Reviews

Surgical aortic valve replacement remains the gold standard treatment for symptomatic aortic valve stenosis in patients at low or moderate risk of surgical complications. But this is a disease of the elderly, many of whom are too frail or too sick to undergo surgery.

Now, patients who cannot undergo this surgery can be offered the less invasive option of transcatheter aortic valve replacement. Balloon valvuloplasty, sodium nitroprusside, and intra-aortic balloon counterpulsation can buy time for ill patients while more permanent mechanical interventions are being considered.

See related editorial

In this review, we will present several cases that highlight management choices for patients with severe aortic stenosis.

A PROGRESSIVE DISEASE OF THE ELDERLY

Aortic stenosis is the most common acquired valvular disease in the United States, and its incidence and prevalence are rising as the population ages. Epidemiologic studies suggest that 2% to 7% of all patients over age 65 have it.^1,2

The natural history of the untreated disease is well established, with several case series showing an average decrease of 0.1 cm² per year in aortic valve area and an increase of 7 mm Hg per year in the pressure gradient across the valve once the diagnosis is made.^3,4 Development of angina, syncope, or heart failure is associated with adverse clinical outcomes, including death, and warrants prompt intervention with aortic valve replacement.^5–7 Without intervention, the mortality rates reach as high as 75% in 3 years once symptoms develop.

Statins, bisphosphonates, and angiotensin-converting enzyme inhibitors have been used in attempts to slow or reverse the progression of aortic stenosis. However, studies of these drugs have had mixed results, and no definitive benefit has been shown.^8–13 Surgical aortic valve replacement, on the other hand, normalizes the life expectancy of patients with aortic stenosis to that of age- and sex-matched controls and remains the gold standard therapy for patients who have symptoms.¹⁴

Traditionally, valve replacement has involved open heart surgery, since it requires direct visualization of the valve while the patient is on cardiopulmonary bypass. Unfortunately, many patients have multiple comorbid conditions and therefore are not candidates for open heart surgery. Options for these patients include aortic valvuloplasty and transcatheter aortic valve replacement. While there is considerable experience with aortic valvuloplasty, transcatheter aortic valve replacement is relatively new. In large randomized trials and registries, the transcatheter procedure has been shown to significantly improve long-term survival compared with medical management alone in inoperable patients and to have benefit similar to that of surgery in the high-risk population.^15–17

CASE 1: SEVERE, SYMPTOMATIC STENOSIS IN A GOOD SURGICAL CANDIDATE

Mr. A, age 83, presents with shortness of breath and peripheral edema that have been worsening over the past several months. His pulse rate is 64 beats per minute and his blood pressure is 110/90 mm Hg. Auscultation reveals an absent aortic second heart sound with a late peaking systolic murmur that increases with expiration.

On echocardiography, his left ventricular ejection fraction is 55%, peak transaortic valve gradient 88 mm Hg, mean gradient 60 mm Hg, and effective valve area 0.6 cm². He undergoes catheterization of the left side of his heart, which shows normal coronary arteries.

Mr. A also has hypertension and hyperlipidemia; his renal and pulmonary functions are normal.

How would you manage Mr. A’s aortic stenosis?

Symptomatic aortic stenosis leads to adverse clinical outcomes if managed medically without mechanical intervention,^5–7 but patients who undergo aortic valve replacement have age-corrected postoperative survival rates that are nearly normal.¹⁴ Furthermore, thanks to improvements in surgical techniques and perioperative management, surgical mortality rates have decreased significantly in recent years and now range from 1% to 8%.^18–20 The accumulated evidence showing clear superiority of a surgical approach over medical therapy has greatly simplified the therapeutic algorithm.²¹

Consequently, the current guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) give surgery a class I indication (evidence or general agreement that the procedure is beneficial, useful, and effective) for symptomatic severe aortic stenosis (Figure 1). This level of recommendation also applies to patients who have severe but asymptomatic aortic stenosis who are undergoing other types of cardiac surgery and also to patients with severe aortic stenosis and left ventricular dysfunction (defined as an ejection fraction < 50%).²¹

Mr. A was referred for surgical aortic valve replacement, given its clear survival benefit.

CASE 2: SYMPTOMS AND LEFT VENTRICULAR DYSFUNCTION

Ms. B, age 79, has hypertension and hyperlipidemia and now presents to the outpatient department with worsening shortness of breath and chest discomfort. Electrocardiography shows significant left ventricular hypertrophy and abnormal repolarization. Left heart catheterization reveals mild nonobstructive coronary artery disease.

Echocardiography reveals an ejection fraction of 25%, severe left ventricular hypertrophy, and global hypokinesis. The aortic valve leaflets appear heavily calcified, with restricted motion. The peak and mean gradients across the aortic valve are 40 and 28 mm Hg, and the valve area is 0.8 cm². Right heart catheterization shows a cardiac output of 3.1 L/min.

Does this patient’s aortic stenosis account for her clinical presentation?

Managing patients who have suspected severe aortic stenosis, left ventricular dysfunction, and low aortic valve gradients can be challenging. Although data for surgical intervention are not as robust for these patient subsets as for patients like Mr. A, several case series have suggested that survival in these patients is significantly better with surgery than with medical therapy alone.^22–27

Specific factors predict whether patients with ventricular dysfunction and low gradients will benefit from aortic valve replacement. Dobutamine stress echocardiography is helpful in distinguishing true severe aortic stenosis from “pseudostenosis,” in which leaflet motion is restricted due to primary cardiomyopathy and low flow. Distinguishing between true aortic stenosis and pseudostenosis is of paramount value, as surgery is associated with improved long-term outcomes in patients with true aortic stenosis (even though they are at higher surgical risk), whereas those with pseudostenosis will not benefit from surgery.^28–31

Infusion of dobutamine increases the flow across the aortic valve (if the left ventricle has contractile reserve; more on this below), and an increasing valve area with increasing doses of dobutamine is consistent with pseudostenosis. In this situation, treatment of the underlying cardiomyopathy is indicated as opposed to replacement of the aortic valve (Figure 2).

Contractile reserve is defined as an increase in stroke volume (> 20%), valvular gradient (> 10 mm Hg), or peak velocity (> 0.6 m/s) with peak dobutamine infusion. The presence of contractile reserve in patients with aortic stenosis identifies a high-risk group that benefits from aortic valve replacement (Figure 2).

Treatment of patients who have inadequate reserve is controversial. In the absence of contractile reserve, an adjunct imaging study such as computed tomography may be of value in detecting calcified valve leaflets, as the presence of calcium is associated with true aortic stenosis. Comorbid conditions should be taken into account as well, given the higher surgical risk in this patient subset, as aortic valve replacement in this already high-risk group of patients might be futile in some cases.

The ACC/AHA guidelines now give dobutamine stress echocardiography a class IIa indication (meaning the weight of the evidence or opinion is in favor of usefulness or efficacy) for determination of contractile reserve and valvular stenosis for patients with an ejection fraction of 30% or less or a mean gradient of 40 mm Hg or less.²¹

Ms. B underwent dobutamine stress echocardiography. It showed increases in ejection fraction, stroke volume, and transvalvular gradients, indicating that she did have contractile reserve and true severe aortic stenosis. Consequently, she was referred for surgical aortic valve replacement.

CASE 3: MODERATE STENOSIS AND THREE-VESSEL CORONARY ARTERY DISEASE

Mr. C, age 81, has hypertension and hyperlipidemia. He now presents to the emergency department with chest discomfort that began suddenly, awakening him from sleep. His presenting electrocardiogram shows nonspecific changes, and he is diagnosed with non-ST-elevation myocardial infarction. He undergoes left heart catheterization, which reveals severe three-vessel coronary artery disease.

Echocardiography reveals an ejection fraction of 55% and aortic stenosis, with an aortic valve area of 1.2 cm², a peak gradient of 44 mm Hg, and a mean gradient of 28 mm Hg.

How would you manage his aortic stenosis?

Moderate aortic stenosis in a patient who needs surgery for severe triple-vessel coronary artery disease, other valve diseases, or aortic disease raises the question of whether aortic valve replacement should be performed in conjunction with these surgeries. Although these patients would not otherwise qualify for aortic valve replacement, the fact that they will undergo a procedure that will expose them to the risks associated with open heart surgery makes them reasonable candidates. Even if the patient does not need aortic valve replacement right now, aortic stenosis progresses at a predictable rate—the valve area decreases by a mean of 0.1 cm²/year and the gradients increase by 7 mm Hg/year. Therefore, clinical judgment should be exercised so that the patient will not need to undergo open heart surgery again in the near future.

The ACC/AHA guidelines recommend aortic valve replacement for patients with moderate aortic stenosis undergoing coronary artery bypass grafting or surgery on the aorta or other heart valves, giving it a class IIa indication.²¹ This recommendation is based on several retrospective case series that evaluated survival, the need for reoperation for aortic valve replacement, or both in patients undergoing coronary artery bypass grafting.^32–35

No data exist, however, on adding aortic valve replacement to coronary artery bypass grafting in cases of mild aortic stenosis. As a result, it is controversial and carries a class IIb recommendation (meaning that its usefulness or efficacy is less well established). The ACC/AHA guidelines state that aortic valve replacement “may be considered” in patients undergoing coronary artery bypass grafting who have mild aortic stenosis (mean gradient < 30 mm Hg or jet velocity < 3 m/s) when there is evidence, such as moderate or severe valve calcification, that progression may be rapid (level of evidence C: based only on consensus opinion of experts, case studies or standard of care).²¹

Mr. C, who has moderate aortic stenosis, underwent aortic valve replacement in conjunction with three-vessel bypass grafting.

CASE 4: ASYMPTOMATIC BUT SEVERE STENOSIS

Mr. D, age 74, has hypertension, hyperlipidemia, and aortic stenosis. He now presents to the outpatient department for his annual echocardiogram to follow his aortic stenosis. He has a sedentary lifestyle but feels well performing activities of daily living. He denies dyspnea on exertion, chest pain, or syncope.

His echocardiogram reveals an effective aortic valve area of 0.7 cm², peak gradient 90 mm Hg, and mean gradient 70 mm Hg. There is evidence of severe left ventricular hypertrophy, and the valve leaflets show bulky calcification and severe restriction. An echocardiogram performed at the same institution a year earlier revealed gradients of 60 and 40 mm Hg.

Blood is drawn for laboratory tests, including N-terminal pro-brain natriuretic peptide, which is 350 pg/mL (reference range for his age < 125 pg/mL). He is referred for a treadmill stress test, which elicits symptoms at a moderate activity level.

How would you manage his aortic stenosis?

Aortic valve replacement can be considered in patients who have asymptomatic but severe aortic stenosis with preserved left ventricular function (class IIb indication).²¹

Clinical assessment of asymptomatic aortic stenosis can be challenging, however, as patients may underreport their symptoms or decrease their activity levels to avoid symptoms. Exercise testing in such patients can elicit symptoms, unmask diminished exercise capacity, and help determine if they should be referred for surgery.^36,37 Natriuretic peptide levels have been shown to correlate with the severity of aortic stenosis,^38,39 and more importantly, to help predict symptom onset, cardiac death, and need for aortic valve replacement.^40–42

Some patients with asymptomatic but severe aortic stenosis are at higher risk of morbidity and death. High-risk subsets include patients with rapid progression of aortic stenosis and those with critical aortic stenosis characterized by an aortic valve area less than 0.60 cm², mean gradient greater than 60 mm Hg, and jet velocity greater than 5.0 m/s. It is reasonable to offer these patients surgery if their expected operative mortality risk is less than 1.0%.²¹

Mr. D has evidence of rapid progression as defined by an increase in aortic jet velocity of more than 0.3 m/s/year. He is at low surgical risk and was referred for elective aortic valve replacement.

CASE 5: TOO FRAIL FOR SURGERY

Mr. E, age 84, has severe aortic stenosis (valve area 0.6 cm², peak and mean gradients of 88 and 56 mm Hg), coronary artery disease status post coronary artery bypass grafting, moderate chronic obstructive pulmonary disease (forced expiratory volume in 1 second 0.8 L), chronic kidney disease (serum creatinine 1.9 mg/dL), hypertension, hyperlipidemia, and diabetes mellitus. He has preserved left ventricular function. He presents to the outpatient department with worsening shortness of breath and peripheral edema over the past several months. Your impression is that he is very frail. How would you manage Mr. E’s aortic stenosis?

Advances in surgical techniques and perioperative management over the years have enabled higher-risk patients to undergo surgical aortic valve replacement with excellent out-comes.18–20,43 Yet many patients still cannot undergo surgery because their risk is too high. Patients ineligible for surgery have traditionally been treated medically—with poor out-comes—or with balloon aortic valvuloplasty to palliate symptoms.

Transcatheter aortic valve replacement, approved by the US Food and Drug Administration (FDA) in 2011, now provides another option for these patients. In this procedure, a bioprosthetic valve mounted on a metal frame is implanted over the native stenotic valve.

Currently, the only FDA-approved and commercially available valve in the United States is the Edwards SAPIEN valve, which has bovine pericardial tissue leaflets fixed to a balloon-expandable stainless steel frame (Figure 3). In the Placement of Aortic Transcatheter Valves (PARTNER) trial,¹⁵ patients who could not undergo surgery who underwent transcatheter replacement with this valve had a significantly better survival rate than patients treated medically.^15,17 Use of this valve has also been compared against conventional surgical aortic valve replacement in high-risk patients and was found to have similar long-term outcomes (Figure 4).¹⁶ It was on the basis of this trial that this valve was granted approval for patients who cannot undergo surgery.

The standard of care for high-risk patients remains surgical aortic valve replacement, although it remains to be seen whether transcatheter replacement will be made available as well to patients eligible for surgery in the near future. There are currently no randomized data for transcatheter aortic valve replacement in patients at moderate to low surgical risk, and these patients should not be considered for this procedure.

Although the initial studies are encouraging for patients who cannot undergo surgery and who are at high risk without it, several issues and concerns remain. Importantly, the long-term durability of the transcatheter valve and longer-term outcomes remain unknown. Furthermore, the risk of vascular complications remains high (10% to 15%), dictating the need for careful patient selection. There are also concerns about the risks of stroke and of paravalvular aortic insufficiency. These issues are being investigated and addressed, however, and we hope that with increasing operator experience and improvements in the technique, outcomes will be improved.

Which approach for transcatheter aortic valve replacement?

There are several considerations in determining a patient’s eligibility for transcatheter aortic valve replacement.

Initially, these valves were placed by a transvenous, transseptal approach, but now retrograde placement through the femoral artery has become standard. In this procedure, the device is advanced retrograde from the femoral artery through the aorta and placed across the native aortic valve under fluoroscopic and echocardiographic guidance.

Patients who are not eligible for transfemoral placement because of severe atherosclerosis, tortuosity, or ectasia of the iliofemoral artery or aorta can still undergo percutaneous treatment with a transapical approach. This is a hybrid surgical-transcatheter approach in which the valve is delivered through a sheath placed by left ventricular apical puncture.^17,44

A newer approach gaining popularity is the transaortic technique, in which the ascending aorta is accessed directly through a ministernotomy and the delivery sheath is placed with a direct puncture. Other approaches are through the axillary and subclavian arteries.

Other valves are under development

Several other valves are under development and will likely change the landscape of transcatheter aortic valve replacement with improving outcomes. Valves that are available in the United States are shown in Figure 3. The CoreValve, consisting of porcine pericardial leaflets mounted on a self-expanding nitinol stent, is currently being studied in a trial in the United States, and the manufacturer (Medtronic) will seek approval when results are complete in the near future.

Mr. E was initially referred for surgery, but when deemed to be unable to undergo surgery was found to be a good candidate for transcatheter aortic valve replacement.

CASE 6: LIFE-LIMITING COMORBID ILLNESS

Mr. F, age 77, has multiple problems: severe aortic stenosis (aortic valve area 0.6 cm²; peak and mean gradients of 92 and 59 mm Hg), stage IV pancreatic cancer, coronary artery disease status post coronary artery bypass grafting, chronic kidney disease (serum creatinine 1.9 mg/dL), hypertension, and hyperlipidemia. He presents to the outpatient department with shortness of breath at rest, orthopnea, effort intolerance, and peripheral edema over the past several months.

On physical examination rales in both lung bases can be heard. Left heart catheterization shows patent bypass grafts.

How would you manage Mr. F’s aortic stenosis?

Aortic valve replacement is not considered an option in patients with noncardiac illnesses and comorbidities that are life-limiting in the near term. Under these circumstances, aortic valvuloplasty can be offered as a means of palliating symptoms or, if the comorbid conditions can be modified, as a bridge to more definitive treatment with aortic valve replacement.

Since first described in 1986,⁴⁵ percutaneous aortic valvuloplasty has been studied in several case series and registries, with consistent findings. Acutely, it increases the valve area and lessens the gradients across the valve, relieving symptoms. The risk of death during the procedure ranged from 3% to 13.5% in several case series, with a 30-day survival rate greater than 85%.⁴⁶ However, the hemodynamic and symptomatic improvement is only short-term, as valve area and gradients gradually worsen within several months.^47,48 Consequently, balloon valvuloplasty is considered a palliative approach.

Mr. F has a potentially life-limiting illness, ie, cancer, which would make him a candidate for aortic valvuloplasty rather than replacement. He can be referred for evaluation for this procedure in hopes of palliating his symptoms by relieving his dyspnea and improving his quality of life.

CASE 7: HEMODYNAMIC INSTABILITY

Mr. G, age 87, is scheduled for surgical aortic valve replacement because of severe aortic stenosis (valve area 0.5 cm², peak and mean gradients 89 and 45 mm Hg) with an ejection fraction of 30%.

Two weeks before his scheduled surgery he presents to the emergency department with worsening fluid overload and increasing shortness of breath. His initial laboratory work shows new-onset renal failure, and he has signs of hypoperfusion on physical examination. He is transferred to the cardiac intensive care unit for further care.

How would you manage his aortic stenosis?

Patients with decompensated aortic stenosis and hemodynamic instability are at extreme risk during surgery. Medical stabilization beforehand may mitigate the risks associated with surgical or transcatheter aortic valve replacement. Aortic valvuloplasty, treatment with sodium nitroprusside, and support with intra-aortic balloon counterpulsation may help stabilize patients in this “low-output” setting.

Sodium nitroprusside has long been used in low-output states. By relaxing vascular smooth muscle, it leads to increased venous capacitance, decreasing preload and congestion. It also decreases systemic vascular resistance with a subsequent decrease in afterload, which in turn improves systolic emptying. Together, these effects reduce systolic and diastolic wall stress, lower myocardial oxygen consumption, and ultimately increase cardiac output.^49,50

These theoretical benefits translate to clinical improvement and increased cardiac output, as shown in a case series of 25 patients with severe aortic stenosis and left ventricular systolic dysfunction (ejection fraction 35%) presenting in a low-output state in the absence of hypotension.⁵¹ These findings have led to a ACC/AHA recommendation for the use of sodium nitroprusside in patients who have severe aortic stenosis presenting in low-output state with decompensated heart failure.²¹

Intra-aortic balloon counterpulsation, introduced in 1968, has been used in several clinical settings, including acute coronary syndromes, intractable ventricular arrhythmias, and refractory heart failure, and for support of hemodynamics in the perioperative setting. Its role in managing ventricular septal rupture and acute mitral regurgitation is well established. It reliably reduces afterload and improves coronary perfusion, augmenting the cardiac output. This in turn leads to improved systemic perfusion, which can buy time for a critically ill patient during which the primary disease process is addressed.

Recently, a case series in which intraaortic balloon counterpulsation devices were placed in patients with severe aortic stenosis and cardiogenic shock showed findings similar to those with sodium nitroprusside infusion. Specifically, their use was associated with improved cardiac indices and filling pressures with a decrease in systemic vascular resistance. These changes have led to increased cardiac performance, resulting in better systemic perfusion.⁵² Thus, intra-aortic balloon counterpulsation can be an option for stabilizing patients with severe aortic stenosis and cardiogenic shock.

Mr. G was treated with sodium nitroprusside and intravenous diuretics. He achieved symptomatic relief and his renal function returned to baseline. He subsequently underwent aortic valve replacement during the hospitalization.

Surgical aortic valve replacement remains the gold standard treatment for symptomatic aortic valve stenosis in patients at low or moderate risk of surgical complications. But this is a disease of the elderly, many of whom are too frail or too sick to undergo surgery.

Now, patients who cannot undergo this surgery can be offered the less invasive option of transcatheter aortic valve replacement. Balloon valvuloplasty, sodium nitroprusside, and intra-aortic balloon counterpulsation can buy time for ill patients while more permanent mechanical interventions are being considered.

See related editorial

In this review, we will present several cases that highlight management choices for patients with severe aortic stenosis.

A PROGRESSIVE DISEASE OF THE ELDERLY

Aortic stenosis is the most common acquired valvular disease in the United States, and its incidence and prevalence are rising as the population ages. Epidemiologic studies suggest that 2% to 7% of all patients over age 65 have it.^1,2

The natural history of the untreated disease is well established, with several case series showing an average decrease of 0.1 cm² per year in aortic valve area and an increase of 7 mm Hg per year in the pressure gradient across the valve once the diagnosis is made.^3,4 Development of angina, syncope, or heart failure is associated with adverse clinical outcomes, including death, and warrants prompt intervention with aortic valve replacement.^5–7 Without intervention, the mortality rates reach as high as 75% in 3 years once symptoms develop.

Statins, bisphosphonates, and angiotensin-converting enzyme inhibitors have been used in attempts to slow or reverse the progression of aortic stenosis. However, studies of these drugs have had mixed results, and no definitive benefit has been shown.^8–13 Surgical aortic valve replacement, on the other hand, normalizes the life expectancy of patients with aortic stenosis to that of age- and sex-matched controls and remains the gold standard therapy for patients who have symptoms.¹⁴

Traditionally, valve replacement has involved open heart surgery, since it requires direct visualization of the valve while the patient is on cardiopulmonary bypass. Unfortunately, many patients have multiple comorbid conditions and therefore are not candidates for open heart surgery. Options for these patients include aortic valvuloplasty and transcatheter aortic valve replacement. While there is considerable experience with aortic valvuloplasty, transcatheter aortic valve replacement is relatively new. In large randomized trials and registries, the transcatheter procedure has been shown to significantly improve long-term survival compared with medical management alone in inoperable patients and to have benefit similar to that of surgery in the high-risk population.^15–17

CASE 1: SEVERE, SYMPTOMATIC STENOSIS IN A GOOD SURGICAL CANDIDATE

Mr. A, age 83, presents with shortness of breath and peripheral edema that have been worsening over the past several months. His pulse rate is 64 beats per minute and his blood pressure is 110/90 mm Hg. Auscultation reveals an absent aortic second heart sound with a late peaking systolic murmur that increases with expiration.

On echocardiography, his left ventricular ejection fraction is 55%, peak transaortic valve gradient 88 mm Hg, mean gradient 60 mm Hg, and effective valve area 0.6 cm². He undergoes catheterization of the left side of his heart, which shows normal coronary arteries.

Mr. A also has hypertension and hyperlipidemia; his renal and pulmonary functions are normal.

How would you manage Mr. A’s aortic stenosis?

Symptomatic aortic stenosis leads to adverse clinical outcomes if managed medically without mechanical intervention,^5–7 but patients who undergo aortic valve replacement have age-corrected postoperative survival rates that are nearly normal.¹⁴ Furthermore, thanks to improvements in surgical techniques and perioperative management, surgical mortality rates have decreased significantly in recent years and now range from 1% to 8%.^18–20 The accumulated evidence showing clear superiority of a surgical approach over medical therapy has greatly simplified the therapeutic algorithm.²¹

Consequently, the current guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) give surgery a class I indication (evidence or general agreement that the procedure is beneficial, useful, and effective) for symptomatic severe aortic stenosis (Figure 1). This level of recommendation also applies to patients who have severe but asymptomatic aortic stenosis who are undergoing other types of cardiac surgery and also to patients with severe aortic stenosis and left ventricular dysfunction (defined as an ejection fraction < 50%).²¹

Mr. A was referred for surgical aortic valve replacement, given its clear survival benefit.

CASE 2: SYMPTOMS AND LEFT VENTRICULAR DYSFUNCTION

Ms. B, age 79, has hypertension and hyperlipidemia and now presents to the outpatient department with worsening shortness of breath and chest discomfort. Electrocardiography shows significant left ventricular hypertrophy and abnormal repolarization. Left heart catheterization reveals mild nonobstructive coronary artery disease.

Echocardiography reveals an ejection fraction of 25%, severe left ventricular hypertrophy, and global hypokinesis. The aortic valve leaflets appear heavily calcified, with restricted motion. The peak and mean gradients across the aortic valve are 40 and 28 mm Hg, and the valve area is 0.8 cm². Right heart catheterization shows a cardiac output of 3.1 L/min.

Does this patient’s aortic stenosis account for her clinical presentation?

Managing patients who have suspected severe aortic stenosis, left ventricular dysfunction, and low aortic valve gradients can be challenging. Although data for surgical intervention are not as robust for these patient subsets as for patients like Mr. A, several case series have suggested that survival in these patients is significantly better with surgery than with medical therapy alone.^22–27

Specific factors predict whether patients with ventricular dysfunction and low gradients will benefit from aortic valve replacement. Dobutamine stress echocardiography is helpful in distinguishing true severe aortic stenosis from “pseudostenosis,” in which leaflet motion is restricted due to primary cardiomyopathy and low flow. Distinguishing between true aortic stenosis and pseudostenosis is of paramount value, as surgery is associated with improved long-term outcomes in patients with true aortic stenosis (even though they are at higher surgical risk), whereas those with pseudostenosis will not benefit from surgery.^28–31

Infusion of dobutamine increases the flow across the aortic valve (if the left ventricle has contractile reserve; more on this below), and an increasing valve area with increasing doses of dobutamine is consistent with pseudostenosis. In this situation, treatment of the underlying cardiomyopathy is indicated as opposed to replacement of the aortic valve (Figure 2).

Contractile reserve is defined as an increase in stroke volume (> 20%), valvular gradient (> 10 mm Hg), or peak velocity (> 0.6 m/s) with peak dobutamine infusion. The presence of contractile reserve in patients with aortic stenosis identifies a high-risk group that benefits from aortic valve replacement (Figure 2).

Treatment of patients who have inadequate reserve is controversial. In the absence of contractile reserve, an adjunct imaging study such as computed tomography may be of value in detecting calcified valve leaflets, as the presence of calcium is associated with true aortic stenosis. Comorbid conditions should be taken into account as well, given the higher surgical risk in this patient subset, as aortic valve replacement in this already high-risk group of patients might be futile in some cases.

The ACC/AHA guidelines now give dobutamine stress echocardiography a class IIa indication (meaning the weight of the evidence or opinion is in favor of usefulness or efficacy) for determination of contractile reserve and valvular stenosis for patients with an ejection fraction of 30% or less or a mean gradient of 40 mm Hg or less.²¹

Ms. B underwent dobutamine stress echocardiography. It showed increases in ejection fraction, stroke volume, and transvalvular gradients, indicating that she did have contractile reserve and true severe aortic stenosis. Consequently, she was referred for surgical aortic valve replacement.

CASE 3: MODERATE STENOSIS AND THREE-VESSEL CORONARY ARTERY DISEASE

Mr. C, age 81, has hypertension and hyperlipidemia. He now presents to the emergency department with chest discomfort that began suddenly, awakening him from sleep. His presenting electrocardiogram shows nonspecific changes, and he is diagnosed with non-ST-elevation myocardial infarction. He undergoes left heart catheterization, which reveals severe three-vessel coronary artery disease.

Echocardiography reveals an ejection fraction of 55% and aortic stenosis, with an aortic valve area of 1.2 cm², a peak gradient of 44 mm Hg, and a mean gradient of 28 mm Hg.

How would you manage his aortic stenosis?

Moderate aortic stenosis in a patient who needs surgery for severe triple-vessel coronary artery disease, other valve diseases, or aortic disease raises the question of whether aortic valve replacement should be performed in conjunction with these surgeries. Although these patients would not otherwise qualify for aortic valve replacement, the fact that they will undergo a procedure that will expose them to the risks associated with open heart surgery makes them reasonable candidates. Even if the patient does not need aortic valve replacement right now, aortic stenosis progresses at a predictable rate—the valve area decreases by a mean of 0.1 cm²/year and the gradients increase by 7 mm Hg/year. Therefore, clinical judgment should be exercised so that the patient will not need to undergo open heart surgery again in the near future.

The ACC/AHA guidelines recommend aortic valve replacement for patients with moderate aortic stenosis undergoing coronary artery bypass grafting or surgery on the aorta or other heart valves, giving it a class IIa indication.²¹ This recommendation is based on several retrospective case series that evaluated survival, the need for reoperation for aortic valve replacement, or both in patients undergoing coronary artery bypass grafting.^32–35

No data exist, however, on adding aortic valve replacement to coronary artery bypass grafting in cases of mild aortic stenosis. As a result, it is controversial and carries a class IIb recommendation (meaning that its usefulness or efficacy is less well established). The ACC/AHA guidelines state that aortic valve replacement “may be considered” in patients undergoing coronary artery bypass grafting who have mild aortic stenosis (mean gradient < 30 mm Hg or jet velocity < 3 m/s) when there is evidence, such as moderate or severe valve calcification, that progression may be rapid (level of evidence C: based only on consensus opinion of experts, case studies or standard of care).²¹

Mr. C, who has moderate aortic stenosis, underwent aortic valve replacement in conjunction with three-vessel bypass grafting.

CASE 4: ASYMPTOMATIC BUT SEVERE STENOSIS

Mr. D, age 74, has hypertension, hyperlipidemia, and aortic stenosis. He now presents to the outpatient department for his annual echocardiogram to follow his aortic stenosis. He has a sedentary lifestyle but feels well performing activities of daily living. He denies dyspnea on exertion, chest pain, or syncope.

His echocardiogram reveals an effective aortic valve area of 0.7 cm², peak gradient 90 mm Hg, and mean gradient 70 mm Hg. There is evidence of severe left ventricular hypertrophy, and the valve leaflets show bulky calcification and severe restriction. An echocardiogram performed at the same institution a year earlier revealed gradients of 60 and 40 mm Hg.

Blood is drawn for laboratory tests, including N-terminal pro-brain natriuretic peptide, which is 350 pg/mL (reference range for his age < 125 pg/mL). He is referred for a treadmill stress test, which elicits symptoms at a moderate activity level.

How would you manage his aortic stenosis?

Aortic valve replacement can be considered in patients who have asymptomatic but severe aortic stenosis with preserved left ventricular function (class IIb indication).²¹

Clinical assessment of asymptomatic aortic stenosis can be challenging, however, as patients may underreport their symptoms or decrease their activity levels to avoid symptoms. Exercise testing in such patients can elicit symptoms, unmask diminished exercise capacity, and help determine if they should be referred for surgery.^36,37 Natriuretic peptide levels have been shown to correlate with the severity of aortic stenosis,^38,39 and more importantly, to help predict symptom onset, cardiac death, and need for aortic valve replacement.^40–42

Some patients with asymptomatic but severe aortic stenosis are at higher risk of morbidity and death. High-risk subsets include patients with rapid progression of aortic stenosis and those with critical aortic stenosis characterized by an aortic valve area less than 0.60 cm², mean gradient greater than 60 mm Hg, and jet velocity greater than 5.0 m/s. It is reasonable to offer these patients surgery if their expected operative mortality risk is less than 1.0%.²¹

Mr. D has evidence of rapid progression as defined by an increase in aortic jet velocity of more than 0.3 m/s/year. He is at low surgical risk and was referred for elective aortic valve replacement.

CASE 5: TOO FRAIL FOR SURGERY

Mr. E, age 84, has severe aortic stenosis (valve area 0.6 cm², peak and mean gradients of 88 and 56 mm Hg), coronary artery disease status post coronary artery bypass grafting, moderate chronic obstructive pulmonary disease (forced expiratory volume in 1 second 0.8 L), chronic kidney disease (serum creatinine 1.9 mg/dL), hypertension, hyperlipidemia, and diabetes mellitus. He has preserved left ventricular function. He presents to the outpatient department with worsening shortness of breath and peripheral edema over the past several months. Your impression is that he is very frail. How would you manage Mr. E’s aortic stenosis?

Advances in surgical techniques and perioperative management over the years have enabled higher-risk patients to undergo surgical aortic valve replacement with excellent out-comes.18–20,43 Yet many patients still cannot undergo surgery because their risk is too high. Patients ineligible for surgery have traditionally been treated medically—with poor out-comes—or with balloon aortic valvuloplasty to palliate symptoms.

Transcatheter aortic valve replacement, approved by the US Food and Drug Administration (FDA) in 2011, now provides another option for these patients. In this procedure, a bioprosthetic valve mounted on a metal frame is implanted over the native stenotic valve.

Currently, the only FDA-approved and commercially available valve in the United States is the Edwards SAPIEN valve, which has bovine pericardial tissue leaflets fixed to a balloon-expandable stainless steel frame (Figure 3). In the Placement of Aortic Transcatheter Valves (PARTNER) trial,¹⁵ patients who could not undergo surgery who underwent transcatheter replacement with this valve had a significantly better survival rate than patients treated medically.^15,17 Use of this valve has also been compared against conventional surgical aortic valve replacement in high-risk patients and was found to have similar long-term outcomes (Figure 4).¹⁶ It was on the basis of this trial that this valve was granted approval for patients who cannot undergo surgery.

The standard of care for high-risk patients remains surgical aortic valve replacement, although it remains to be seen whether transcatheter replacement will be made available as well to patients eligible for surgery in the near future. There are currently no randomized data for transcatheter aortic valve replacement in patients at moderate to low surgical risk, and these patients should not be considered for this procedure.

Although the initial studies are encouraging for patients who cannot undergo surgery and who are at high risk without it, several issues and concerns remain. Importantly, the long-term durability of the transcatheter valve and longer-term outcomes remain unknown. Furthermore, the risk of vascular complications remains high (10% to 15%), dictating the need for careful patient selection. There are also concerns about the risks of stroke and of paravalvular aortic insufficiency. These issues are being investigated and addressed, however, and we hope that with increasing operator experience and improvements in the technique, outcomes will be improved.

Which approach for transcatheter aortic valve replacement?

There are several considerations in determining a patient’s eligibility for transcatheter aortic valve replacement.

Initially, these valves were placed by a transvenous, transseptal approach, but now retrograde placement through the femoral artery has become standard. In this procedure, the device is advanced retrograde from the femoral artery through the aorta and placed across the native aortic valve under fluoroscopic and echocardiographic guidance.

Patients who are not eligible for transfemoral placement because of severe atherosclerosis, tortuosity, or ectasia of the iliofemoral artery or aorta can still undergo percutaneous treatment with a transapical approach. This is a hybrid surgical-transcatheter approach in which the valve is delivered through a sheath placed by left ventricular apical puncture.^17,44

A newer approach gaining popularity is the transaortic technique, in which the ascending aorta is accessed directly through a ministernotomy and the delivery sheath is placed with a direct puncture. Other approaches are through the axillary and subclavian arteries.

Other valves are under development

Several other valves are under development and will likely change the landscape of transcatheter aortic valve replacement with improving outcomes. Valves that are available in the United States are shown in Figure 3. The CoreValve, consisting of porcine pericardial leaflets mounted on a self-expanding nitinol stent, is currently being studied in a trial in the United States, and the manufacturer (Medtronic) will seek approval when results are complete in the near future.

Mr. E was initially referred for surgery, but when deemed to be unable to undergo surgery was found to be a good candidate for transcatheter aortic valve replacement.

CASE 6: LIFE-LIMITING COMORBID ILLNESS

Mr. F, age 77, has multiple problems: severe aortic stenosis (aortic valve area 0.6 cm²; peak and mean gradients of 92 and 59 mm Hg), stage IV pancreatic cancer, coronary artery disease status post coronary artery bypass grafting, chronic kidney disease (serum creatinine 1.9 mg/dL), hypertension, and hyperlipidemia. He presents to the outpatient department with shortness of breath at rest, orthopnea, effort intolerance, and peripheral edema over the past several months.

On physical examination rales in both lung bases can be heard. Left heart catheterization shows patent bypass grafts.

How would you manage Mr. F’s aortic stenosis?

Aortic valve replacement is not considered an option in patients with noncardiac illnesses and comorbidities that are life-limiting in the near term. Under these circumstances, aortic valvuloplasty can be offered as a means of palliating symptoms or, if the comorbid conditions can be modified, as a bridge to more definitive treatment with aortic valve replacement.

Since first described in 1986,⁴⁵ percutaneous aortic valvuloplasty has been studied in several case series and registries, with consistent findings. Acutely, it increases the valve area and lessens the gradients across the valve, relieving symptoms. The risk of death during the procedure ranged from 3% to 13.5% in several case series, with a 30-day survival rate greater than 85%.⁴⁶ However, the hemodynamic and symptomatic improvement is only short-term, as valve area and gradients gradually worsen within several months.^47,48 Consequently, balloon valvuloplasty is considered a palliative approach.

Mr. F has a potentially life-limiting illness, ie, cancer, which would make him a candidate for aortic valvuloplasty rather than replacement. He can be referred for evaluation for this procedure in hopes of palliating his symptoms by relieving his dyspnea and improving his quality of life.

CASE 7: HEMODYNAMIC INSTABILITY

Mr. G, age 87, is scheduled for surgical aortic valve replacement because of severe aortic stenosis (valve area 0.5 cm², peak and mean gradients 89 and 45 mm Hg) with an ejection fraction of 30%.

Two weeks before his scheduled surgery he presents to the emergency department with worsening fluid overload and increasing shortness of breath. His initial laboratory work shows new-onset renal failure, and he has signs of hypoperfusion on physical examination. He is transferred to the cardiac intensive care unit for further care.

How would you manage his aortic stenosis?

Patients with decompensated aortic stenosis and hemodynamic instability are at extreme risk during surgery. Medical stabilization beforehand may mitigate the risks associated with surgical or transcatheter aortic valve replacement. Aortic valvuloplasty, treatment with sodium nitroprusside, and support with intra-aortic balloon counterpulsation may help stabilize patients in this “low-output” setting.

Sodium nitroprusside has long been used in low-output states. By relaxing vascular smooth muscle, it leads to increased venous capacitance, decreasing preload and congestion. It also decreases systemic vascular resistance with a subsequent decrease in afterload, which in turn improves systolic emptying. Together, these effects reduce systolic and diastolic wall stress, lower myocardial oxygen consumption, and ultimately increase cardiac output.^49,50

These theoretical benefits translate to clinical improvement and increased cardiac output, as shown in a case series of 25 patients with severe aortic stenosis and left ventricular systolic dysfunction (ejection fraction 35%) presenting in a low-output state in the absence of hypotension.⁵¹ These findings have led to a ACC/AHA recommendation for the use of sodium nitroprusside in patients who have severe aortic stenosis presenting in low-output state with decompensated heart failure.²¹

Intra-aortic balloon counterpulsation, introduced in 1968, has been used in several clinical settings, including acute coronary syndromes, intractable ventricular arrhythmias, and refractory heart failure, and for support of hemodynamics in the perioperative setting. Its role in managing ventricular septal rupture and acute mitral regurgitation is well established. It reliably reduces afterload and improves coronary perfusion, augmenting the cardiac output. This in turn leads to improved systemic perfusion, which can buy time for a critically ill patient during which the primary disease process is addressed.

Recently, a case series in which intraaortic balloon counterpulsation devices were placed in patients with severe aortic stenosis and cardiogenic shock showed findings similar to those with sodium nitroprusside infusion. Specifically, their use was associated with improved cardiac indices and filling pressures with a decrease in systemic vascular resistance. These changes have led to increased cardiac performance, resulting in better systemic perfusion.⁵² Thus, intra-aortic balloon counterpulsation can be an option for stabilizing patients with severe aortic stenosis and cardiogenic shock.

Mr. G was treated with sodium nitroprusside and intravenous diuretics. He achieved symptomatic relief and his renal function returned to baseline. He subsequently underwent aortic valve replacement during the hospitalization.

Surgical aortic valve replacement remains the gold standard treatment for symptomatic aortic valve stenosis in patients at low or moderate risk of surgical complications. But this is a disease of the elderly, many of whom are too frail or too sick to undergo surgery.

Now, patients who cannot undergo this surgery can be offered the less invasive option of transcatheter aortic valve replacement. Balloon valvuloplasty, sodium nitroprusside, and intra-aortic balloon counterpulsation can buy time for ill patients while more permanent mechanical interventions are being considered.

See related editorial

In this review, we will present several cases that highlight management choices for patients with severe aortic stenosis.

A PROGRESSIVE DISEASE OF THE ELDERLY

Aortic stenosis is the most common acquired valvular disease in the United States, and its incidence and prevalence are rising as the population ages. Epidemiologic studies suggest that 2% to 7% of all patients over age 65 have it.^1,2

The natural history of the untreated disease is well established, with several case series showing an average decrease of 0.1 cm² per year in aortic valve area and an increase of 7 mm Hg per year in the pressure gradient across the valve once the diagnosis is made.^3,4 Development of angina, syncope, or heart failure is associated with adverse clinical outcomes, including death, and warrants prompt intervention with aortic valve replacement.^5–7 Without intervention, the mortality rates reach as high as 75% in 3 years once symptoms develop.

Statins, bisphosphonates, and angiotensin-converting enzyme inhibitors have been used in attempts to slow or reverse the progression of aortic stenosis. However, studies of these drugs have had mixed results, and no definitive benefit has been shown.^8–13 Surgical aortic valve replacement, on the other hand, normalizes the life expectancy of patients with aortic stenosis to that of age- and sex-matched controls and remains the gold standard therapy for patients who have symptoms.¹⁴

Traditionally, valve replacement has involved open heart surgery, since it requires direct visualization of the valve while the patient is on cardiopulmonary bypass. Unfortunately, many patients have multiple comorbid conditions and therefore are not candidates for open heart surgery. Options for these patients include aortic valvuloplasty and transcatheter aortic valve replacement. While there is considerable experience with aortic valvuloplasty, transcatheter aortic valve replacement is relatively new. In large randomized trials and registries, the transcatheter procedure has been shown to significantly improve long-term survival compared with medical management alone in inoperable patients and to have benefit similar to that of surgery in the high-risk population.^15–17

CASE 1: SEVERE, SYMPTOMATIC STENOSIS IN A GOOD SURGICAL CANDIDATE

Mr. A, age 83, presents with shortness of breath and peripheral edema that have been worsening over the past several months. His pulse rate is 64 beats per minute and his blood pressure is 110/90 mm Hg. Auscultation reveals an absent aortic second heart sound with a late peaking systolic murmur that increases with expiration.

On echocardiography, his left ventricular ejection fraction is 55%, peak transaortic valve gradient 88 mm Hg, mean gradient 60 mm Hg, and effective valve area 0.6 cm². He undergoes catheterization of the left side of his heart, which shows normal coronary arteries.

Mr. A also has hypertension and hyperlipidemia; his renal and pulmonary functions are normal.

How would you manage Mr. A’s aortic stenosis?

Symptomatic aortic stenosis leads to adverse clinical outcomes if managed medically without mechanical intervention,^5–7 but patients who undergo aortic valve replacement have age-corrected postoperative survival rates that are nearly normal.¹⁴ Furthermore, thanks to improvements in surgical techniques and perioperative management, surgical mortality rates have decreased significantly in recent years and now range from 1% to 8%.^18–20 The accumulated evidence showing clear superiority of a surgical approach over medical therapy has greatly simplified the therapeutic algorithm.²¹

Consequently, the current guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) give surgery a class I indication (evidence or general agreement that the procedure is beneficial, useful, and effective) for symptomatic severe aortic stenosis (Figure 1). This level of recommendation also applies to patients who have severe but asymptomatic aortic stenosis who are undergoing other types of cardiac surgery and also to patients with severe aortic stenosis and left ventricular dysfunction (defined as an ejection fraction < 50%).²¹

Mr. A was referred for surgical aortic valve replacement, given its clear survival benefit.

CASE 2: SYMPTOMS AND LEFT VENTRICULAR DYSFUNCTION

Ms. B, age 79, has hypertension and hyperlipidemia and now presents to the outpatient department with worsening shortness of breath and chest discomfort. Electrocardiography shows significant left ventricular hypertrophy and abnormal repolarization. Left heart catheterization reveals mild nonobstructive coronary artery disease.

Echocardiography reveals an ejection fraction of 25%, severe left ventricular hypertrophy, and global hypokinesis. The aortic valve leaflets appear heavily calcified, with restricted motion. The peak and mean gradients across the aortic valve are 40 and 28 mm Hg, and the valve area is 0.8 cm². Right heart catheterization shows a cardiac output of 3.1 L/min.

Does this patient’s aortic stenosis account for her clinical presentation?

Managing patients who have suspected severe aortic stenosis, left ventricular dysfunction, and low aortic valve gradients can be challenging. Although data for surgical intervention are not as robust for these patient subsets as for patients like Mr. A, several case series have suggested that survival in these patients is significantly better with surgery than with medical therapy alone.^22–27

Specific factors predict whether patients with ventricular dysfunction and low gradients will benefit from aortic valve replacement. Dobutamine stress echocardiography is helpful in distinguishing true severe aortic stenosis from “pseudostenosis,” in which leaflet motion is restricted due to primary cardiomyopathy and low flow. Distinguishing between true aortic stenosis and pseudostenosis is of paramount value, as surgery is associated with improved long-term outcomes in patients with true aortic stenosis (even though they are at higher surgical risk), whereas those with pseudostenosis will not benefit from surgery.^28–31

Infusion of dobutamine increases the flow across the aortic valve (if the left ventricle has contractile reserve; more on this below), and an increasing valve area with increasing doses of dobutamine is consistent with pseudostenosis. In this situation, treatment of the underlying cardiomyopathy is indicated as opposed to replacement of the aortic valve (Figure 2).

Contractile reserve is defined as an increase in stroke volume (> 20%), valvular gradient (> 10 mm Hg), or peak velocity (> 0.6 m/s) with peak dobutamine infusion. The presence of contractile reserve in patients with aortic stenosis identifies a high-risk group that benefits from aortic valve replacement (Figure 2).

Treatment of patients who have inadequate reserve is controversial. In the absence of contractile reserve, an adjunct imaging study such as computed tomography may be of value in detecting calcified valve leaflets, as the presence of calcium is associated with true aortic stenosis. Comorbid conditions should be taken into account as well, given the higher surgical risk in this patient subset, as aortic valve replacement in this already high-risk group of patients might be futile in some cases.

The ACC/AHA guidelines now give dobutamine stress echocardiography a class IIa indication (meaning the weight of the evidence or opinion is in favor of usefulness or efficacy) for determination of contractile reserve and valvular stenosis for patients with an ejection fraction of 30% or less or a mean gradient of 40 mm Hg or less.²¹

Ms. B underwent dobutamine stress echocardiography. It showed increases in ejection fraction, stroke volume, and transvalvular gradients, indicating that she did have contractile reserve and true severe aortic stenosis. Consequently, she was referred for surgical aortic valve replacement.

CASE 3: MODERATE STENOSIS AND THREE-VESSEL CORONARY ARTERY DISEASE

Mr. C, age 81, has hypertension and hyperlipidemia. He now presents to the emergency department with chest discomfort that began suddenly, awakening him from sleep. His presenting electrocardiogram shows nonspecific changes, and he is diagnosed with non-ST-elevation myocardial infarction. He undergoes left heart catheterization, which reveals severe three-vessel coronary artery disease.

Echocardiography reveals an ejection fraction of 55% and aortic stenosis, with an aortic valve area of 1.2 cm², a peak gradient of 44 mm Hg, and a mean gradient of 28 mm Hg.

How would you manage his aortic stenosis?

Moderate aortic stenosis in a patient who needs surgery for severe triple-vessel coronary artery disease, other valve diseases, or aortic disease raises the question of whether aortic valve replacement should be performed in conjunction with these surgeries. Although these patients would not otherwise qualify for aortic valve replacement, the fact that they will undergo a procedure that will expose them to the risks associated with open heart surgery makes them reasonable candidates. Even if the patient does not need aortic valve replacement right now, aortic stenosis progresses at a predictable rate—the valve area decreases by a mean of 0.1 cm²/year and the gradients increase by 7 mm Hg/year. Therefore, clinical judgment should be exercised so that the patient will not need to undergo open heart surgery again in the near future.

The ACC/AHA guidelines recommend aortic valve replacement for patients with moderate aortic stenosis undergoing coronary artery bypass grafting or surgery on the aorta or other heart valves, giving it a class IIa indication.²¹ This recommendation is based on several retrospective case series that evaluated survival, the need for reoperation for aortic valve replacement, or both in patients undergoing coronary artery bypass grafting.^32–35

No data exist, however, on adding aortic valve replacement to coronary artery bypass grafting in cases of mild aortic stenosis. As a result, it is controversial and carries a class IIb recommendation (meaning that its usefulness or efficacy is less well established). The ACC/AHA guidelines state that aortic valve replacement “may be considered” in patients undergoing coronary artery bypass grafting who have mild aortic stenosis (mean gradient < 30 mm Hg or jet velocity < 3 m/s) when there is evidence, such as moderate or severe valve calcification, that progression may be rapid (level of evidence C: based only on consensus opinion of experts, case studies or standard of care).²¹

Mr. C, who has moderate aortic stenosis, underwent aortic valve replacement in conjunction with three-vessel bypass grafting.

CASE 4: ASYMPTOMATIC BUT SEVERE STENOSIS

Mr. D, age 74, has hypertension, hyperlipidemia, and aortic stenosis. He now presents to the outpatient department for his annual echocardiogram to follow his aortic stenosis. He has a sedentary lifestyle but feels well performing activities of daily living. He denies dyspnea on exertion, chest pain, or syncope.

His echocardiogram reveals an effective aortic valve area of 0.7 cm², peak gradient 90 mm Hg, and mean gradient 70 mm Hg. There is evidence of severe left ventricular hypertrophy, and the valve leaflets show bulky calcification and severe restriction. An echocardiogram performed at the same institution a year earlier revealed gradients of 60 and 40 mm Hg.

Blood is drawn for laboratory tests, including N-terminal pro-brain natriuretic peptide, which is 350 pg/mL (reference range for his age < 125 pg/mL). He is referred for a treadmill stress test, which elicits symptoms at a moderate activity level.

How would you manage his aortic stenosis?

Aortic valve replacement can be considered in patients who have asymptomatic but severe aortic stenosis with preserved left ventricular function (class IIb indication).²¹

Clinical assessment of asymptomatic aortic stenosis can be challenging, however, as patients may underreport their symptoms or decrease their activity levels to avoid symptoms. Exercise testing in such patients can elicit symptoms, unmask diminished exercise capacity, and help determine if they should be referred for surgery.^36,37 Natriuretic peptide levels have been shown to correlate with the severity of aortic stenosis,^38,39 and more importantly, to help predict symptom onset, cardiac death, and need for aortic valve replacement.^40–42

Some patients with asymptomatic but severe aortic stenosis are at higher risk of morbidity and death. High-risk subsets include patients with rapid progression of aortic stenosis and those with critical aortic stenosis characterized by an aortic valve area less than 0.60 cm², mean gradient greater than 60 mm Hg, and jet velocity greater than 5.0 m/s. It is reasonable to offer these patients surgery if their expected operative mortality risk is less than 1.0%.²¹

Mr. D has evidence of rapid progression as defined by an increase in aortic jet velocity of more than 0.3 m/s/year. He is at low surgical risk and was referred for elective aortic valve replacement.

CASE 5: TOO FRAIL FOR SURGERY

Mr. E, age 84, has severe aortic stenosis (valve area 0.6 cm², peak and mean gradients of 88 and 56 mm Hg), coronary artery disease status post coronary artery bypass grafting, moderate chronic obstructive pulmonary disease (forced expiratory volume in 1 second 0.8 L), chronic kidney disease (serum creatinine 1.9 mg/dL), hypertension, hyperlipidemia, and diabetes mellitus. He has preserved left ventricular function. He presents to the outpatient department with worsening shortness of breath and peripheral edema over the past several months. Your impression is that he is very frail. How would you manage Mr. E’s aortic stenosis?

Advances in surgical techniques and perioperative management over the years have enabled higher-risk patients to undergo surgical aortic valve replacement with excellent out-comes.18–20,43 Yet many patients still cannot undergo surgery because their risk is too high. Patients ineligible for surgery have traditionally been treated medically—with poor out-comes—or with balloon aortic valvuloplasty to palliate symptoms.

Transcatheter aortic valve replacement, approved by the US Food and Drug Administration (FDA) in 2011, now provides another option for these patients. In this procedure, a bioprosthetic valve mounted on a metal frame is implanted over the native stenotic valve.

Currently, the only FDA-approved and commercially available valve in the United States is the Edwards SAPIEN valve, which has bovine pericardial tissue leaflets fixed to a balloon-expandable stainless steel frame (Figure 3). In the Placement of Aortic Transcatheter Valves (PARTNER) trial,¹⁵ patients who could not undergo surgery who underwent transcatheter replacement with this valve had a significantly better survival rate than patients treated medically.^15,17 Use of this valve has also been compared against conventional surgical aortic valve replacement in high-risk patients and was found to have similar long-term outcomes (Figure 4).¹⁶ It was on the basis of this trial that this valve was granted approval for patients who cannot undergo surgery.

The standard of care for high-risk patients remains surgical aortic valve replacement, although it remains to be seen whether transcatheter replacement will be made available as well to patients eligible for surgery in the near future. There are currently no randomized data for transcatheter aortic valve replacement in patients at moderate to low surgical risk, and these patients should not be considered for this procedure.

Although the initial studies are encouraging for patients who cannot undergo surgery and who are at high risk without it, several issues and concerns remain. Importantly, the long-term durability of the transcatheter valve and longer-term outcomes remain unknown. Furthermore, the risk of vascular complications remains high (10% to 15%), dictating the need for careful patient selection. There are also concerns about the risks of stroke and of paravalvular aortic insufficiency. These issues are being investigated and addressed, however, and we hope that with increasing operator experience and improvements in the technique, outcomes will be improved.

Which approach for transcatheter aortic valve replacement?

There are several considerations in determining a patient’s eligibility for transcatheter aortic valve replacement.

Initially, these valves were placed by a transvenous, transseptal approach, but now retrograde placement through the femoral artery has become standard. In this procedure, the device is advanced retrograde from the femoral artery through the aorta and placed across the native aortic valve under fluoroscopic and echocardiographic guidance.

Patients who are not eligible for transfemoral placement because of severe atherosclerosis, tortuosity, or ectasia of the iliofemoral artery or aorta can still undergo percutaneous treatment with a transapical approach. This is a hybrid surgical-transcatheter approach in which the valve is delivered through a sheath placed by left ventricular apical puncture.^17,44

A newer approach gaining popularity is the transaortic technique, in which the ascending aorta is accessed directly through a ministernotomy and the delivery sheath is placed with a direct puncture. Other approaches are through the axillary and subclavian arteries.

Other valves are under development

Several other valves are under development and will likely change the landscape of transcatheter aortic valve replacement with improving outcomes. Valves that are available in the United States are shown in Figure 3. The CoreValve, consisting of porcine pericardial leaflets mounted on a self-expanding nitinol stent, is currently being studied in a trial in the United States, and the manufacturer (Medtronic) will seek approval when results are complete in the near future.

Mr. E was initially referred for surgery, but when deemed to be unable to undergo surgery was found to be a good candidate for transcatheter aortic valve replacement.

CASE 6: LIFE-LIMITING COMORBID ILLNESS

Mr. F, age 77, has multiple problems: severe aortic stenosis (aortic valve area 0.6 cm²; peak and mean gradients of 92 and 59 mm Hg), stage IV pancreatic cancer, coronary artery disease status post coronary artery bypass grafting, chronic kidney disease (serum creatinine 1.9 mg/dL), hypertension, and hyperlipidemia. He presents to the outpatient department with shortness of breath at rest, orthopnea, effort intolerance, and peripheral edema over the past several months.

On physical examination rales in both lung bases can be heard. Left heart catheterization shows patent bypass grafts.

How would you manage Mr. F’s aortic stenosis?

Aortic valve replacement is not considered an option in patients with noncardiac illnesses and comorbidities that are life-limiting in the near term. Under these circumstances, aortic valvuloplasty can be offered as a means of palliating symptoms or, if the comorbid conditions can be modified, as a bridge to more definitive treatment with aortic valve replacement.

Since first described in 1986,⁴⁵ percutaneous aortic valvuloplasty has been studied in several case series and registries, with consistent findings. Acutely, it increases the valve area and lessens the gradients across the valve, relieving symptoms. The risk of death during the procedure ranged from 3% to 13.5% in several case series, with a 30-day survival rate greater than 85%.⁴⁶ However, the hemodynamic and symptomatic improvement is only short-term, as valve area and gradients gradually worsen within several months.^47,48 Consequently, balloon valvuloplasty is considered a palliative approach.

Mr. F has a potentially life-limiting illness, ie, cancer, which would make him a candidate for aortic valvuloplasty rather than replacement. He can be referred for evaluation for this procedure in hopes of palliating his symptoms by relieving his dyspnea and improving his quality of life.

CASE 7: HEMODYNAMIC INSTABILITY

Mr. G, age 87, is scheduled for surgical aortic valve replacement because of severe aortic stenosis (valve area 0.5 cm², peak and mean gradients 89 and 45 mm Hg) with an ejection fraction of 30%.

Two weeks before his scheduled surgery he presents to the emergency department with worsening fluid overload and increasing shortness of breath. His initial laboratory work shows new-onset renal failure, and he has signs of hypoperfusion on physical examination. He is transferred to the cardiac intensive care unit for further care.

How would you manage his aortic stenosis?

Patients with decompensated aortic stenosis and hemodynamic instability are at extreme risk during surgery. Medical stabilization beforehand may mitigate the risks associated with surgical or transcatheter aortic valve replacement. Aortic valvuloplasty, treatment with sodium nitroprusside, and support with intra-aortic balloon counterpulsation may help stabilize patients in this “low-output” setting.

Sodium nitroprusside has long been used in low-output states. By relaxing vascular smooth muscle, it leads to increased venous capacitance, decreasing preload and congestion. It also decreases systemic vascular resistance with a subsequent decrease in afterload, which in turn improves systolic emptying. Together, these effects reduce systolic and diastolic wall stress, lower myocardial oxygen consumption, and ultimately increase cardiac output.^49,50

These theoretical benefits translate to clinical improvement and increased cardiac output, as shown in a case series of 25 patients with severe aortic stenosis and left ventricular systolic dysfunction (ejection fraction 35%) presenting in a low-output state in the absence of hypotension.⁵¹ These findings have led to a ACC/AHA recommendation for the use of sodium nitroprusside in patients who have severe aortic stenosis presenting in low-output state with decompensated heart failure.²¹

Intra-aortic balloon counterpulsation, introduced in 1968, has been used in several clinical settings, including acute coronary syndromes, intractable ventricular arrhythmias, and refractory heart failure, and for support of hemodynamics in the perioperative setting. Its role in managing ventricular septal rupture and acute mitral regurgitation is well established. It reliably reduces afterload and improves coronary perfusion, augmenting the cardiac output. This in turn leads to improved systemic perfusion, which can buy time for a critically ill patient during which the primary disease process is addressed.

Recently, a case series in which intraaortic balloon counterpulsation devices were placed in patients with severe aortic stenosis and cardiogenic shock showed findings similar to those with sodium nitroprusside infusion. Specifically, their use was associated with improved cardiac indices and filling pressures with a decrease in systemic vascular resistance. These changes have led to increased cardiac performance, resulting in better systemic perfusion.⁵² Thus, intra-aortic balloon counterpulsation can be an option for stabilizing patients with severe aortic stenosis and cardiogenic shock.

Mr. G was treated with sodium nitroprusside and intravenous diuretics. He achieved symptomatic relief and his renal function returned to baseline. He subsequently underwent aortic valve replacement during the hospitalization.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.