therapy when it is not warranted.

However, while there is general agreement about the utility of using as short an antimicrobial course as is consistent with efficacy, there has been a general dearth of information about exactly what the optimal duration is for particular agents (or drug classes) used to treat particular infections. This is especially the case for most infections occurring in critically ill patients in the hospital setting. Appropriate duration of therapy has been established for some infections, notably group A streptococcus pharyngitis, urinary tract infections, and some sexually transmitted diseases,2831 but treatment duration has not been firmly established for most serious infections. Furthermore, clinicians are often reluctant to shorten the duration of antimicrobial therapy in patients with serious infections for fear of incompletely eradicating the pathogen, thereby leading to relapses and significant morbidity or mortality.

Nevertheless, several studies have now been published that point to the effectiveness of shorter‐course antimicrobial therapy for community‐acquired pneumonia (CAP)3235 and hospital‐acquired pneumonia (HAP) or ventilator‐associated pneumonia (VAP),3645 and a more limited number pointing to the effectiveness of shorter‐course therapy for intra‐abdominal infections38, 46, 47 or bacteremia.4851 In addition, clinical practice guidelines recommend shorter‐course antimicrobial therapy for most patients with CAP,52 uncomplicated healthcare‐associated pneumonia (HCAP) or HAP/VAP,53 and complicated intra‐abdominal infections54and clinical practice guidelines for the management of intravascular catheter‐related infection, including bacteremia, specify a standard duration of therapy and conditions under which a shorter (or longer) course may be considered.55 Shorter‐course therapy can be best implemented based on clinical parameters (eg, resolution of fever, reduction of leukocytosis) along with clinical judgment of the well‐informed clinician with guidance from evidenced‐based guidelines.

The remainder of this section will examine some of the preclinical and clinical evidence supporting shorter‐course therapy for CAP. Subsequent sections of the article utilize 3 case studies to discuss current guidelines and supportive evidence for use of shorter‐course antimicrobial therapy in patients with HCAP or HAP/VAP, complicated intra‐abdominal infections, and bacteremia. The discussion of CAP is intended as an introduction that lays down some general concepts concerning shorter‐duration therapy before delving into the serious hospital‐ or healthcare‐related infections outlined above. Because there is more clinical research on duration of treatment for patients with HAP/VAP than for complicated intra‐abdominal infections or bacteremia, the section on HCAP/HAP/VAP is much longer and detailed than the ones for complicated intra‐abdominal infections or bacteremia.

CAP is defined as pneumonia developing in individuals who are not residents in a nursing home or extended‐care facility, and who have not recently been hospitalized or had significant exposure to the healthcare setting. Pneumonia developing after 48 hours of hospital admission, and that was not incubating at the time of admission, is known as HAP,53, 56 and VAP is a subset of HAP, more precisely defined as HAP that arises after endotracheal intubation.53 HCAP includes patients characterized by residence in a nursing home or extended‐care facility or hospitalization for 2 days in the preceding 90 days or other significant exposure to the healthcare setting.53, 57, 58

DURATION OF THERAPY FOR CAP

A number of studies have reported similar efficacy with shortened versus longer durations of antimicrobial therapy for CAP.33, 5964 Consistent with this, 2 recent meta‐analyses of studies comparing shorter‐ versus longer‐course therapy for mild‐to‐moderate CAP (22 randomized controlled trials and >8000 patients between them) reported similar efficacy and safety with shorter‐course therapy.65, 66 In addition, other studies have reported an association between longer durations of antimicrobial therapy and development of resistance by community respiratory pathogens, especially when lower doses have been used.67, 68 These findings are consistent with the belief that prolonged treatment with a suboptimal antimicrobial regimen creates particularly fertile conditions for selection or development of antimicrobial‐resistant strains.65, 66

Data from preclinical studies provide a basis for understanding the effectiveness of shorter‐dosing regimens of adequate antimicrobial therapy for CAP or other forms of pneumonia. In particular, in vitro time‐kill studies6974 and animal models of infection7577 have demonstrated that Streptococcus pneumoniae can be rapidly eradicated without use of long‐term therapy when appropriate antimicrobials are used. Consistent with these preclinical data, various clinical studies have also shown that S pneumoniae and other respiratory pathogens are rapidly eradicated from lower respiratory tract secretions after initiation of appropriate antimicrobial treatment. For example, Montravers et al. reported that 94% of respiratory pathogens were eradicated from the lungs of 76 patients with VAP after just 3 days of antimicrobial therapy.78

Based on the available data, the 2007 Infectious Diseases Society of America (IDSA)/America Thoracic Society (ATS) guidelines for CAP management recommend a minimum of 5 days of antimicrobial treatment, while noting that most patients become clinically stable within 3‐7 days of treatment onset and rarely require longer durations.52 The guidelines further recommend that CAP patients should be afebrile for 4872 hours and should have no more than 1 CAP‐associated sign of clinical instability before discontinuation of therapy. Although the general movement is toward use of shorter‐duration treatment courses than the traditional 710 days or longer, the IDSA/ATS guidelines acknowledge that longer durations may be needed in certain situations.79

CASE 1: HEALTHCARE‐ASSOCIATED PNEUMONIA

Case 1 is a 72‐year‐old woman admitted with findings consistent with HCAP who was initiated on an empiric therapy regimen of vancomycin and piperacillin‐tazobactam. Results from blood and sputum cultures obtained prior to treatment initiation came back on day 3, and were negative for pathogenic bacteria. White blood cell (WBC) counts were trending downward, and the patient appeared to be stabilizing. She still had an elevated WBC count, slight fever (temperature maximum of 101.4F for the past 24 hours), and lung crackles at the right lung base. Because Gram stain failed to identify Gram‐positive cocci clusters, and there was no culture evidence of methicillin‐resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa, vancomycin treatment was terminated and the patient was switched to single‐agent therapy with intravenous ceftriaxone, a nonpseudomonal third‐generation cephalosporin. On hospital day 5, there was continuing evidence of response to antimicrobial therapy. The patient reported feeling better and she was breathing comfortably. Her cough was much improved, sputum production was markedly decreased, and her fever had resolved. Now, on day 7, the patient is still afebrile, her WBC count is normal, and she has 96% oxygen saturation on room air.

The question before the clinician is whether to terminate or continue antimicrobial therapy, and if continued, with what regimen and for how long? In addition, if a decision is made to continue antimicrobial therapy, there is a possibility of switching from an intravenous to oral treatment regimen. An examination of the literature and current treatment guidelines for HCAP/HAP/VAP should enable a more informed decision, one that optimally benefits not only this patient, but all subsequent ones who might be exposed and infected with a resistant pathogen that develops when treatment is continued longer than necessary.

Clinical Trial to Support Shortened Duration of HCAP/HAP/VAP Therapy

A French study published in JAMA in 2003 provides more direct support that approximately 1 week of antimicrobial therapy produces effectiveness comparable to more traditional 23‐week therapy for most patients with VAP.37 In this prospective, multicenter, randomized, double‐blind (until day 8) clinical trial, 401 patients with microbiologically proven VAP were randomly assigned to receive either 8 days (n = 197) or 15 days (n = 204) of initial empiric antimicrobial therapy selected by the treating physician. No significant differences were observed between the 8‐day and 15‐day treatment groups for the 2 primary efficacy endpoints of death from any cause (18.8% vs 17.2%) and microbiologically documented pulmonary infection recurrence (28.9% vs 26.0%). There were also no differences between the groups for number of mechanical ventilation‐free days (8.7 vs 9.1 days), number of organ‐failure‐free days (8.7 vs 8.9 days), length of ICU stay (30.0 vs 27.5 days), unfavorable outcome (death, pulmonary infection recurrence, or prescription of a new antimicrobial) (46.2% vs 43.6%), mortality rate on day 60 (25.4% vs 27.9%), or in‐hospital mortality (32% vs 29.9%).

Conversely, patients in the 8‐day treatment group had significantly more antimicrobial‐free days (13.1 vs 8.7 days, P 0.001), and among patients who developed recurrent infections, multidrug‐resistant pathogens emerged more frequently in patients in the 15‐day versus 8‐day treatment group (62.0% vs 42.1%, P = 0.04). However, there was an apparent exception to the general comparable efficacy of the 8‐ and 15‐day treatment regimens for infections caused by nonfermenting Gram‐negative bacilli, including P aeruginosa. For primary infections caused by nonfermenting Gram‐negative bacilli, the 8‐day versus 15‐day regimen was associated with higher rates of pulmonary recurrence (40.6% vs 25.4%). Interestingly, the 8‐day regimen was not associated with more adverse outcomes here, just a higher recurrence rate. With respect to primary infections caused by MRSA, no differences were observed between the 2 treatment regimens for death for all causes (23.4% vs 30.2%) or pulmonary infection recurrence (33.3% vs 42.9%). Figure 1 presents the probability of survival data for the 8‐day and 15‐day treatment groups.

Figure 1

Hence, the data from the Chastre et al. study37 support use of an 8‐day (or shortened) regimen as standard antimicrobial therapy for most patients with VAP, with some possible exceptions. Additional studies provide further support for this general conclusion. For example, a prospective, randomized, controlled trial by Micek et al. evaluated the impact of using an antimicrobial discontinuation policy based on clinical criteria (discontinuation group; n = 150)versus the decision of treating physicians (conventional group, n = 140)to determine the duration of antimicrobial therapy for VAP, and observed a statistically shorter treatment duration in the discontinuation versus conventional management group (6.0 vs 8.0 days, P = 0.001), but no difference between the groups for hospital mortality (32.0% vs 37.1%), ICU length of stay (6.8 vs 7.0 days), or VAP recurrence (17.3% vs 19.3%).42 A prior study by the same group reported a shorter duration of antimicrobial therapy for VAP following implementation of an antimicrobial guideline (vs prior to implementation) (8.6 vs 14.8 days, P 0.001), and a lower rate of VAP recurrence among patients in the after period (7.7% vs 24.0%, P = 0.03). However, interpretation of the results was complicated by the fact that initial empiric therapy was more often appropriate during the after versus before guideline implementation period (94.2% vs 48.0%, P 0.001).40

A limited number of studies have focused further on shortened duration of therapy for patients with VAP caused by Gram‐negative bacteria, and particularly by nonfermenting Gram‐negative bacilli. A retrospective study by Hedrick et al. analyzed the relationship between antimicrobial duration and outcomes of 452 episodes of VAP in the ICU, 154 caused by nonfermenting Gram‐negative bacilli.39 In the study, 127 patients infected with a nonfermenting Gram‐negative bacillus received 9 days (mean 17.1 0.7 days) of antimicrobial therapy, while 27 received 3‐8 days (mean 6.4 0.3 days) of therapy. No significant differences were observed between the shorter‐ and longer‐duration groups for mortality (22% vs 14%, P = 0.38) or VAP recurrence (22% vs 34%, P = 0.27) for these patient populations. Table 2 provides the results for all 452 VAP episodes based on 8 days or 9 days of antimicrobial therapy.

Table 2.VAP in All Patients According to Treatment Duration

Patient Characteristic	8 Days (n = 98)	9 Days (n = 354)	P Value
NOTE: Adapted from Hedrick et al.39 Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; VAP, ventilator‐associated pneumonia.
Mean antimicrobial days	6.2	16.8	0.0001
Mean APACHE II	18	20	0.0009
% Trauma	71	68	0.63
Mean time to onset, days	17.7	17.8	0.97
Recurrence	11%	25%	0.004
Death	13%	11%	0.59
Nonfermenting Gram‐negative bacilli recurrence	22% (n = 27)	34% (n = 127)	0.27
Staphylococcus aureus recurrence	20% (n = 10)	38% (n = 47)	0.47

The retrospective nature of the study limits the ability to more confidently interpret the results, but the data appear to be consistent with the conclusion that short‐duration therapy does not necessarily increase recurrence or worsen other outcomes in patients with VAP caused by nonfermenting Gram‐negative bacilli. The most common Gram‐negative bacilli associated with VAP in the study were P aeruginosa (18% of all infections), Enterobacter cloacae (11%), Acinetobacter spp (11%), Klebsiella pneumoniae (7%), Stenotrophomonas maltophilia (7%), Serratia spp (7%), H influenzae (6%), and Escherichia coli (4%). In addition, the study results suggest that short‐duration therapy is at least as effective as longer‐duration therapy for the overall VAP population, with potential benefits in terms of reduced antimicrobial use and lower rate of recurrence.

Another recent retrospective analysis examining an even shorter course of antimicrobial therapy (5 days) for patients with HAP associated with Gram‐negative bacteria reported a low overall recurrence rate (14%) and a critical care mortality rate (34.2%) in line with prior studies of short‐term therapy for VAP/HAP.44 However, the HAP relapse rate was significantly higher in patients with HAP caused by nonfermenting Gram‐negative bacilli versus other Gram‐negative species (17% vs 2%, P = 0.03).

A recent US pilot study explored the use of repeat bronchoalveolar lavage (BAL) to guide antimicrobial duration in 52 patients with VAP, and compared the results with a matched control group of 52 VAP patients treated before institution of the BAL pathway.43 Antimicrobial therapy in the pathway patients was discontinued if pathogen growth was 10,000 colony forming units/mL on the repeat BAL performed on day 4 of therapy. One objective was to determine whether a repeat BAL strategy, such as the one here, might be able to identify patients with VAP due to nonfermenting Gram‐negative bacilli or other microorganisms who could be safely and effectively treated with shorter‐duration therapy.

Results showed that the antimicrobial duration was significantly shorter for patients in the pathway group than the matched control group (9.8 vs 3.8 days, P 0.001), including the subset of patients with VAP associated with nonfermenting Gram‐negative bacilli (10.7 vs 14.4 days, P 0.001). No significant differences were observed between the overall treatment populations for VAP recurrence, mechanical ventilator‐free ICU days, ICU‐free hospital days, or mortality. Repeat BAL showed most VAP isolates in the study group (83%) responded to initial therapy with a mean duration of 8.8 days. Nonresponders without concomitant infections received significantly longer treatment than pure responding isolates (14.4 vs 7.3 days, P 0.001), and the most common nonresponding microorganisms were P aeruginosa (41% response rate) and S maltophilia (50% response rate), 2 nonfermenting Gram‐negative bacilli.

Most nonfermenting Gram‐negative bacilli‐associated VAP isolates in the study group did respond on repeat BAL (59%). These responders were treated for a mean duration of 8.2 days, and exhibited a similar recurrence rate versus that observed for the matched control group (12.0% vs 17.9%, P = 0.71). These pilot study results suggest that repeat BAL might be used to identify patients likely to benefit from short‐duration therapy, including patients infected with nonfermenting Gram‐negative bacilli. Further study on this is needed.