David R. Snydman, MD, FACP, FIDSA

Early appropriate antimicrobial therapy is necessary to minimize the morbidity and mortality associated with hospital‐ or healthcare‐associated infections (HAIs). A number of studies have demonstrated that delayed or inadequate antimicrobial therapy leads to worse clinical outcomes and higher healthcare costs.1, 2 Inadequate antimicrobial therapy can also promote or enhance the development of resistance,2 with potential wide‐ranging impact beyond the immediate patient under care. Because delaying treatment until availability of culture results decreases the likelihood of a successful outcome, patients with a suspected invasive HAI commonly receive empiric therapy with a regimen expected to cover the most likely causative pathogens. Based on characteristics of the patient and healthcare facility or unit, likely pathogens may include bacteria or other pathogens resistant to 1 or more antimicrobial drug classes. This article discusses the various processes and factors that need to be considered when choosing empiric antibiotics in the hospital or other healthcare setting, and uses 3 case studies dealing with pneumonia, intra‐abdominal infection, and bacteremia, respectively, to illustrate points of interest.

IMPORTANCE OF EARLY ADEQUATE ANTIBIOTIC USE

The initial selection and early deployment of adequate antimicrobial therapy is critical for successful resolution of HAIs. The terms inadequate and inappropriate antimicrobial therapy are commonly used interchangeably in the literature, and can be defined as use of antimicrobial treatment without (sufficient) activity against the identified pathogen.2 Using an antibiotic for a fungal infection would be inadequate, as would using a drug or dosing regimen that is ineffective against the identified bacterial species due to resistance or a failure to achieve the drug's pharmacokinetic/pharmacodynamic target for efficacy against the pathogen. The complete absence of antimicrobial therapy is also considered inadequate therapy. Some investigators consider inappropriate therapy a more general term that includes excessive treatment as well as inadequate treatment.1 Others reserve the term inappropriate for use of an antimicrobial without activity against the identified pathogen, and the term inadequate for use of an insufficient regimen, either in terms of optimal dose, route of administration, timeliness, or failure to use combination therapy when appropriate.3 However, many or most research articles do not make the distinction, and the current article does not make a distinction.

In addition, some articles arbitrarily define inadequate therapy as either use (or absence) of a treatment without activity against the identified pathogen or a delay in appropriate or adequate treatment, eg, no patient exposure to adequate treatment within 24 hours of hospital admission. It is important to recognize this when evaluating articles in the literature. Other studies separate inadequate and delayed therapy as variables. However, when dealing with empiric therapy, the adequacy of initial empiric therapy cannot be fully determined until subsequent possession of the tissue/blood culture results.

PRACTICAL GUIDELINES FOR CHOOSING EMPIRIC ANTIBIOTICS

When choosing initial empiric therapy for a suspected hospital‐ or healthcare‐related bacterial infection, it is first important to determine if the patient has received prior antibiotic therapy, and if the patient has, then the clinician should consider choosing an antibiotic from a different drug class. This is because prior antibiotic therapy increases risk of infection with a pathogen resistant to the initial antibiotic drug and other members of its class. Also, depending on the site of the infection and likely pathogenic bacteria, the clinician will need to decide whether to initiate empiric therapy with a single antibiotic or combination of agents. A number of patient‐ and institution‐related factors can be utilized by clinicians to better identify the likely pathogen responsible for the infection, and it is critical to use this information when selecting initial empiric therapy. Finally, as is true whenever choosing antimicrobial or other drug therapies, clinicians need to consider and weigh the safety/tolerability profile, potential for drugdrug interactions, and relative cost of different treatment options. These will vary for individual patients receiving the same drug or drug combination.

MINIMIZING ANTIMICROBIAL RESISTANCE IN THE HOSPITAL OR HEALTHCARE SETTING

It is also important to consider the potential for development of antibiotic resistance when choosing initial empiric therapy. The current paradigm for treatment of serious hospital or healthcare infections is to prescribe broad‐spectrum antimicrobial therapy upfront while awaiting culture results, and to de‐escalate (or terminate) therapy once culture results are available4042or as 2 authors recently put it, get it right the first time, hit hard up front, and use large doses of broad‐spectrum antibiotics for a short period.41 The initial empiric antibiotic regimen should have a high likelihood of covering the most likely causative pathogens, including resistant species or strains. Furthermore, emergence of resistance is minimized when the initial regimen effectively covers the most likely causative pathogens, and subsequent culture results are utilized to streamline or narrow the initial regimen, when possible.40, 42 Emergence of resistance is also minimized by using the shortest duration of treatment with maximal clinical effect. (These latter 2 points are discussed in greater detail in the Kaye and File articles in this supplement.)

CASE 1: HEALTHCARE‐ASSOCIATED PNEUMONIA

Table 1 provides the key initial data for Case 1. The patient has a history of hypertension, congestive heart failure (CHF), and myocardial infarction (MI), and is receiving medications consistent with such a history. In terms of her acute presentation, cough, fever, chills, dyspnea, lung crackles (rales), X‐ray evidence of lung infiltrate, reduced oxygen saturation, elevated white blood cell (WBC) count, and increased percentage of WBC bands are all consistent with a diagnosis of pneumonia of relatively recent origin. Progressive worsening of symptoms within the previous 36 hours is also consistent with infection of recent origin. There are no neurologic symptoms, and cardiac function appears relatively normal, with no evidence of MI or cardiac arrhythmia based on electrocardiogram or heart rate, although there is evidence of continuing hypertension and perhaps CHF.

Given the patient's history of recent hospitalization, the clinician should consider that the pneumonia is most likely hospital‐ or healthcare‐acquired. Because she was described as developing the problem while in rehabilitation, it can be assumed that hospitalization occurred relatively recently. Hospital‐acquired pneumonia (HAP) is defined as pneumonia that occurs within 48 hours of hospital admission, and that was not incubating at the time of admission.47, 65 HAP accounts for approximately of 15% of all nosocomial/hospital‐acquired infections in the United States and up to 27% in the ICU,65, 66 and is a frequent cause of morbidity and mortality in this setting.65 In addition to hospitalization, other characteristics or risk factors for HAP include severe illness, hemodynamic compromise, depressed immune function, use of nasogastric tubes, and mechanical ventilation for the important subset of HAP patients with VAP.65 VAP is more precisely defined as HAP that arises >48‐72 hours after endotracheal intubation.47

Healthcare‐associated pneumonia (HCAP) is a more recently defined category that includes patients with HAP and VAP, and is characterized by hospitalization for 2 days in the preceding 90 days, or residence in a nursing home or extended‐care facility.47, 67, 68 Additional risk factors for HCAP include intravenous therapy at home (including antibiotics); intravenous chemotherapy or wound care within 30 days of the current infection; and recent attendance at a hospital or hemodialysis clinic.47 Most HAP or HCAP data have been derived from patients with VAP, and the 2005 American Thoracic Society (ATS)/IDSA guidelines for management of HAP, VAP, and HCAP recommend similar approaches for the initial treatment of patients with nonintubated HAP, VAP, and HCAP.47 There are general similarities between these 3 disease categories with respect to etiology, epidemiology of likely pathogens, and prognosis, and important differences compared with community‐acquired pneumonia (CAP), which in turn gives rise to different treatment strategies for HAP/VAP/HCAP and CAP.

Given an initial diagnosis of HAP or HCAP, the clinician should be considering the following questions: 1) What are the appropriate choices of antimicrobials? 2) What are the clinical parameters that should alert one to resistant organisms? 3) What are the appropriate cultures to order? 4) What is the role of Gram stain, if any?

CASE 2: INTRA‐ABDOMINAL INFECTION (DIVERTICULITIS)

Case 2 is a 56‐year‐old woman with no past medical history of note, who presented to her physician about 3 days ago, after 5 days of abdominal pain and fever (101.7F). She had an outpatient computed tomography (CT) scan, and the results suggested diverticulitis. After the CT scan, she was given amoxicillin/clavulanate. She now presents to the emergency department (3 days later) with worsening pain, fever, and severe weakness. A physical exam shows low blood pressure (84/58 mmHg) and tachycardia (132 bpm). Her respiratory rate is 22 breaths per minute. Oxygenation (O₂ saturation 99% on room air) is normal, and the patient's lungs are clear. Abdominal examination reveals bowel sounds and diffuse tenderness, particularly at the left lower quadrant, and there is evidence of guarding and rebound. Her blood chemistry is generally normal, although the WBC count is elevated (15,200/mm³). No abnormalities are evident on chest X‐ray. The patient's blood pressure increases to 96/64 mmHg after she is infused with 2 liters of normal saline. She undergoes another CT scan and is admitted to the ICU. The CT scan shows diverticulitis with abscess and walled‐off perforation. An interventional radiologist inserts a pigtail catheter into the abscess for sample collection, and the samples are sent to the microbiology laboratory for culture.

The radiology results indicate that the patient has what may be considered a complicated intra‐abdominal infection (diverticulitis with abscess), community‐acquired. Because empiric therapy is usually necessary for patients with complicated or even uncomplicated intra‐abdominal infections, the clinician should now be asking: What is optimal empiric antimicrobial therapy for this patient? Both prior75 and current guidelines76 for the management of intra‐abdominal infection indicate that antimicrobial therapy should be initiated when a patient receives such a diagnosis or when such an infection is considered likely. In making the determination of initial empiric therapy, the clinician should also be considering whether there is likely involvement of resistant Gram‐negative bacteria, and if so, how that would change the choice of antibiotic therapy.

Enteric Gram‐negative bacilli such as E coli and K pneumoniae are the most common microorganisms isolated from patients with intra‐abdominal infections, although Gram‐positive cocci (Staphylococcus or Streptococcus spp, and less commonly, enterococci) and obligate anaerobic organisms (particularly, Bacteroides fragilis) are also frequent components of intra‐abdominal infections.77 The relative frequency of bacterial pathogens shifts in patients who acquired their intra‐abdominal infection in the hospital versus community setting, with greater prevalence of Enterobacter, P aeruginosa, and Enterococcus spp, and less frequent isolation of E coli and streptococci.77 Recent results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) indicate a general increase in resistance among Gram‐negative bacilli isolated from patients with intra‐abdominal infections treated in medical centers, primarily due to acquisition of ESBLs.78, 79 This is true both in the United States79 and worldwide.78 Carbapenems continue to exhibit consistent activity against Gram‐negative bacilli isolated from intra‐abdominal infections, including ESBL‐producers.

Selection of initial empiric therapy should incorporate information from the literature and local antibiograms to determine the most likely causative pathogen(s), including ones with reduced susceptibility or resistance to commonly employed antibiotics. Then an antibiotic regimen should be selected that provides coverage of likely pathogens with minimal adverse events, including risk of collateral damage such as Clostridium difficile‐associated disease. Dose and dosing interval considerations are also important, particularly in patients with reduced renal or hepatic function. The general approach is to select an antibiotic or combination of antibiotic agents to provide coverage of the bacterial pathogens most commonly isolated from patients with intra‐abdominal infections, ie, aerobic/facultative anaerobic Gram‐negative bacilli, aerobic Gram‐positive cocci, and obligate anaerobic organisms.77 Table 4 presents the antibiotic treatment recommendations from the Surgical Infection Society and IDSA 2010 guidelines for management of patients with complicated intra‐abdominal infections.76 The guidelines are based on whether the patient has mild‐to‐moderate or high‐risk/severe community‐acquired complicated intra‐abdominal infections. Recommendations for the empiric treatment of hospital or healthcare‐associated complicated intra‐abdominal infections are largely based on local antibiogram (microbiologic) results, and include some similarities and differences compared with recommended treatment of high‐risk community‐acquired infections, as illustrated in Table 5.76 A patient with mild‐to‐moderate infection would be someone who does not require intensive care, and has community‐acquired intra‐abdominal infection due to secondary peritonitis. Severe intra‐abdominal infection would be defined by requiring intensive care, having sepsis, or having healthcare‐acquired peritonitis (such as a bowel leak following surgery). In line with these guidelines, and considering the case patient's risk profile, ciprofloxacin plus metronidazole was selected as initial empiric therapy, because she had not been hospitalized previously. Although she was hypotensive, the blood pressure was easily raised with fluids.

There are a number of controversies in intra‐abdominal sepsis management. These include whether or when initial empiric therapy should provide coverage of Enterococcus/vancomycin‐resistant enterococci or MRSA, when the regimen should include an antifungal to cover possible Candida spp infection, the role of resistant Bacteroides in intra‐abdominal infections, and when clinicians should be particularly concerned about ESBL‐producing or other resistant Gram‐negative bacteria. These topics are beyond the reach of the present article, but are and will continue to be important issues for clinicians to grapple with when selecting initial empiric therapy for patients with intra‐abdominal infections.

CASE 3: CENTRAL LINE‐ASSOCIATED BACTEREMIA

The third case is a 56‐year‐old man with epilepsy who presents to the emergency department with status epilepticus. Subsequent resuscitative efforts included intubation and placement of an internal jugular central line. The patient was admitted to the ICU, and aggressive treatment was initiated with repeated intravenous dosing of lorazepam and loading with fosphenytoin, which successfully broke the seizure. Subsequent imaging and laboratory tests failed to reveal any specific cause for the status epilepticus. The patient was extubated on day 4 and transferred out of the ICU. On day 5, he spiked a fever of 103.4F. He did not report any new symptoms, and there was no evidence of cough, sputum, shortness of breath, abdominal pain, diarrhea, or urinary symptoms. Physical examination revealed normal blood pressure (122/68 mmHg) and oxygen saturation (95% on room air), a normal respiratory rate (12 breaths per minute), clear lungs, no edema, no heart murmur, and normal neurologic findings. The patient's heart rate was somewhat high (102 bpm), and his temperature remained elevated (103.4F). Abdominal examination revealed no tenderness, and bowel sounds were present. Laboratory results were normal, except for an elevated WBC count (17,000/mm3 of blood). The chest X‐ray was clear.

This is an example of a patient with fever and leukocytosis of unknown origin. There are no focal findings indicative of a particular infection site or process. The patient was treated in the ICU, including use of a central catheter. Differential diagnosis of fever and leukocytosis without source, in a patient from the ICU with a central line, should consider catheter‐associated bacteremia; C difficile‐associated disease; a silent intra‐abdominal process, such as cholangitis or gangrenous cholecystitis; drug fever related to (in this patient) anticonvulsant therapy; urinary tract infection (no evidence for in this patient); or pulmonary embolism. The clinician needs to make a decision as to the relative benefits of empiric antibiotic or other antimicrobial treatment versus observation. If the patient is to be treated with an antibiotic, then a choice has to be made as to the best agent for the patient at hand.

In terms of the choice of antibiotics for a patient such as the one here, the clinician needs to assess the severity of illness and, when doing so, determine what infection site or sites should be covered, and the most likely sites of infection. A determination of likely pathogens also needs to be made. Cultures should be obtained prior to initiating therapy with a regimen providing broad coverage of the most likely pathogen(s), while allowing for the possibility of later de‐escalation based on clinical evaluation and culture results. This is similar to the situation for initial empiric treatment of pneumonia or intra‐abdominal infection. In general, the clinician should obtain blood, urine, and possibly sputum cultures to aid in future decision making. Furthermore, if the patient has diarrhea (which the current one does not), the clinician should obtain a stool for C difficile toxin analysis.

For the case illustrated here, the clinician determined catheter‐associated bacteremia was a strong possibility, and decided to initiate empiric therapy with vancomycin and piperacillin‐tazobactam to provide coverage of MRSA and resistant Gram‐negative bacteria. The most common causes of nosocomial or catheter‐associated bloodstream infections (BSIs) are coagulase‐negative staphylococci, S aureus, enterococci, and Candida spp,8082 but Gram‐negative bacilli like P aeruginosa, Klebsiella spp, and E coli (among others) are also frequently involved, particularly in patients with catheter‐associated BSIs.81 Moreover, significant and increasing percentages of Gram‐negative bacilli exhibit resistance to 1 or more antibiotic classes,8385 and >50% of S aureus are typically MRSA,82, 83, 85, 86 although there has been some decline in MRSA central line‐associated BSIs in US ICUs in recent years.87

Clinical practice guidelines from the IDSA recommend vancomycin (or daptomycin) for the management of MRSA bacteremia,88 while piperacillin‐tazobactam is frequently empirically added to Gram‐positive coverage for serious hospital‐acquired infections because of its broad activity against many pathogenic bacteria, including some ESBL‐producing Gram‐negative bacteria and P aeruginosa,89 which are significant causes of patient morbidity and mortality.36, 90 However, to be effective, both vancomycin and piperacillin‐tazobactam need to be properly dosed to maximize their pharmacodynamic properties. Guidelines from the American Society of Health‐System Pharmacists, IDSA, and Society of Infectious Diseases Pharmacists recommend vancomycin serum trough concentrations of 15‐20 mg/L for patients with bacteremia due to MRSA.91 These levels are recommended to improve penetration, increase the probability of obtaining optimal target serum concentrations, and improve clinical outcomes. To achieve these trough levels, the guidelines recommend doses of 15‐20 mg/kg of actual body weight given every 8‐12 hours for most patients with normal renal function, assuming a minimum inhibitory concentration (MIC) of 1 mg/L. In seriously ill patients, the guidelines recommend using a loading dose of 25‐30 mg/kg to facilitate rapid attainment of the target trough serum vancomycin level. (If the MIC is 2 mg/L, then the targeted pharmacodynamic parameter for vancomycin is unachievable, and an alternative therapy should be considered.)

The pharmacodynamic parameter that best predicts efficacy for ‐lactams like piperacillin is the duration of time that free drug concentrations remain above the MIC (T>MIC), with near maximal bactericidal effects for penicillins when the free drug concentrations remain above the MIC for 50% of the dosing interval.92 The target pharmacodynamic parameter for piperacillin‐tazobactam (50% T>MIC) may be better achieved with use of prolonged or extended infusion regimens than with intermittent, more rapidly infused, administration schedules. Lodise and coworkers recently reported that extended infusion (3.375 g intravenously [IV] for 4 hours every 8 hours) versus intermittent infusion of piperacillin‐tazobactam (3.375 g IV for 30 minutes every 4 to 6 hours) was associated with a significantly lower 14‐day mortality rate (12.2% vs 31.6%, P = 0.04) and median duration of hospital stay (21 vs 38 days, P = 0.02) in a cohort of hospitalized patients with a P aeruginosa infection.93 Based on data such as these, the case patient here was initiated on vancomycin (15‐20 mg/kg every 812 hours) and piperacillin‐tazobactam (3.375 g IV for 4 hours every 8 hours).

CONCLUSIONS

Successful treatment of patients with serious, life‐threatening hospital‐ or healthcare‐associated infections depends on early adequate antimicrobial treatment. To accomplish this, empiric therapy is typically employed with a broad‐spectrum regimen intended to cover likely causative pathogen(s) based on local antibiograms and risk factors for involvement of resistant microorganisms. Choice of empiric therapy should also be based on the site of infection, and make use of clinical practice guidelines, when available. Although this approach often means treatment with a regimen that is unnecessarily broad, based on subsequent culture findings, it is warranted based on the significant negative impact of initial inadequate/emnappropriate empiric therapy, and the inability to remedy this negative effect by later modification of antimicrobial therapy. The possibility of de‐escalating the initial broad‐spectrum regimen is revisited after the results from cultures collected prior to beginning empiric therapy become available, generally 2‐4 days after beginning the process. In this manner, both the dangers of initial inadequate empiric therapy and overuse or misuse of antimicrobials are minimized. To further minimize the risk of antimicrobial resistance linked to overuse or misuse of antimicrobial agents, care should be taken to avoid treatment of colonization or culture contamination.

Early appropriate antimicrobial therapy is necessary to minimize the morbidity and mortality associated with hospital‐ or healthcare‐associated infections (HAIs). A number of studies have demonstrated that delayed or inadequate antimicrobial therapy leads to worse clinical outcomes and higher healthcare costs.1, 2 Inadequate antimicrobial therapy can also promote or enhance the development of resistance,2 with potential wide‐ranging impact beyond the immediate patient under care. Because delaying treatment until availability of culture results decreases the likelihood of a successful outcome, patients with a suspected invasive HAI commonly receive empiric therapy with a regimen expected to cover the most likely causative pathogens. Based on characteristics of the patient and healthcare facility or unit, likely pathogens may include bacteria or other pathogens resistant to 1 or more antimicrobial drug classes. This article discusses the various processes and factors that need to be considered when choosing empiric antibiotics in the hospital or other healthcare setting, and uses 3 case studies dealing with pneumonia, intra‐abdominal infection, and bacteremia, respectively, to illustrate points of interest.

IMPORTANCE OF EARLY ADEQUATE ANTIBIOTIC USE

The initial selection and early deployment of adequate antimicrobial therapy is critical for successful resolution of HAIs. The terms inadequate and inappropriate antimicrobial therapy are commonly used interchangeably in the literature, and can be defined as use of antimicrobial treatment without (sufficient) activity against the identified pathogen.2 Using an antibiotic for a fungal infection would be inadequate, as would using a drug or dosing regimen that is ineffective against the identified bacterial species due to resistance or a failure to achieve the drug's pharmacokinetic/pharmacodynamic target for efficacy against the pathogen. The complete absence of antimicrobial therapy is also considered inadequate therapy. Some investigators consider inappropriate therapy a more general term that includes excessive treatment as well as inadequate treatment.1 Others reserve the term inappropriate for use of an antimicrobial without activity against the identified pathogen, and the term inadequate for use of an insufficient regimen, either in terms of optimal dose, route of administration, timeliness, or failure to use combination therapy when appropriate.3 However, many or most research articles do not make the distinction, and the current article does not make a distinction.

In addition, some articles arbitrarily define inadequate therapy as either use (or absence) of a treatment without activity against the identified pathogen or a delay in appropriate or adequate treatment, eg, no patient exposure to adequate treatment within 24 hours of hospital admission. It is important to recognize this when evaluating articles in the literature. Other studies separate inadequate and delayed therapy as variables. However, when dealing with empiric therapy, the adequacy of initial empiric therapy cannot be fully determined until subsequent possession of the tissue/blood culture results.

PRACTICAL GUIDELINES FOR CHOOSING EMPIRIC ANTIBIOTICS

When choosing initial empiric therapy for a suspected hospital‐ or healthcare‐related bacterial infection, it is first important to determine if the patient has received prior antibiotic therapy, and if the patient has, then the clinician should consider choosing an antibiotic from a different drug class. This is because prior antibiotic therapy increases risk of infection with a pathogen resistant to the initial antibiotic drug and other members of its class. Also, depending on the site of the infection and likely pathogenic bacteria, the clinician will need to decide whether to initiate empiric therapy with a single antibiotic or combination of agents. A number of patient‐ and institution‐related factors can be utilized by clinicians to better identify the likely pathogen responsible for the infection, and it is critical to use this information when selecting initial empiric therapy. Finally, as is true whenever choosing antimicrobial or other drug therapies, clinicians need to consider and weigh the safety/tolerability profile, potential for drugdrug interactions, and relative cost of different treatment options. These will vary for individual patients receiving the same drug or drug combination.

MINIMIZING ANTIMICROBIAL RESISTANCE IN THE HOSPITAL OR HEALTHCARE SETTING

It is also important to consider the potential for development of antibiotic resistance when choosing initial empiric therapy. The current paradigm for treatment of serious hospital or healthcare infections is to prescribe broad‐spectrum antimicrobial therapy upfront while awaiting culture results, and to de‐escalate (or terminate) therapy once culture results are available4042or as 2 authors recently put it, get it right the first time, hit hard up front, and use large doses of broad‐spectrum antibiotics for a short period.41 The initial empiric antibiotic regimen should have a high likelihood of covering the most likely causative pathogens, including resistant species or strains. Furthermore, emergence of resistance is minimized when the initial regimen effectively covers the most likely causative pathogens, and subsequent culture results are utilized to streamline or narrow the initial regimen, when possible.40, 42 Emergence of resistance is also minimized by using the shortest duration of treatment with maximal clinical effect. (These latter 2 points are discussed in greater detail in the Kaye and File articles in this supplement.)

CASE 1: HEALTHCARE‐ASSOCIATED PNEUMONIA

Table 1 provides the key initial data for Case 1. The patient has a history of hypertension, congestive heart failure (CHF), and myocardial infarction (MI), and is receiving medications consistent with such a history. In terms of her acute presentation, cough, fever, chills, dyspnea, lung crackles (rales), X‐ray evidence of lung infiltrate, reduced oxygen saturation, elevated white blood cell (WBC) count, and increased percentage of WBC bands are all consistent with a diagnosis of pneumonia of relatively recent origin. Progressive worsening of symptoms within the previous 36 hours is also consistent with infection of recent origin. There are no neurologic symptoms, and cardiac function appears relatively normal, with no evidence of MI or cardiac arrhythmia based on electrocardiogram or heart rate, although there is evidence of continuing hypertension and perhaps CHF.

Given the patient's history of recent hospitalization, the clinician should consider that the pneumonia is most likely hospital‐ or healthcare‐acquired. Because she was described as developing the problem while in rehabilitation, it can be assumed that hospitalization occurred relatively recently. Hospital‐acquired pneumonia (HAP) is defined as pneumonia that occurs within 48 hours of hospital admission, and that was not incubating at the time of admission.47, 65 HAP accounts for approximately of 15% of all nosocomial/hospital‐acquired infections in the United States and up to 27% in the ICU,65, 66 and is a frequent cause of morbidity and mortality in this setting.65 In addition to hospitalization, other characteristics or risk factors for HAP include severe illness, hemodynamic compromise, depressed immune function, use of nasogastric tubes, and mechanical ventilation for the important subset of HAP patients with VAP.65 VAP is more precisely defined as HAP that arises >48‐72 hours after endotracheal intubation.47

Healthcare‐associated pneumonia (HCAP) is a more recently defined category that includes patients with HAP and VAP, and is characterized by hospitalization for 2 days in the preceding 90 days, or residence in a nursing home or extended‐care facility.47, 67, 68 Additional risk factors for HCAP include intravenous therapy at home (including antibiotics); intravenous chemotherapy or wound care within 30 days of the current infection; and recent attendance at a hospital or hemodialysis clinic.47 Most HAP or HCAP data have been derived from patients with VAP, and the 2005 American Thoracic Society (ATS)/IDSA guidelines for management of HAP, VAP, and HCAP recommend similar approaches for the initial treatment of patients with nonintubated HAP, VAP, and HCAP.47 There are general similarities between these 3 disease categories with respect to etiology, epidemiology of likely pathogens, and prognosis, and important differences compared with community‐acquired pneumonia (CAP), which in turn gives rise to different treatment strategies for HAP/VAP/HCAP and CAP.

Given an initial diagnosis of HAP or HCAP, the clinician should be considering the following questions: 1) What are the appropriate choices of antimicrobials? 2) What are the clinical parameters that should alert one to resistant organisms? 3) What are the appropriate cultures to order? 4) What is the role of Gram stain, if any?

CASE 2: INTRA‐ABDOMINAL INFECTION (DIVERTICULITIS)

Case 2 is a 56‐year‐old woman with no past medical history of note, who presented to her physician about 3 days ago, after 5 days of abdominal pain and fever (101.7F). She had an outpatient computed tomography (CT) scan, and the results suggested diverticulitis. After the CT scan, she was given amoxicillin/clavulanate. She now presents to the emergency department (3 days later) with worsening pain, fever, and severe weakness. A physical exam shows low blood pressure (84/58 mmHg) and tachycardia (132 bpm). Her respiratory rate is 22 breaths per minute. Oxygenation (O₂ saturation 99% on room air) is normal, and the patient's lungs are clear. Abdominal examination reveals bowel sounds and diffuse tenderness, particularly at the left lower quadrant, and there is evidence of guarding and rebound. Her blood chemistry is generally normal, although the WBC count is elevated (15,200/mm³). No abnormalities are evident on chest X‐ray. The patient's blood pressure increases to 96/64 mmHg after she is infused with 2 liters of normal saline. She undergoes another CT scan and is admitted to the ICU. The CT scan shows diverticulitis with abscess and walled‐off perforation. An interventional radiologist inserts a pigtail catheter into the abscess for sample collection, and the samples are sent to the microbiology laboratory for culture.

The radiology results indicate that the patient has what may be considered a complicated intra‐abdominal infection (diverticulitis with abscess), community‐acquired. Because empiric therapy is usually necessary for patients with complicated or even uncomplicated intra‐abdominal infections, the clinician should now be asking: What is optimal empiric antimicrobial therapy for this patient? Both prior75 and current guidelines76 for the management of intra‐abdominal infection indicate that antimicrobial therapy should be initiated when a patient receives such a diagnosis or when such an infection is considered likely. In making the determination of initial empiric therapy, the clinician should also be considering whether there is likely involvement of resistant Gram‐negative bacteria, and if so, how that would change the choice of antibiotic therapy.

Enteric Gram‐negative bacilli such as E coli and K pneumoniae are the most common microorganisms isolated from patients with intra‐abdominal infections, although Gram‐positive cocci (Staphylococcus or Streptococcus spp, and less commonly, enterococci) and obligate anaerobic organisms (particularly, Bacteroides fragilis) are also frequent components of intra‐abdominal infections.77 The relative frequency of bacterial pathogens shifts in patients who acquired their intra‐abdominal infection in the hospital versus community setting, with greater prevalence of Enterobacter, P aeruginosa, and Enterococcus spp, and less frequent isolation of E coli and streptococci.77 Recent results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) indicate a general increase in resistance among Gram‐negative bacilli isolated from patients with intra‐abdominal infections treated in medical centers, primarily due to acquisition of ESBLs.78, 79 This is true both in the United States79 and worldwide.78 Carbapenems continue to exhibit consistent activity against Gram‐negative bacilli isolated from intra‐abdominal infections, including ESBL‐producers.

Selection of initial empiric therapy should incorporate information from the literature and local antibiograms to determine the most likely causative pathogen(s), including ones with reduced susceptibility or resistance to commonly employed antibiotics. Then an antibiotic regimen should be selected that provides coverage of likely pathogens with minimal adverse events, including risk of collateral damage such as Clostridium difficile‐associated disease. Dose and dosing interval considerations are also important, particularly in patients with reduced renal or hepatic function. The general approach is to select an antibiotic or combination of antibiotic agents to provide coverage of the bacterial pathogens most commonly isolated from patients with intra‐abdominal infections, ie, aerobic/facultative anaerobic Gram‐negative bacilli, aerobic Gram‐positive cocci, and obligate anaerobic organisms.77 Table 4 presents the antibiotic treatment recommendations from the Surgical Infection Society and IDSA 2010 guidelines for management of patients with complicated intra‐abdominal infections.76 The guidelines are based on whether the patient has mild‐to‐moderate or high‐risk/severe community‐acquired complicated intra‐abdominal infections. Recommendations for the empiric treatment of hospital or healthcare‐associated complicated intra‐abdominal infections are largely based on local antibiogram (microbiologic) results, and include some similarities and differences compared with recommended treatment of high‐risk community‐acquired infections, as illustrated in Table 5.76 A patient with mild‐to‐moderate infection would be someone who does not require intensive care, and has community‐acquired intra‐abdominal infection due to secondary peritonitis. Severe intra‐abdominal infection would be defined by requiring intensive care, having sepsis, or having healthcare‐acquired peritonitis (such as a bowel leak following surgery). In line with these guidelines, and considering the case patient's risk profile, ciprofloxacin plus metronidazole was selected as initial empiric therapy, because she had not been hospitalized previously. Although she was hypotensive, the blood pressure was easily raised with fluids.

There are a number of controversies in intra‐abdominal sepsis management. These include whether or when initial empiric therapy should provide coverage of Enterococcus/vancomycin‐resistant enterococci or MRSA, when the regimen should include an antifungal to cover possible Candida spp infection, the role of resistant Bacteroides in intra‐abdominal infections, and when clinicians should be particularly concerned about ESBL‐producing or other resistant Gram‐negative bacteria. These topics are beyond the reach of the present article, but are and will continue to be important issues for clinicians to grapple with when selecting initial empiric therapy for patients with intra‐abdominal infections.

CASE 3: CENTRAL LINE‐ASSOCIATED BACTEREMIA

The third case is a 56‐year‐old man with epilepsy who presents to the emergency department with status epilepticus. Subsequent resuscitative efforts included intubation and placement of an internal jugular central line. The patient was admitted to the ICU, and aggressive treatment was initiated with repeated intravenous dosing of lorazepam and loading with fosphenytoin, which successfully broke the seizure. Subsequent imaging and laboratory tests failed to reveal any specific cause for the status epilepticus. The patient was extubated on day 4 and transferred out of the ICU. On day 5, he spiked a fever of 103.4F. He did not report any new symptoms, and there was no evidence of cough, sputum, shortness of breath, abdominal pain, diarrhea, or urinary symptoms. Physical examination revealed normal blood pressure (122/68 mmHg) and oxygen saturation (95% on room air), a normal respiratory rate (12 breaths per minute), clear lungs, no edema, no heart murmur, and normal neurologic findings. The patient's heart rate was somewhat high (102 bpm), and his temperature remained elevated (103.4F). Abdominal examination revealed no tenderness, and bowel sounds were present. Laboratory results were normal, except for an elevated WBC count (17,000/mm3 of blood). The chest X‐ray was clear.

This is an example of a patient with fever and leukocytosis of unknown origin. There are no focal findings indicative of a particular infection site or process. The patient was treated in the ICU, including use of a central catheter. Differential diagnosis of fever and leukocytosis without source, in a patient from the ICU with a central line, should consider catheter‐associated bacteremia; C difficile‐associated disease; a silent intra‐abdominal process, such as cholangitis or gangrenous cholecystitis; drug fever related to (in this patient) anticonvulsant therapy; urinary tract infection (no evidence for in this patient); or pulmonary embolism. The clinician needs to make a decision as to the relative benefits of empiric antibiotic or other antimicrobial treatment versus observation. If the patient is to be treated with an antibiotic, then a choice has to be made as to the best agent for the patient at hand.

In terms of the choice of antibiotics for a patient such as the one here, the clinician needs to assess the severity of illness and, when doing so, determine what infection site or sites should be covered, and the most likely sites of infection. A determination of likely pathogens also needs to be made. Cultures should be obtained prior to initiating therapy with a regimen providing broad coverage of the most likely pathogen(s), while allowing for the possibility of later de‐escalation based on clinical evaluation and culture results. This is similar to the situation for initial empiric treatment of pneumonia or intra‐abdominal infection. In general, the clinician should obtain blood, urine, and possibly sputum cultures to aid in future decision making. Furthermore, if the patient has diarrhea (which the current one does not), the clinician should obtain a stool for C difficile toxin analysis.

For the case illustrated here, the clinician determined catheter‐associated bacteremia was a strong possibility, and decided to initiate empiric therapy with vancomycin and piperacillin‐tazobactam to provide coverage of MRSA and resistant Gram‐negative bacteria. The most common causes of nosocomial or catheter‐associated bloodstream infections (BSIs) are coagulase‐negative staphylococci, S aureus, enterococci, and Candida spp,8082 but Gram‐negative bacilli like P aeruginosa, Klebsiella spp, and E coli (among others) are also frequently involved, particularly in patients with catheter‐associated BSIs.81 Moreover, significant and increasing percentages of Gram‐negative bacilli exhibit resistance to 1 or more antibiotic classes,8385 and >50% of S aureus are typically MRSA,82, 83, 85, 86 although there has been some decline in MRSA central line‐associated BSIs in US ICUs in recent years.87

Clinical practice guidelines from the IDSA recommend vancomycin (or daptomycin) for the management of MRSA bacteremia,88 while piperacillin‐tazobactam is frequently empirically added to Gram‐positive coverage for serious hospital‐acquired infections because of its broad activity against many pathogenic bacteria, including some ESBL‐producing Gram‐negative bacteria and P aeruginosa,89 which are significant causes of patient morbidity and mortality.36, 90 However, to be effective, both vancomycin and piperacillin‐tazobactam need to be properly dosed to maximize their pharmacodynamic properties. Guidelines from the American Society of Health‐System Pharmacists, IDSA, and Society of Infectious Diseases Pharmacists recommend vancomycin serum trough concentrations of 15‐20 mg/L for patients with bacteremia due to MRSA.91 These levels are recommended to improve penetration, increase the probability of obtaining optimal target serum concentrations, and improve clinical outcomes. To achieve these trough levels, the guidelines recommend doses of 15‐20 mg/kg of actual body weight given every 8‐12 hours for most patients with normal renal function, assuming a minimum inhibitory concentration (MIC) of 1 mg/L. In seriously ill patients, the guidelines recommend using a loading dose of 25‐30 mg/kg to facilitate rapid attainment of the target trough serum vancomycin level. (If the MIC is 2 mg/L, then the targeted pharmacodynamic parameter for vancomycin is unachievable, and an alternative therapy should be considered.)

The pharmacodynamic parameter that best predicts efficacy for ‐lactams like piperacillin is the duration of time that free drug concentrations remain above the MIC (T>MIC), with near maximal bactericidal effects for penicillins when the free drug concentrations remain above the MIC for 50% of the dosing interval.92 The target pharmacodynamic parameter for piperacillin‐tazobactam (50% T>MIC) may be better achieved with use of prolonged or extended infusion regimens than with intermittent, more rapidly infused, administration schedules. Lodise and coworkers recently reported that extended infusion (3.375 g intravenously [IV] for 4 hours every 8 hours) versus intermittent infusion of piperacillin‐tazobactam (3.375 g IV for 30 minutes every 4 to 6 hours) was associated with a significantly lower 14‐day mortality rate (12.2% vs 31.6%, P = 0.04) and median duration of hospital stay (21 vs 38 days, P = 0.02) in a cohort of hospitalized patients with a P aeruginosa infection.93 Based on data such as these, the case patient here was initiated on vancomycin (15‐20 mg/kg every 812 hours) and piperacillin‐tazobactam (3.375 g IV for 4 hours every 8 hours).

CONCLUSIONS

Successful treatment of patients with serious, life‐threatening hospital‐ or healthcare‐associated infections depends on early adequate antimicrobial treatment. To accomplish this, empiric therapy is typically employed with a broad‐spectrum regimen intended to cover likely causative pathogen(s) based on local antibiograms and risk factors for involvement of resistant microorganisms. Choice of empiric therapy should also be based on the site of infection, and make use of clinical practice guidelines, when available. Although this approach often means treatment with a regimen that is unnecessarily broad, based on subsequent culture findings, it is warranted based on the significant negative impact of initial inadequate/emnappropriate empiric therapy, and the inability to remedy this negative effect by later modification of antimicrobial therapy. The possibility of de‐escalating the initial broad‐spectrum regimen is revisited after the results from cultures collected prior to beginning empiric therapy become available, generally 2‐4 days after beginning the process. In this manner, both the dangers of initial inadequate empiric therapy and overuse or misuse of antimicrobials are minimized. To further minimize the risk of antimicrobial resistance linked to overuse or misuse of antimicrobial agents, care should be taken to avoid treatment of colonization or culture contamination.

Early appropriate antimicrobial therapy is necessary to minimize the morbidity and mortality associated with hospital‐ or healthcare‐associated infections (HAIs). A number of studies have demonstrated that delayed or inadequate antimicrobial therapy leads to worse clinical outcomes and higher healthcare costs.1, 2 Inadequate antimicrobial therapy can also promote or enhance the development of resistance,2 with potential wide‐ranging impact beyond the immediate patient under care. Because delaying treatment until availability of culture results decreases the likelihood of a successful outcome, patients with a suspected invasive HAI commonly receive empiric therapy with a regimen expected to cover the most likely causative pathogens. Based on characteristics of the patient and healthcare facility or unit, likely pathogens may include bacteria or other pathogens resistant to 1 or more antimicrobial drug classes. This article discusses the various processes and factors that need to be considered when choosing empiric antibiotics in the hospital or other healthcare setting, and uses 3 case studies dealing with pneumonia, intra‐abdominal infection, and bacteremia, respectively, to illustrate points of interest.

IMPORTANCE OF EARLY ADEQUATE ANTIBIOTIC USE

The initial selection and early deployment of adequate antimicrobial therapy is critical for successful resolution of HAIs. The terms inadequate and inappropriate antimicrobial therapy are commonly used interchangeably in the literature, and can be defined as use of antimicrobial treatment without (sufficient) activity against the identified pathogen.2 Using an antibiotic for a fungal infection would be inadequate, as would using a drug or dosing regimen that is ineffective against the identified bacterial species due to resistance or a failure to achieve the drug's pharmacokinetic/pharmacodynamic target for efficacy against the pathogen. The complete absence of antimicrobial therapy is also considered inadequate therapy. Some investigators consider inappropriate therapy a more general term that includes excessive treatment as well as inadequate treatment.1 Others reserve the term inappropriate for use of an antimicrobial without activity against the identified pathogen, and the term inadequate for use of an insufficient regimen, either in terms of optimal dose, route of administration, timeliness, or failure to use combination therapy when appropriate.3 However, many or most research articles do not make the distinction, and the current article does not make a distinction.

In addition, some articles arbitrarily define inadequate therapy as either use (or absence) of a treatment without activity against the identified pathogen or a delay in appropriate or adequate treatment, eg, no patient exposure to adequate treatment within 24 hours of hospital admission. It is important to recognize this when evaluating articles in the literature. Other studies separate inadequate and delayed therapy as variables. However, when dealing with empiric therapy, the adequacy of initial empiric therapy cannot be fully determined until subsequent possession of the tissue/blood culture results.

PRACTICAL GUIDELINES FOR CHOOSING EMPIRIC ANTIBIOTICS

When choosing initial empiric therapy for a suspected hospital‐ or healthcare‐related bacterial infection, it is first important to determine if the patient has received prior antibiotic therapy, and if the patient has, then the clinician should consider choosing an antibiotic from a different drug class. This is because prior antibiotic therapy increases risk of infection with a pathogen resistant to the initial antibiotic drug and other members of its class. Also, depending on the site of the infection and likely pathogenic bacteria, the clinician will need to decide whether to initiate empiric therapy with a single antibiotic or combination of agents. A number of patient‐ and institution‐related factors can be utilized by clinicians to better identify the likely pathogen responsible for the infection, and it is critical to use this information when selecting initial empiric therapy. Finally, as is true whenever choosing antimicrobial or other drug therapies, clinicians need to consider and weigh the safety/tolerability profile, potential for drugdrug interactions, and relative cost of different treatment options. These will vary for individual patients receiving the same drug or drug combination.

MINIMIZING ANTIMICROBIAL RESISTANCE IN THE HOSPITAL OR HEALTHCARE SETTING

It is also important to consider the potential for development of antibiotic resistance when choosing initial empiric therapy. The current paradigm for treatment of serious hospital or healthcare infections is to prescribe broad‐spectrum antimicrobial therapy upfront while awaiting culture results, and to de‐escalate (or terminate) therapy once culture results are available4042or as 2 authors recently put it, get it right the first time, hit hard up front, and use large doses of broad‐spectrum antibiotics for a short period.41 The initial empiric antibiotic regimen should have a high likelihood of covering the most likely causative pathogens, including resistant species or strains. Furthermore, emergence of resistance is minimized when the initial regimen effectively covers the most likely causative pathogens, and subsequent culture results are utilized to streamline or narrow the initial regimen, when possible.40, 42 Emergence of resistance is also minimized by using the shortest duration of treatment with maximal clinical effect. (These latter 2 points are discussed in greater detail in the Kaye and File articles in this supplement.)

CASE 1: HEALTHCARE‐ASSOCIATED PNEUMONIA

Table 1 provides the key initial data for Case 1. The patient has a history of hypertension, congestive heart failure (CHF), and myocardial infarction (MI), and is receiving medications consistent with such a history. In terms of her acute presentation, cough, fever, chills, dyspnea, lung crackles (rales), X‐ray evidence of lung infiltrate, reduced oxygen saturation, elevated white blood cell (WBC) count, and increased percentage of WBC bands are all consistent with a diagnosis of pneumonia of relatively recent origin. Progressive worsening of symptoms within the previous 36 hours is also consistent with infection of recent origin. There are no neurologic symptoms, and cardiac function appears relatively normal, with no evidence of MI or cardiac arrhythmia based on electrocardiogram or heart rate, although there is evidence of continuing hypertension and perhaps CHF.

Given the patient's history of recent hospitalization, the clinician should consider that the pneumonia is most likely hospital‐ or healthcare‐acquired. Because she was described as developing the problem while in rehabilitation, it can be assumed that hospitalization occurred relatively recently. Hospital‐acquired pneumonia (HAP) is defined as pneumonia that occurs within 48 hours of hospital admission, and that was not incubating at the time of admission.47, 65 HAP accounts for approximately of 15% of all nosocomial/hospital‐acquired infections in the United States and up to 27% in the ICU,65, 66 and is a frequent cause of morbidity and mortality in this setting.65 In addition to hospitalization, other characteristics or risk factors for HAP include severe illness, hemodynamic compromise, depressed immune function, use of nasogastric tubes, and mechanical ventilation for the important subset of HAP patients with VAP.65 VAP is more precisely defined as HAP that arises >48‐72 hours after endotracheal intubation.47

Healthcare‐associated pneumonia (HCAP) is a more recently defined category that includes patients with HAP and VAP, and is characterized by hospitalization for 2 days in the preceding 90 days, or residence in a nursing home or extended‐care facility.47, 67, 68 Additional risk factors for HCAP include intravenous therapy at home (including antibiotics); intravenous chemotherapy or wound care within 30 days of the current infection; and recent attendance at a hospital or hemodialysis clinic.47 Most HAP or HCAP data have been derived from patients with VAP, and the 2005 American Thoracic Society (ATS)/IDSA guidelines for management of HAP, VAP, and HCAP recommend similar approaches for the initial treatment of patients with nonintubated HAP, VAP, and HCAP.47 There are general similarities between these 3 disease categories with respect to etiology, epidemiology of likely pathogens, and prognosis, and important differences compared with community‐acquired pneumonia (CAP), which in turn gives rise to different treatment strategies for HAP/VAP/HCAP and CAP.

Given an initial diagnosis of HAP or HCAP, the clinician should be considering the following questions: 1) What are the appropriate choices of antimicrobials? 2) What are the clinical parameters that should alert one to resistant organisms? 3) What are the appropriate cultures to order? 4) What is the role of Gram stain, if any?

CASE 2: INTRA‐ABDOMINAL INFECTION (DIVERTICULITIS)

Case 2 is a 56‐year‐old woman with no past medical history of note, who presented to her physician about 3 days ago, after 5 days of abdominal pain and fever (101.7F). She had an outpatient computed tomography (CT) scan, and the results suggested diverticulitis. After the CT scan, she was given amoxicillin/clavulanate. She now presents to the emergency department (3 days later) with worsening pain, fever, and severe weakness. A physical exam shows low blood pressure (84/58 mmHg) and tachycardia (132 bpm). Her respiratory rate is 22 breaths per minute. Oxygenation (O₂ saturation 99% on room air) is normal, and the patient's lungs are clear. Abdominal examination reveals bowel sounds and diffuse tenderness, particularly at the left lower quadrant, and there is evidence of guarding and rebound. Her blood chemistry is generally normal, although the WBC count is elevated (15,200/mm³). No abnormalities are evident on chest X‐ray. The patient's blood pressure increases to 96/64 mmHg after she is infused with 2 liters of normal saline. She undergoes another CT scan and is admitted to the ICU. The CT scan shows diverticulitis with abscess and walled‐off perforation. An interventional radiologist inserts a pigtail catheter into the abscess for sample collection, and the samples are sent to the microbiology laboratory for culture.

The radiology results indicate that the patient has what may be considered a complicated intra‐abdominal infection (diverticulitis with abscess), community‐acquired. Because empiric therapy is usually necessary for patients with complicated or even uncomplicated intra‐abdominal infections, the clinician should now be asking: What is optimal empiric antimicrobial therapy for this patient? Both prior75 and current guidelines76 for the management of intra‐abdominal infection indicate that antimicrobial therapy should be initiated when a patient receives such a diagnosis or when such an infection is considered likely. In making the determination of initial empiric therapy, the clinician should also be considering whether there is likely involvement of resistant Gram‐negative bacteria, and if so, how that would change the choice of antibiotic therapy.

Enteric Gram‐negative bacilli such as E coli and K pneumoniae are the most common microorganisms isolated from patients with intra‐abdominal infections, although Gram‐positive cocci (Staphylococcus or Streptococcus spp, and less commonly, enterococci) and obligate anaerobic organisms (particularly, Bacteroides fragilis) are also frequent components of intra‐abdominal infections.77 The relative frequency of bacterial pathogens shifts in patients who acquired their intra‐abdominal infection in the hospital versus community setting, with greater prevalence of Enterobacter, P aeruginosa, and Enterococcus spp, and less frequent isolation of E coli and streptococci.77 Recent results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) indicate a general increase in resistance among Gram‐negative bacilli isolated from patients with intra‐abdominal infections treated in medical centers, primarily due to acquisition of ESBLs.78, 79 This is true both in the United States79 and worldwide.78 Carbapenems continue to exhibit consistent activity against Gram‐negative bacilli isolated from intra‐abdominal infections, including ESBL‐producers.

Selection of initial empiric therapy should incorporate information from the literature and local antibiograms to determine the most likely causative pathogen(s), including ones with reduced susceptibility or resistance to commonly employed antibiotics. Then an antibiotic regimen should be selected that provides coverage of likely pathogens with minimal adverse events, including risk of collateral damage such as Clostridium difficile‐associated disease. Dose and dosing interval considerations are also important, particularly in patients with reduced renal or hepatic function. The general approach is to select an antibiotic or combination of antibiotic agents to provide coverage of the bacterial pathogens most commonly isolated from patients with intra‐abdominal infections, ie, aerobic/facultative anaerobic Gram‐negative bacilli, aerobic Gram‐positive cocci, and obligate anaerobic organisms.77 Table 4 presents the antibiotic treatment recommendations from the Surgical Infection Society and IDSA 2010 guidelines for management of patients with complicated intra‐abdominal infections.76 The guidelines are based on whether the patient has mild‐to‐moderate or high‐risk/severe community‐acquired complicated intra‐abdominal infections. Recommendations for the empiric treatment of hospital or healthcare‐associated complicated intra‐abdominal infections are largely based on local antibiogram (microbiologic) results, and include some similarities and differences compared with recommended treatment of high‐risk community‐acquired infections, as illustrated in Table 5.76 A patient with mild‐to‐moderate infection would be someone who does not require intensive care, and has community‐acquired intra‐abdominal infection due to secondary peritonitis. Severe intra‐abdominal infection would be defined by requiring intensive care, having sepsis, or having healthcare‐acquired peritonitis (such as a bowel leak following surgery). In line with these guidelines, and considering the case patient's risk profile, ciprofloxacin plus metronidazole was selected as initial empiric therapy, because she had not been hospitalized previously. Although she was hypotensive, the blood pressure was easily raised with fluids.

There are a number of controversies in intra‐abdominal sepsis management. These include whether or when initial empiric therapy should provide coverage of Enterococcus/vancomycin‐resistant enterococci or MRSA, when the regimen should include an antifungal to cover possible Candida spp infection, the role of resistant Bacteroides in intra‐abdominal infections, and when clinicians should be particularly concerned about ESBL‐producing or other resistant Gram‐negative bacteria. These topics are beyond the reach of the present article, but are and will continue to be important issues for clinicians to grapple with when selecting initial empiric therapy for patients with intra‐abdominal infections.

CASE 3: CENTRAL LINE‐ASSOCIATED BACTEREMIA

The third case is a 56‐year‐old man with epilepsy who presents to the emergency department with status epilepticus. Subsequent resuscitative efforts included intubation and placement of an internal jugular central line. The patient was admitted to the ICU, and aggressive treatment was initiated with repeated intravenous dosing of lorazepam and loading with fosphenytoin, which successfully broke the seizure. Subsequent imaging and laboratory tests failed to reveal any specific cause for the status epilepticus. The patient was extubated on day 4 and transferred out of the ICU. On day 5, he spiked a fever of 103.4F. He did not report any new symptoms, and there was no evidence of cough, sputum, shortness of breath, abdominal pain, diarrhea, or urinary symptoms. Physical examination revealed normal blood pressure (122/68 mmHg) and oxygen saturation (95% on room air), a normal respiratory rate (12 breaths per minute), clear lungs, no edema, no heart murmur, and normal neurologic findings. The patient's heart rate was somewhat high (102 bpm), and his temperature remained elevated (103.4F). Abdominal examination revealed no tenderness, and bowel sounds were present. Laboratory results were normal, except for an elevated WBC count (17,000/mm3 of blood). The chest X‐ray was clear.

This is an example of a patient with fever and leukocytosis of unknown origin. There are no focal findings indicative of a particular infection site or process. The patient was treated in the ICU, including use of a central catheter. Differential diagnosis of fever and leukocytosis without source, in a patient from the ICU with a central line, should consider catheter‐associated bacteremia; C difficile‐associated disease; a silent intra‐abdominal process, such as cholangitis or gangrenous cholecystitis; drug fever related to (in this patient) anticonvulsant therapy; urinary tract infection (no evidence for in this patient); or pulmonary embolism. The clinician needs to make a decision as to the relative benefits of empiric antibiotic or other antimicrobial treatment versus observation. If the patient is to be treated with an antibiotic, then a choice has to be made as to the best agent for the patient at hand.

In terms of the choice of antibiotics for a patient such as the one here, the clinician needs to assess the severity of illness and, when doing so, determine what infection site or sites should be covered, and the most likely sites of infection. A determination of likely pathogens also needs to be made. Cultures should be obtained prior to initiating therapy with a regimen providing broad coverage of the most likely pathogen(s), while allowing for the possibility of later de‐escalation based on clinical evaluation and culture results. This is similar to the situation for initial empiric treatment of pneumonia or intra‐abdominal infection. In general, the clinician should obtain blood, urine, and possibly sputum cultures to aid in future decision making. Furthermore, if the patient has diarrhea (which the current one does not), the clinician should obtain a stool for C difficile toxin analysis.

For the case illustrated here, the clinician determined catheter‐associated bacteremia was a strong possibility, and decided to initiate empiric therapy with vancomycin and piperacillin‐tazobactam to provide coverage of MRSA and resistant Gram‐negative bacteria. The most common causes of nosocomial or catheter‐associated bloodstream infections (BSIs) are coagulase‐negative staphylococci, S aureus, enterococci, and Candida spp,8082 but Gram‐negative bacilli like P aeruginosa, Klebsiella spp, and E coli (among others) are also frequently involved, particularly in patients with catheter‐associated BSIs.81 Moreover, significant and increasing percentages of Gram‐negative bacilli exhibit resistance to 1 or more antibiotic classes,8385 and >50% of S aureus are typically MRSA,82, 83, 85, 86 although there has been some decline in MRSA central line‐associated BSIs in US ICUs in recent years.87

Clinical practice guidelines from the IDSA recommend vancomycin (or daptomycin) for the management of MRSA bacteremia,88 while piperacillin‐tazobactam is frequently empirically added to Gram‐positive coverage for serious hospital‐acquired infections because of its broad activity against many pathogenic bacteria, including some ESBL‐producing Gram‐negative bacteria and P aeruginosa,89 which are significant causes of patient morbidity and mortality.36, 90 However, to be effective, both vancomycin and piperacillin‐tazobactam need to be properly dosed to maximize their pharmacodynamic properties. Guidelines from the American Society of Health‐System Pharmacists, IDSA, and Society of Infectious Diseases Pharmacists recommend vancomycin serum trough concentrations of 15‐20 mg/L for patients with bacteremia due to MRSA.91 These levels are recommended to improve penetration, increase the probability of obtaining optimal target serum concentrations, and improve clinical outcomes. To achieve these trough levels, the guidelines recommend doses of 15‐20 mg/kg of actual body weight given every 8‐12 hours for most patients with normal renal function, assuming a minimum inhibitory concentration (MIC) of 1 mg/L. In seriously ill patients, the guidelines recommend using a loading dose of 25‐30 mg/kg to facilitate rapid attainment of the target trough serum vancomycin level. (If the MIC is 2 mg/L, then the targeted pharmacodynamic parameter for vancomycin is unachievable, and an alternative therapy should be considered.)

The pharmacodynamic parameter that best predicts efficacy for ‐lactams like piperacillin is the duration of time that free drug concentrations remain above the MIC (T>MIC), with near maximal bactericidal effects for penicillins when the free drug concentrations remain above the MIC for 50% of the dosing interval.92 The target pharmacodynamic parameter for piperacillin‐tazobactam (50% T>MIC) may be better achieved with use of prolonged or extended infusion regimens than with intermittent, more rapidly infused, administration schedules. Lodise and coworkers recently reported that extended infusion (3.375 g intravenously [IV] for 4 hours every 8 hours) versus intermittent infusion of piperacillin‐tazobactam (3.375 g IV for 30 minutes every 4 to 6 hours) was associated with a significantly lower 14‐day mortality rate (12.2% vs 31.6%, P = 0.04) and median duration of hospital stay (21 vs 38 days, P = 0.02) in a cohort of hospitalized patients with a P aeruginosa infection.93 Based on data such as these, the case patient here was initiated on vancomycin (15‐20 mg/kg every 812 hours) and piperacillin‐tazobactam (3.375 g IV for 4 hours every 8 hours).

CONCLUSIONS

Successful treatment of patients with serious, life‐threatening hospital‐ or healthcare‐associated infections depends on early adequate antimicrobial treatment. To accomplish this, empiric therapy is typically employed with a broad‐spectrum regimen intended to cover likely causative pathogen(s) based on local antibiograms and risk factors for involvement of resistant microorganisms. Choice of empiric therapy should also be based on the site of infection, and make use of clinical practice guidelines, when available. Although this approach often means treatment with a regimen that is unnecessarily broad, based on subsequent culture findings, it is warranted based on the significant negative impact of initial inadequate/emnappropriate empiric therapy, and the inability to remedy this negative effect by later modification of antimicrobial therapy. The possibility of de‐escalating the initial broad‐spectrum regimen is revisited after the results from cultures collected prior to beginning empiric therapy become available, generally 2‐4 days after beginning the process. In this manner, both the dangers of initial inadequate empiric therapy and overuse or misuse of antimicrobials are minimized. To further minimize the risk of antimicrobial resistance linked to overuse or misuse of antimicrobial agents, care should be taken to avoid treatment of colonization or culture contamination.