After another round of epinephrine, I started chest compressionsagain. Warm sweat seeped down my neck and back. In just 10 minutes, the 24‐bed pediatric intensive care unit (PICU) had become much smaller and more confined. Everyone funneled into this one room, this one bed. Beyond it was a blur of color and sound. I forced my strength onto Ricky, my 17‐year‐old patient with muscular dystrophy and end‐stage heart failure. He was admitted 1 week ago with respiratory distress, and he had only gotten worse since then.

Ricky's body, now cool and pale, was a blob of relaxed skin and loose bone beneath me. I straightened my arms, jutted the heel of my left hand over my right and pushed onto his chest. I pushed hard and fast, like I was taught; a dumb robotic motion again and again, trying to keep good position and form. I stared up at the monitor between every few compressions, looking at all the waveforms, anticipating, as if something on the screen was going to pop up suddenly and say EVERYTHING IS GOING TO BE OKAY. But it didn't.

I glanced beyond the bedside. There was a flurry of people bumping each other, asking for things, telling things, giving and receiving things. All of them were moving, but really had no place to go. This was the place. And in the far corner of the room, stood Mom and Dad.

In between the sink and recliner chair filled with clothes and books, they were the only people that stood still. Swollen feet planted in white socks. Their shoulders sagged.

I love you, I love you, Ricky. No, no, no. Mom and Dad kept on saying between sobs. I wondered if he could hear them. I wished he could hear them. Then I wished they would stop saying anything at all. I felt a rib give under my hands.

From the corner of my left eye, I saw Dad holding Mom upright by the wall. She wore red‐rimmed eyes and wet cheeks and took puttering breaths. Dad squeezed tissues in his hand, then into his eyes and nose and then back into his fist. They kept saying the words over and over, like they knew no other. I pushed harder and faster, but he didn't turn any pinker. Damn it. Damn it. There was plenty of noise, but above it all, I heard their voices. When I was told to hold compressions to check for a pulse, I stood still with my hands at my sides. I felt unnecessary. My precious little contribution to the commotion interrupted.

We all looked up at the monitor.

Stop, please stop. That's it, dad said, somewhere in the infinite pause. Mom still mumbled no over and over again. I turned to her and listened. I watched her pursed mouth and I imagined what it was Dad felt as he held her. Her body shook a Morse code into him, telling him it was time to give up. That it was over. That she couldn't take watching me pound away on her son's chest anymore. That it was okay to let Ricky rest. All the words that she couldn't find, or have the coordination to say, Dad translated for her.

He held her with a desperate grip, for a few moments longer. Maybe, the harder he squeezed, the more life he could push out of her, out of himself, and that effervescent pulse would find its way to their son's heart. But maybe all he could sense was her quiet internal whisper. And they told us again, as I remembered, just like all the soft conversations we had before in the back of the room, while Ricky slept, sedated on narcotics.

I put my fingers over his radial artery and closed my eyes.

Don't let Ricky feel pain, she said. It was the day we intubated him, only hours after he had been admitted.

Do what you can do, just don't Dad trailed off. He stared up at the ceiling and sighed. We listened to the gasp and hiss of the ventilator for a few more moments in silence.

We can try what you say, but no pain. We should know when to quitfor Ricky. Okay? Mom said, waiting for the tears as her nose moistened. She stared up at me.

Okay, I said. I nodded and stared back.

Dad squeezed her arm again, wrapped his around hers and massaged her. She had started to shake.

No pulse. I opened my eyes.

I stared at Ricky's face. His eyelids were half open, his lips were blue. No change on the monitor. I motioned to start compressions again.

Okay, Dad said.

Okay, stop! He's had enough. His dry lips and wet face moved and voiced the end. The room froze.

My muscles relaxed and I splayed my fingers wide, my way of showing that I was letting up. I watched myself lean back, unbelieving, and looked at the screen again. The rhythm drifted from pulseless electrical activity to asystole.

Mom and Dad simultaneously shut their eyes as if they saw something that we didn't and couldn't bear to see anymore. They opened them, looked at Ricky and slowly, as everyone stared, moved to the foot of the bed and began to rub his bare feet.

In subtle efficiency, the room was transformed. We turned off the monitors, we pushed out the carts and equipment, we picked up after ourselves, we dimmed the lights, we pulled the curtains and we left Mom and Dad with their son. Slow, deliberate whispers and motion now, it sounded empty without the background of rhythmic mechanical sounds. No dings, bleeps or rings; no pistons, suctions or pumps; only the occasional sound of tissue being ripped out of a box.

We sat with the family an hour later, in the conference room, to sign papers, for autopsy, for death certificates, for funeral preparations. Mom and Dad didn't know how to answer, and they drifted together to consider how they wanted Ricky's body cared for. Burial? Cremation?

I don't know, Mom said as she tried to fold the shredded tissues in her hand. He had a spinal rod placed his back years ago for his scoliosis. A titanium rod in his spine. Would that even burn? she asked.

We stared at each other, confused and unknowing.

We never thought of that, she said. She began to think out loud. If he were cremated, I don't think I'd want his spinal rod as a reminder. She cocked her head back. What a weird keepsake! She laughed, Where would I keep it? Above the fireplace? How odd. She rolled her eyes, and started to cry again.

After another round of epinephrine, I started chest compressionsagain. Warm sweat seeped down my neck and back. In just 10 minutes, the 24‐bed pediatric intensive care unit (PICU) had become much smaller and more confined. Everyone funneled into this one room, this one bed. Beyond it was a blur of color and sound. I forced my strength onto Ricky, my 17‐year‐old patient with muscular dystrophy and end‐stage heart failure. He was admitted 1 week ago with respiratory distress, and he had only gotten worse since then.

Ricky's body, now cool and pale, was a blob of relaxed skin and loose bone beneath me. I straightened my arms, jutted the heel of my left hand over my right and pushed onto his chest. I pushed hard and fast, like I was taught; a dumb robotic motion again and again, trying to keep good position and form. I stared up at the monitor between every few compressions, looking at all the waveforms, anticipating, as if something on the screen was going to pop up suddenly and say EVERYTHING IS GOING TO BE OKAY. But it didn't.

I glanced beyond the bedside. There was a flurry of people bumping each other, asking for things, telling things, giving and receiving things. All of them were moving, but really had no place to go. This was the place. And in the far corner of the room, stood Mom and Dad.

In between the sink and recliner chair filled with clothes and books, they were the only people that stood still. Swollen feet planted in white socks. Their shoulders sagged.

I love you, I love you, Ricky. No, no, no. Mom and Dad kept on saying between sobs. I wondered if he could hear them. I wished he could hear them. Then I wished they would stop saying anything at all. I felt a rib give under my hands.

From the corner of my left eye, I saw Dad holding Mom upright by the wall. She wore red‐rimmed eyes and wet cheeks and took puttering breaths. Dad squeezed tissues in his hand, then into his eyes and nose and then back into his fist. They kept saying the words over and over, like they knew no other. I pushed harder and faster, but he didn't turn any pinker. Damn it. Damn it. There was plenty of noise, but above it all, I heard their voices. When I was told to hold compressions to check for a pulse, I stood still with my hands at my sides. I felt unnecessary. My precious little contribution to the commotion interrupted.

We all looked up at the monitor.

Stop, please stop. That's it, dad said, somewhere in the infinite pause. Mom still mumbled no over and over again. I turned to her and listened. I watched her pursed mouth and I imagined what it was Dad felt as he held her. Her body shook a Morse code into him, telling him it was time to give up. That it was over. That she couldn't take watching me pound away on her son's chest anymore. That it was okay to let Ricky rest. All the words that she couldn't find, or have the coordination to say, Dad translated for her.

He held her with a desperate grip, for a few moments longer. Maybe, the harder he squeezed, the more life he could push out of her, out of himself, and that effervescent pulse would find its way to their son's heart. But maybe all he could sense was her quiet internal whisper. And they told us again, as I remembered, just like all the soft conversations we had before in the back of the room, while Ricky slept, sedated on narcotics.

I put my fingers over his radial artery and closed my eyes.

Don't let Ricky feel pain, she said. It was the day we intubated him, only hours after he had been admitted.

Do what you can do, just don't Dad trailed off. He stared up at the ceiling and sighed. We listened to the gasp and hiss of the ventilator for a few more moments in silence.

We can try what you say, but no pain. We should know when to quitfor Ricky. Okay? Mom said, waiting for the tears as her nose moistened. She stared up at me.

Okay, I said. I nodded and stared back.

Dad squeezed her arm again, wrapped his around hers and massaged her. She had started to shake.

No pulse. I opened my eyes.

I stared at Ricky's face. His eyelids were half open, his lips were blue. No change on the monitor. I motioned to start compressions again.

Okay, Dad said.

Okay, stop! He's had enough. His dry lips and wet face moved and voiced the end. The room froze.

My muscles relaxed and I splayed my fingers wide, my way of showing that I was letting up. I watched myself lean back, unbelieving, and looked at the screen again. The rhythm drifted from pulseless electrical activity to asystole.

Mom and Dad simultaneously shut their eyes as if they saw something that we didn't and couldn't bear to see anymore. They opened them, looked at Ricky and slowly, as everyone stared, moved to the foot of the bed and began to rub his bare feet.

In subtle efficiency, the room was transformed. We turned off the monitors, we pushed out the carts and equipment, we picked up after ourselves, we dimmed the lights, we pulled the curtains and we left Mom and Dad with their son. Slow, deliberate whispers and motion now, it sounded empty without the background of rhythmic mechanical sounds. No dings, bleeps or rings; no pistons, suctions or pumps; only the occasional sound of tissue being ripped out of a box.

We sat with the family an hour later, in the conference room, to sign papers, for autopsy, for death certificates, for funeral preparations. Mom and Dad didn't know how to answer, and they drifted together to consider how they wanted Ricky's body cared for. Burial? Cremation?

I don't know, Mom said as she tried to fold the shredded tissues in her hand. He had a spinal rod placed his back years ago for his scoliosis. A titanium rod in his spine. Would that even burn? she asked.

We stared at each other, confused and unknowing.

We never thought of that, she said. She began to think out loud. If he were cremated, I don't think I'd want his spinal rod as a reminder. She cocked her head back. What a weird keepsake! She laughed, Where would I keep it? Above the fireplace? How odd. She rolled her eyes, and started to cry again.

After another round of epinephrine, I started chest compressionsagain. Warm sweat seeped down my neck and back. In just 10 minutes, the 24‐bed pediatric intensive care unit (PICU) had become much smaller and more confined. Everyone funneled into this one room, this one bed. Beyond it was a blur of color and sound. I forced my strength onto Ricky, my 17‐year‐old patient with muscular dystrophy and end‐stage heart failure. He was admitted 1 week ago with respiratory distress, and he had only gotten worse since then.

Ricky's body, now cool and pale, was a blob of relaxed skin and loose bone beneath me. I straightened my arms, jutted the heel of my left hand over my right and pushed onto his chest. I pushed hard and fast, like I was taught; a dumb robotic motion again and again, trying to keep good position and form. I stared up at the monitor between every few compressions, looking at all the waveforms, anticipating, as if something on the screen was going to pop up suddenly and say EVERYTHING IS GOING TO BE OKAY. But it didn't.

I glanced beyond the bedside. There was a flurry of people bumping each other, asking for things, telling things, giving and receiving things. All of them were moving, but really had no place to go. This was the place. And in the far corner of the room, stood Mom and Dad.

In between the sink and recliner chair filled with clothes and books, they were the only people that stood still. Swollen feet planted in white socks. Their shoulders sagged.

I love you, I love you, Ricky. No, no, no. Mom and Dad kept on saying between sobs. I wondered if he could hear them. I wished he could hear them. Then I wished they would stop saying anything at all. I felt a rib give under my hands.

From the corner of my left eye, I saw Dad holding Mom upright by the wall. She wore red‐rimmed eyes and wet cheeks and took puttering breaths. Dad squeezed tissues in his hand, then into his eyes and nose and then back into his fist. They kept saying the words over and over, like they knew no other. I pushed harder and faster, but he didn't turn any pinker. Damn it. Damn it. There was plenty of noise, but above it all, I heard their voices. When I was told to hold compressions to check for a pulse, I stood still with my hands at my sides. I felt unnecessary. My precious little contribution to the commotion interrupted.

We all looked up at the monitor.

Stop, please stop. That's it, dad said, somewhere in the infinite pause. Mom still mumbled no over and over again. I turned to her and listened. I watched her pursed mouth and I imagined what it was Dad felt as he held her. Her body shook a Morse code into him, telling him it was time to give up. That it was over. That she couldn't take watching me pound away on her son's chest anymore. That it was okay to let Ricky rest. All the words that she couldn't find, or have the coordination to say, Dad translated for her.

He held her with a desperate grip, for a few moments longer. Maybe, the harder he squeezed, the more life he could push out of her, out of himself, and that effervescent pulse would find its way to their son's heart. But maybe all he could sense was her quiet internal whisper. And they told us again, as I remembered, just like all the soft conversations we had before in the back of the room, while Ricky slept, sedated on narcotics.

I put my fingers over his radial artery and closed my eyes.

Don't let Ricky feel pain, she said. It was the day we intubated him, only hours after he had been admitted.

Do what you can do, just don't Dad trailed off. He stared up at the ceiling and sighed. We listened to the gasp and hiss of the ventilator for a few more moments in silence.

We can try what you say, but no pain. We should know when to quitfor Ricky. Okay? Mom said, waiting for the tears as her nose moistened. She stared up at me.

Okay, I said. I nodded and stared back.

Dad squeezed her arm again, wrapped his around hers and massaged her. She had started to shake.

No pulse. I opened my eyes.

I stared at Ricky's face. His eyelids were half open, his lips were blue. No change on the monitor. I motioned to start compressions again.

Okay, Dad said.

Okay, stop! He's had enough. His dry lips and wet face moved and voiced the end. The room froze.

My muscles relaxed and I splayed my fingers wide, my way of showing that I was letting up. I watched myself lean back, unbelieving, and looked at the screen again. The rhythm drifted from pulseless electrical activity to asystole.

Mom and Dad simultaneously shut their eyes as if they saw something that we didn't and couldn't bear to see anymore. They opened them, looked at Ricky and slowly, as everyone stared, moved to the foot of the bed and began to rub his bare feet.

In subtle efficiency, the room was transformed. We turned off the monitors, we pushed out the carts and equipment, we picked up after ourselves, we dimmed the lights, we pulled the curtains and we left Mom and Dad with their son. Slow, deliberate whispers and motion now, it sounded empty without the background of rhythmic mechanical sounds. No dings, bleeps or rings; no pistons, suctions or pumps; only the occasional sound of tissue being ripped out of a box.

We sat with the family an hour later, in the conference room, to sign papers, for autopsy, for death certificates, for funeral preparations. Mom and Dad didn't know how to answer, and they drifted together to consider how they wanted Ricky's body cared for. Burial? Cremation?

I don't know, Mom said as she tried to fold the shredded tissues in her hand. He had a spinal rod placed his back years ago for his scoliosis. A titanium rod in his spine. Would that even burn? she asked.

We stared at each other, confused and unknowing.

We never thought of that, she said. She began to think out loud. If he were cremated, I don't think I'd want his spinal rod as a reminder. She cocked her head back. What a weird keepsake! She laughed, Where would I keep it? Above the fireplace? How odd. She rolled her eyes, and started to cry again.

Bacterial meningitis can be a devastating disease in children. Overall mortality in children in the United States is 4%1 while long‐term morbidity is present in up to 25%2 of surviving children. The introduction of Haemophilus influenzae type B vaccine, heptavalent pneumococcal conjugate vaccine, and the quadrivalent meningococcal conjugate vaccine has altered the epidemiology of bacterial meningitis.24 Currently, little is known about the epidemiology of systemic complications and associated focal infections that occur during episodes of bacterial meningitis in children and how the presence of such complications affects in‐hospital healthcare resource utilization.

In a randomized controlled trial, the administration of adjuvant corticosteroids was associated with lower mortality rates in adults with bacterial meningitis due to all causes, with the greatest reduction in those with pneumococcal meningitis.5 In a post hoc analysis of data from this trial, reductions in systemic complications, such as septic shock, pneumonia, and acute respiratory distress syndrome, rather than neurologic complications were thought to be the underlying reason for the decrease in mortality associated with pneumococcal meningitis among corticosteroid recipients.6 However, children with bacterial meningitis have an overall 4‐fold lower mortality rate than adults with bacterial meningitis. An even greater difference in mortality rates exists between children and adults with pneumococcal meningitis.1, 5 Children do not benefit from adjuvant corticosteroids as adults do.1, 5, 7 Therefore, the pathogenesis of bacterial meningitis may differ in children from adults and account for the difference in response to adjuvant corticosteroids. Understanding the epidemiology of systemic complications and associated focal infections can aid in the understanding of the pathogenesis of the disease in varying age groups of children.

Previous studies in children have documented the frequency of certain bacterial meningitis‐associated conditions such as respiratory failure, pneumonia, endocarditis, and mastoiditis. Researchers have used the presence of such conditions to predict either mortality or neurologic sequelae in children.810 These studies were small and only included a few types of complications associated with bacterial meningitis. In‐hospital healthcare resource utilization, which may be an important indicator of in‐hospital morbidity, was also not considered as an outcome. In‐hospital morbidity may represent aspects of disease burden not captured by mortality rates or markers for long‐term morbidity alone. In future vaccine efficacy trails or novel therapeutics evaluations, consideration of these associated conditions is important.

The quantification of the use of in‐hospital healthcare utilization is also important for hospital planning and resource allocation in children with bacterial meningitis. A child presenting with bacterial meningitis and a systemic complication or an associated focal infection may require additional resource planning initially to expedite care to enhance recovery and decrease hospital length of stay (LOS).

Our goal was to document the frequency of bacterial meningitis‐associated conditions (systemic complications and associated focal infections) in a large cohort of children with bacterial meningitis treated at tertiary care children's hospitals in the United States, and determine how the presence of such conditions impacted in‐hospital healthcare resource utilization.

Patients and Methods

Results

Bacterial Meningitis‐Associated Conditions

Overall, 574 (25%) of children with bacterial meningitis suffered a systemic complication or an associated focal infection. Figure 1 shows the types of associated condition stratified by age category. Older children had a higher frequency of associated focal infections while younger children had a higher frequency of systemic complications (P = 0.002, chi‐square test for trend). Figure 2 shows the distribution of specific conditions among children in each age category. The frequency of sepsis decreased with age (P < 0.001, chi‐square test) while the frequency of mastoiditis (P < 0.001, Fisher's exact test) and osteomyelitis (P = 0.005, Fisher's exact test) increased with age. There did not appear to be substantial variability in the proportion of patients with SIRS or sepsis across hospitals, suggesting that hospital‐level variability in coding for these conditions was likely minimal. The median proportion of patients with SIRS by hospital was 2.4% (IQR, 1.2‐4.8%) while the median proportion of patients with sepsis by hospital was 13.4% (IQR, 10.0‐16.9%).

Figure 1

Figure 2

Of the 151 children with an associated focal infection, only 3 (2%) of children had more than 1 infection (1 child had mastoiditis and endocarditis, 1 child had pneumonia and osteomyelitis, and 1 child had pneumonia and endocarditis). However, of the 479 children with systemic complications, 116 (24%) had more than 1 systemic disease (Table 1).

Table 1.Children With Systemic Complications

Types of Systemic Complications	Systemic Complications in All Bacterial Meningitis, n (%)	Systemic Complications in Meningococcal Meningitis, n (%)	Systemic Complications in Pneumococcal Meningitis, n (%)
NOTE: Percentages may not add to 100 due to rounding. Abbreviations: SIRS, systemic inflammatory response syndrome.
Sepsis only	209 (44)	16 (21)	69 (54)
Respiratory failure only	139 (29)	38 (49)	30 (24)
SIRS only	15 (3)	9 (12)	1 (1)
Sepsis and respiratory failure	52 (11)	4 (5)	18 (14)
SIRS and sepsis	27 (6)	2 (3)	4 (3)
SIRS and respiratory failure	9 (2)	5 (6)	0 (0)
SIRS and respiratory failure and sepsis	28 (6)	3 (4)	5 (4)
Total systemic complications	479	77	127

In sub‐group analyses, 269 children had meningococcal meningitis and 470 children had pneumococcal meningitis. Of the children with meningococcal meningitis, 31.2% had a meningitis‐associated condition: 26.4% had a systemic complication, 2.6% had a focal infection, and 2.2% had both conditions. The most common associated conditions in children with meningococcal meningitis were respiratory failure (18.6%; n = 50), sepsis (9.3%; n = 25), and SIRS (7.1%; n = 19). In children with pneumococcal meningitis, 32.3% had a meningitis‐associated complication: 24.7% had a systemic complication, 5.3% had a focal infection, and 2.3% had both conditions. The most common associated conditions in children with pneumococcal meningitis were sepsis (20.4%; n = 96), respiratory failure (11.3%; n = 53), and pneumonia (4.7%; n = 22); mastoiditis was present in 2.3% (n = 11) of children with pneumococcal meningitis. Respiratory failure was more common in meningococcal meningitis (18.6%) than in pneumococcal meningitis (11.3%; P = 0.006). In contrast, sepsis was less common in meningococcal meningitis (9.3%) than in pneumococcal meningitis (20.4%; P < 0.001).

Hospital Charges

Overall, the median charges per hospital ranged from $20,158 to $53,823. In‐hospital charges for children with bacterial meningitis with and without any identified associated conditions are presented in Table 2. In multivariate analyses, the presence of systemic conditions, associated focal infections, or both conditions was independently associated with significantly higher total in‐hospital charges (Table 2). When conditions were considered individually, bone and joint infections (213% increase; 95% CI, 113‐260%), endocarditis (108% increase; 95% CI, 23‐258%), and pneumonia (107% increase; 95% CI, 58‐171%) were associated with the highest increases in total hospital charges (Figure 3). In contrast, SIRS and mastoiditis were not associated with higher hospital charges (Figure 3).

Table 2.Comparison of Total Hospital Charges and Length of Stay by Complication Type

	Charges		LOS
	Median, $ (IQR)	Adjusted Increase,* % (95% CI)	Median, days (IQR)	Adjusted Increase,* % (95% CI)
Abbreviations: CI, confidence interval; IQR, interquartile range. * Adjusted for age category, race, sex, vancomycin receipt, and adjuvant corticosteroid therapy. P value <0.001 for all comparisons.
None (n = 1,745)	$27,110 (15,823‐48,307)	Reference**	9 (6‐14)	Reference
Systemic (n = 423)	$66,690 (39,546136,756)	136 (108269)	14 (923)	72 (5196)
Focal Infection (n = 95)	$58,016 (29,056125,813)	118 (77168)	13 (928)	78 (40126)
Both (n = 56)	$130,744 (62,397299,288)	351 (237503)	21.5 (1245)	211 (142303)

Figure 3

LOS

The median LOS was 9 days (IQR, 6‐15 days); 5% of children had a LOS >42 days. Table 2 summarizes difference in LOS by the presence and absence of systemic conditions and focal infections. In multivariate analyses, the presence of systemic conditions, associated focal infections, or both conditions was independently associated with a significantly longer LOS (Table 2). When conditions were considered individually, endocarditis (152% increase; 95% CI, 60‐300%) and pneumonia (136% increase; 95% CI, 85‐201%) were associated with the greatest adjusted increases in LOS (Figure 4); only mastoiditis was not associated with an increased LOS compared with those without complications.

Figure 4

Discussion

To our knowledge, this is the first study to examine bacterial meningitis‐associated conditions in children and their impact on in‐hospital resource utilization. We found that 25% of the cohort of children with bacterial meningitis suffered from at least one focal infection or systemic complication. This represents a significant invasive disease burden among children with bacterial meningitis who do not have underlying comorbid conditions. Younger children were more likely to have systemic complications when compared with older children, specifically due to a higher frequency of sepsis in children <1 year. Older children were more likely to have an associated focal infection, specifically due to an increase in mastoiditis and osteomyelitis in children >1 year. Only 2% of children had more than 1 focal infection, while 24% of children had more than 1 systemic complication.

Importantly, the presence of a systemic complication in a child with bacterial meningitis increased their in‐hospital adjusted charges by 136%. The presence of a focal infection increased in‐hospital adjusted charges by 118%. A child with both a systemic complication and a focal infection and had a 351% increase in in‐hospital adjusted charges.

The presence of systemic complications or associated focal infections was significantly associated with higher in‐hospital charges and longer hospital LOS. Most individual meningitis‐associated conditions included in this study were associated with higher in‐hospital charges with the exception of SIRS and mastoiditis. All individual meningitis‐associated conditions were associated with a longer LOS except mastoiditis. This finding is not surprising as the LOS for children with mastoiditis is typically shorter than for children with bacterial meningitis. Glikich et al.14 reported a mean LOS of approximately 8 days for children with mastoiditis. As meningitis in the context of mastoiditis is likely caused by direct extension of infection, patients with meningitis and mastoiditis likely required extended hospitalization to treat meningitis rather than mastoiditis. In contrast, patients with meningitis occurring in the context of metastatic dissemination of infection (eg, endocarditis, pneumonia) often have hemodynamic instability requiring prolonged intensive care support.

A study of children with sepsis found that increasing severity of illness was associated with greater hospital resource utilization.15 Our study shows that this may also be true in children with bacterial meningitis. We found that in children with bacterial meningitis, having systemic complications or an associated focal infection was associated with greater in‐hospital resource utilization. This finding may therefore indicate greater in‐hospital morbidity among children with a bacterial meningitis‐associated condition. Since mortality rates for bacterial meningitis are low in children, in‐hospital morbidity may be a better indicator of disease burden.

Our data show that, in contrast to adults, bacterial meningitis in children is not typically associated with other focal infections. Some focal complications such as mastoiditis and osteomyelitis disproportionately affect older children. These complications are typically accompanied by overt clinical manifestations. Therefore, we believe that the evaluation for the presence of concomitant focal infections can be guided by clinical examination findings and that routine radiologic evaluation for focal complications may not be necessary. Additionally, focal infections tend to occur in the absence of concomitant systemic complications. Of the 151 children with at least 1 associated focal infection, only 37% had a systemic complication. Bacterial meningitis may lie on a continuum of invasive disease depending on the virulence factors of the invading pathogen as well as specific host factors. Understanding the epidemiology of these associated conditions can enhance our understanding of the pathogenesis of bacterial meningitis in children. Understanding why some children suffer from septicemia rather than bacteremia may help in developing novel therapeutics.

There are several limitations to our study. First, since we identified focal infections and systemic complications using billing charges and ICD‐9 discharge diagnosis codes, it was impossible to determine when these conditions represented true complications of bacterial meningitis and when they represented the primary source of infection. Therefore, some of our primary outcomes may represent the cause of meningitis rather than a direct complication. We attempted to minimize such misclassification by limiting the cohort to those with a primary discharge diagnosis of bacterial meningitis though such misclassification is still possible.

Second, the use of ICD‐9 codes to accurately identify systemic complications and associated focal infections is a potential limitation. For example, respiratory failure, defined as the requirement of endotracheal intubation in our study, may not capture children receiving non‐invasive mechanical ventilation (eg, bilevel positive airway pressure). If use of noninvasive ventilation strategies did not depend exclusively on illness severity, our study would underestimate the frequency of respiratory failure. Furthermore, there may be inconsistencies among pediatric physicians in coding conditions such as SIRS and sepsis. Even in the clinical setting, a uniform definition of SIRS and sepsis is problematic due to physiologic differences between adults and children of varying age groups.16 An international panel of pediatricians proposed age‐specific definitions for sepsis and SIRS, while acknowledging the paucity of evidence to support some of their recommendations.16 None of the proposed definitions could be applied using administrative data. Limitations in the use of ICD‐9 discharge diagnosis codes to identify children with bacterial meningitis were discussed previously.1

Third, only free‐standing children's hospitals were included in the analysis. It is likely that many children with uncomplicated bacterial meningitis are treated at community hospitals or smaller academic centers. Our study may overestimate the rate of bacterial meningitis‐associated focal infections and systemic complications since participating hospitals serve as regional referral centers. To address the potential for such referral bias, we repeated the analysis while restricting the cohort to those children who had a lumbar puncture performed at the treating facility. No difference in frequency of associated conditions or in‐hospital resource utilization was found between children transferred and children not transferred. Finally, the PHIS database reports billed charge data rather than cost data. Billed data may overestimate the actual economic impact of bacterial meningitis‐associated complications since payers often reimburse at lesser rates. Resource utilization may also vary widely between hospitals and geographic locations as previously shown.15

In conclusion, bacterial meningitis remains an important cause of morbidity in children. Systemic complications such as sepsis and respiratory failure are common. Respiratory failure occurred more commonly among patients with meningococcal meningitis while sepsis occurred more commonly among patients with pneumococcal meningitis. While focal complications are uncommon, children >5 years of age are more likely than younger children to have concomitant mastoiditis or osteomyelitis. The presence of both systemic and focal complications is associated with substantially greater resource utilization than either complication alone.

Dr. Shah had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. Study concept and design: Shah, Mongelluzzo; acquisition of data: Shah, Mohamad; analysis and interpretation of data: Mongelluzzo, Mohamad, Ten Have, Shah; drafting of the manuscript: Mongelluzzo; critical revision of the manuscript for important intellectual content: Mongelluzzo, Mohamad, Ten Have, Shah; statistical analysis: Shah, Mongelluzzo, Ten Have; obtained funding: Shah, Mongelluzzo; administrative, technical, or material support: Shah; study supervision: Shah.

Bacterial meningitis can be a devastating disease in children. Overall mortality in children in the United States is 4%1 while long‐term morbidity is present in up to 25%2 of surviving children. The introduction of Haemophilus influenzae type B vaccine, heptavalent pneumococcal conjugate vaccine, and the quadrivalent meningococcal conjugate vaccine has altered the epidemiology of bacterial meningitis.24 Currently, little is known about the epidemiology of systemic complications and associated focal infections that occur during episodes of bacterial meningitis in children and how the presence of such complications affects in‐hospital healthcare resource utilization.

In a randomized controlled trial, the administration of adjuvant corticosteroids was associated with lower mortality rates in adults with bacterial meningitis due to all causes, with the greatest reduction in those with pneumococcal meningitis.5 In a post hoc analysis of data from this trial, reductions in systemic complications, such as septic shock, pneumonia, and acute respiratory distress syndrome, rather than neurologic complications were thought to be the underlying reason for the decrease in mortality associated with pneumococcal meningitis among corticosteroid recipients.6 However, children with bacterial meningitis have an overall 4‐fold lower mortality rate than adults with bacterial meningitis. An even greater difference in mortality rates exists between children and adults with pneumococcal meningitis.1, 5 Children do not benefit from adjuvant corticosteroids as adults do.1, 5, 7 Therefore, the pathogenesis of bacterial meningitis may differ in children from adults and account for the difference in response to adjuvant corticosteroids. Understanding the epidemiology of systemic complications and associated focal infections can aid in the understanding of the pathogenesis of the disease in varying age groups of children.

Previous studies in children have documented the frequency of certain bacterial meningitis‐associated conditions such as respiratory failure, pneumonia, endocarditis, and mastoiditis. Researchers have used the presence of such conditions to predict either mortality or neurologic sequelae in children.810 These studies were small and only included a few types of complications associated with bacterial meningitis. In‐hospital healthcare resource utilization, which may be an important indicator of in‐hospital morbidity, was also not considered as an outcome. In‐hospital morbidity may represent aspects of disease burden not captured by mortality rates or markers for long‐term morbidity alone. In future vaccine efficacy trails or novel therapeutics evaluations, consideration of these associated conditions is important.

The quantification of the use of in‐hospital healthcare utilization is also important for hospital planning and resource allocation in children with bacterial meningitis. A child presenting with bacterial meningitis and a systemic complication or an associated focal infection may require additional resource planning initially to expedite care to enhance recovery and decrease hospital length of stay (LOS).

Our goal was to document the frequency of bacterial meningitis‐associated conditions (systemic complications and associated focal infections) in a large cohort of children with bacterial meningitis treated at tertiary care children's hospitals in the United States, and determine how the presence of such conditions impacted in‐hospital healthcare resource utilization.

Patients and Methods

Results

Bacterial Meningitis‐Associated Conditions

Overall, 574 (25%) of children with bacterial meningitis suffered a systemic complication or an associated focal infection. Figure 1 shows the types of associated condition stratified by age category. Older children had a higher frequency of associated focal infections while younger children had a higher frequency of systemic complications (P = 0.002, chi‐square test for trend). Figure 2 shows the distribution of specific conditions among children in each age category. The frequency of sepsis decreased with age (P < 0.001, chi‐square test) while the frequency of mastoiditis (P < 0.001, Fisher's exact test) and osteomyelitis (P = 0.005, Fisher's exact test) increased with age. There did not appear to be substantial variability in the proportion of patients with SIRS or sepsis across hospitals, suggesting that hospital‐level variability in coding for these conditions was likely minimal. The median proportion of patients with SIRS by hospital was 2.4% (IQR, 1.2‐4.8%) while the median proportion of patients with sepsis by hospital was 13.4% (IQR, 10.0‐16.9%).

Figure 1

Figure 2

Of the 151 children with an associated focal infection, only 3 (2%) of children had more than 1 infection (1 child had mastoiditis and endocarditis, 1 child had pneumonia and osteomyelitis, and 1 child had pneumonia and endocarditis). However, of the 479 children with systemic complications, 116 (24%) had more than 1 systemic disease (Table 1).

Table 1.Children With Systemic Complications

Types of Systemic Complications	Systemic Complications in All Bacterial Meningitis, n (%)	Systemic Complications in Meningococcal Meningitis, n (%)	Systemic Complications in Pneumococcal Meningitis, n (%)
NOTE: Percentages may not add to 100 due to rounding. Abbreviations: SIRS, systemic inflammatory response syndrome.
Sepsis only	209 (44)	16 (21)	69 (54)
Respiratory failure only	139 (29)	38 (49)	30 (24)
SIRS only	15 (3)	9 (12)	1 (1)
Sepsis and respiratory failure	52 (11)	4 (5)	18 (14)
SIRS and sepsis	27 (6)	2 (3)	4 (3)
SIRS and respiratory failure	9 (2)	5 (6)	0 (0)
SIRS and respiratory failure and sepsis	28 (6)	3 (4)	5 (4)
Total systemic complications	479	77	127

In sub‐group analyses, 269 children had meningococcal meningitis and 470 children had pneumococcal meningitis. Of the children with meningococcal meningitis, 31.2% had a meningitis‐associated condition: 26.4% had a systemic complication, 2.6% had a focal infection, and 2.2% had both conditions. The most common associated conditions in children with meningococcal meningitis were respiratory failure (18.6%; n = 50), sepsis (9.3%; n = 25), and SIRS (7.1%; n = 19). In children with pneumococcal meningitis, 32.3% had a meningitis‐associated complication: 24.7% had a systemic complication, 5.3% had a focal infection, and 2.3% had both conditions. The most common associated conditions in children with pneumococcal meningitis were sepsis (20.4%; n = 96), respiratory failure (11.3%; n = 53), and pneumonia (4.7%; n = 22); mastoiditis was present in 2.3% (n = 11) of children with pneumococcal meningitis. Respiratory failure was more common in meningococcal meningitis (18.6%) than in pneumococcal meningitis (11.3%; P = 0.006). In contrast, sepsis was less common in meningococcal meningitis (9.3%) than in pneumococcal meningitis (20.4%; P < 0.001).

Hospital Charges

Overall, the median charges per hospital ranged from $20,158 to $53,823. In‐hospital charges for children with bacterial meningitis with and without any identified associated conditions are presented in Table 2. In multivariate analyses, the presence of systemic conditions, associated focal infections, or both conditions was independently associated with significantly higher total in‐hospital charges (Table 2). When conditions were considered individually, bone and joint infections (213% increase; 95% CI, 113‐260%), endocarditis (108% increase; 95% CI, 23‐258%), and pneumonia (107% increase; 95% CI, 58‐171%) were associated with the highest increases in total hospital charges (Figure 3). In contrast, SIRS and mastoiditis were not associated with higher hospital charges (Figure 3).

Table 2.Comparison of Total Hospital Charges and Length of Stay by Complication Type

	Charges		LOS
	Median, $ (IQR)	Adjusted Increase,* % (95% CI)	Median, days (IQR)	Adjusted Increase,* % (95% CI)
Abbreviations: CI, confidence interval; IQR, interquartile range. * Adjusted for age category, race, sex, vancomycin receipt, and adjuvant corticosteroid therapy. P value <0.001 for all comparisons.
None (n = 1,745)	$27,110 (15,823‐48,307)	Reference**	9 (6‐14)	Reference
Systemic (n = 423)	$66,690 (39,546136,756)	136 (108269)	14 (923)	72 (5196)
Focal Infection (n = 95)	$58,016 (29,056125,813)	118 (77168)	13 (928)	78 (40126)
Both (n = 56)	$130,744 (62,397299,288)	351 (237503)	21.5 (1245)	211 (142303)

Figure 3

LOS

The median LOS was 9 days (IQR, 6‐15 days); 5% of children had a LOS >42 days. Table 2 summarizes difference in LOS by the presence and absence of systemic conditions and focal infections. In multivariate analyses, the presence of systemic conditions, associated focal infections, or both conditions was independently associated with a significantly longer LOS (Table 2). When conditions were considered individually, endocarditis (152% increase; 95% CI, 60‐300%) and pneumonia (136% increase; 95% CI, 85‐201%) were associated with the greatest adjusted increases in LOS (Figure 4); only mastoiditis was not associated with an increased LOS compared with those without complications.

Figure 4

Discussion

To our knowledge, this is the first study to examine bacterial meningitis‐associated conditions in children and their impact on in‐hospital resource utilization. We found that 25% of the cohort of children with bacterial meningitis suffered from at least one focal infection or systemic complication. This represents a significant invasive disease burden among children with bacterial meningitis who do not have underlying comorbid conditions. Younger children were more likely to have systemic complications when compared with older children, specifically due to a higher frequency of sepsis in children <1 year. Older children were more likely to have an associated focal infection, specifically due to an increase in mastoiditis and osteomyelitis in children >1 year. Only 2% of children had more than 1 focal infection, while 24% of children had more than 1 systemic complication.

Importantly, the presence of a systemic complication in a child with bacterial meningitis increased their in‐hospital adjusted charges by 136%. The presence of a focal infection increased in‐hospital adjusted charges by 118%. A child with both a systemic complication and a focal infection and had a 351% increase in in‐hospital adjusted charges.

The presence of systemic complications or associated focal infections was significantly associated with higher in‐hospital charges and longer hospital LOS. Most individual meningitis‐associated conditions included in this study were associated with higher in‐hospital charges with the exception of SIRS and mastoiditis. All individual meningitis‐associated conditions were associated with a longer LOS except mastoiditis. This finding is not surprising as the LOS for children with mastoiditis is typically shorter than for children with bacterial meningitis. Glikich et al.14 reported a mean LOS of approximately 8 days for children with mastoiditis. As meningitis in the context of mastoiditis is likely caused by direct extension of infection, patients with meningitis and mastoiditis likely required extended hospitalization to treat meningitis rather than mastoiditis. In contrast, patients with meningitis occurring in the context of metastatic dissemination of infection (eg, endocarditis, pneumonia) often have hemodynamic instability requiring prolonged intensive care support.

A study of children with sepsis found that increasing severity of illness was associated with greater hospital resource utilization.15 Our study shows that this may also be true in children with bacterial meningitis. We found that in children with bacterial meningitis, having systemic complications or an associated focal infection was associated with greater in‐hospital resource utilization. This finding may therefore indicate greater in‐hospital morbidity among children with a bacterial meningitis‐associated condition. Since mortality rates for bacterial meningitis are low in children, in‐hospital morbidity may be a better indicator of disease burden.

Our data show that, in contrast to adults, bacterial meningitis in children is not typically associated with other focal infections. Some focal complications such as mastoiditis and osteomyelitis disproportionately affect older children. These complications are typically accompanied by overt clinical manifestations. Therefore, we believe that the evaluation for the presence of concomitant focal infections can be guided by clinical examination findings and that routine radiologic evaluation for focal complications may not be necessary. Additionally, focal infections tend to occur in the absence of concomitant systemic complications. Of the 151 children with at least 1 associated focal infection, only 37% had a systemic complication. Bacterial meningitis may lie on a continuum of invasive disease depending on the virulence factors of the invading pathogen as well as specific host factors. Understanding the epidemiology of these associated conditions can enhance our understanding of the pathogenesis of bacterial meningitis in children. Understanding why some children suffer from septicemia rather than bacteremia may help in developing novel therapeutics.

There are several limitations to our study. First, since we identified focal infections and systemic complications using billing charges and ICD‐9 discharge diagnosis codes, it was impossible to determine when these conditions represented true complications of bacterial meningitis and when they represented the primary source of infection. Therefore, some of our primary outcomes may represent the cause of meningitis rather than a direct complication. We attempted to minimize such misclassification by limiting the cohort to those with a primary discharge diagnosis of bacterial meningitis though such misclassification is still possible.

Second, the use of ICD‐9 codes to accurately identify systemic complications and associated focal infections is a potential limitation. For example, respiratory failure, defined as the requirement of endotracheal intubation in our study, may not capture children receiving non‐invasive mechanical ventilation (eg, bilevel positive airway pressure). If use of noninvasive ventilation strategies did not depend exclusively on illness severity, our study would underestimate the frequency of respiratory failure. Furthermore, there may be inconsistencies among pediatric physicians in coding conditions such as SIRS and sepsis. Even in the clinical setting, a uniform definition of SIRS and sepsis is problematic due to physiologic differences between adults and children of varying age groups.16 An international panel of pediatricians proposed age‐specific definitions for sepsis and SIRS, while acknowledging the paucity of evidence to support some of their recommendations.16 None of the proposed definitions could be applied using administrative data. Limitations in the use of ICD‐9 discharge diagnosis codes to identify children with bacterial meningitis were discussed previously.1

Third, only free‐standing children's hospitals were included in the analysis. It is likely that many children with uncomplicated bacterial meningitis are treated at community hospitals or smaller academic centers. Our study may overestimate the rate of bacterial meningitis‐associated focal infections and systemic complications since participating hospitals serve as regional referral centers. To address the potential for such referral bias, we repeated the analysis while restricting the cohort to those children who had a lumbar puncture performed at the treating facility. No difference in frequency of associated conditions or in‐hospital resource utilization was found between children transferred and children not transferred. Finally, the PHIS database reports billed charge data rather than cost data. Billed data may overestimate the actual economic impact of bacterial meningitis‐associated complications since payers often reimburse at lesser rates. Resource utilization may also vary widely between hospitals and geographic locations as previously shown.15

In conclusion, bacterial meningitis remains an important cause of morbidity in children. Systemic complications such as sepsis and respiratory failure are common. Respiratory failure occurred more commonly among patients with meningococcal meningitis while sepsis occurred more commonly among patients with pneumococcal meningitis. While focal complications are uncommon, children >5 years of age are more likely than younger children to have concomitant mastoiditis or osteomyelitis. The presence of both systemic and focal complications is associated with substantially greater resource utilization than either complication alone.

Dr. Shah had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. Study concept and design: Shah, Mongelluzzo; acquisition of data: Shah, Mohamad; analysis and interpretation of data: Mongelluzzo, Mohamad, Ten Have, Shah; drafting of the manuscript: Mongelluzzo; critical revision of the manuscript for important intellectual content: Mongelluzzo, Mohamad, Ten Have, Shah; statistical analysis: Shah, Mongelluzzo, Ten Have; obtained funding: Shah, Mongelluzzo; administrative, technical, or material support: Shah; study supervision: Shah.

Bacterial meningitis can be a devastating disease in children. Overall mortality in children in the United States is 4%1 while long‐term morbidity is present in up to 25%2 of surviving children. The introduction of Haemophilus influenzae type B vaccine, heptavalent pneumococcal conjugate vaccine, and the quadrivalent meningococcal conjugate vaccine has altered the epidemiology of bacterial meningitis.24 Currently, little is known about the epidemiology of systemic complications and associated focal infections that occur during episodes of bacterial meningitis in children and how the presence of such complications affects in‐hospital healthcare resource utilization.

In a randomized controlled trial, the administration of adjuvant corticosteroids was associated with lower mortality rates in adults with bacterial meningitis due to all causes, with the greatest reduction in those with pneumococcal meningitis.5 In a post hoc analysis of data from this trial, reductions in systemic complications, such as septic shock, pneumonia, and acute respiratory distress syndrome, rather than neurologic complications were thought to be the underlying reason for the decrease in mortality associated with pneumococcal meningitis among corticosteroid recipients.6 However, children with bacterial meningitis have an overall 4‐fold lower mortality rate than adults with bacterial meningitis. An even greater difference in mortality rates exists between children and adults with pneumococcal meningitis.1, 5 Children do not benefit from adjuvant corticosteroids as adults do.1, 5, 7 Therefore, the pathogenesis of bacterial meningitis may differ in children from adults and account for the difference in response to adjuvant corticosteroids. Understanding the epidemiology of systemic complications and associated focal infections can aid in the understanding of the pathogenesis of the disease in varying age groups of children.

Previous studies in children have documented the frequency of certain bacterial meningitis‐associated conditions such as respiratory failure, pneumonia, endocarditis, and mastoiditis. Researchers have used the presence of such conditions to predict either mortality or neurologic sequelae in children.810 These studies were small and only included a few types of complications associated with bacterial meningitis. In‐hospital healthcare resource utilization, which may be an important indicator of in‐hospital morbidity, was also not considered as an outcome. In‐hospital morbidity may represent aspects of disease burden not captured by mortality rates or markers for long‐term morbidity alone. In future vaccine efficacy trails or novel therapeutics evaluations, consideration of these associated conditions is important.

The quantification of the use of in‐hospital healthcare utilization is also important for hospital planning and resource allocation in children with bacterial meningitis. A child presenting with bacterial meningitis and a systemic complication or an associated focal infection may require additional resource planning initially to expedite care to enhance recovery and decrease hospital length of stay (LOS).

Our goal was to document the frequency of bacterial meningitis‐associated conditions (systemic complications and associated focal infections) in a large cohort of children with bacterial meningitis treated at tertiary care children's hospitals in the United States, and determine how the presence of such conditions impacted in‐hospital healthcare resource utilization.

Patients and Methods

Results

Bacterial Meningitis‐Associated Conditions

Overall, 574 (25%) of children with bacterial meningitis suffered a systemic complication or an associated focal infection. Figure 1 shows the types of associated condition stratified by age category. Older children had a higher frequency of associated focal infections while younger children had a higher frequency of systemic complications (P = 0.002, chi‐square test for trend). Figure 2 shows the distribution of specific conditions among children in each age category. The frequency of sepsis decreased with age (P < 0.001, chi‐square test) while the frequency of mastoiditis (P < 0.001, Fisher's exact test) and osteomyelitis (P = 0.005, Fisher's exact test) increased with age. There did not appear to be substantial variability in the proportion of patients with SIRS or sepsis across hospitals, suggesting that hospital‐level variability in coding for these conditions was likely minimal. The median proportion of patients with SIRS by hospital was 2.4% (IQR, 1.2‐4.8%) while the median proportion of patients with sepsis by hospital was 13.4% (IQR, 10.0‐16.9%).

Figure 1

Figure 2

Of the 151 children with an associated focal infection, only 3 (2%) of children had more than 1 infection (1 child had mastoiditis and endocarditis, 1 child had pneumonia and osteomyelitis, and 1 child had pneumonia and endocarditis). However, of the 479 children with systemic complications, 116 (24%) had more than 1 systemic disease (Table 1).

Table 1.Children With Systemic Complications

Types of Systemic Complications	Systemic Complications in All Bacterial Meningitis, n (%)	Systemic Complications in Meningococcal Meningitis, n (%)	Systemic Complications in Pneumococcal Meningitis, n (%)
NOTE: Percentages may not add to 100 due to rounding. Abbreviations: SIRS, systemic inflammatory response syndrome.
Sepsis only	209 (44)	16 (21)	69 (54)
Respiratory failure only	139 (29)	38 (49)	30 (24)
SIRS only	15 (3)	9 (12)	1 (1)
Sepsis and respiratory failure	52 (11)	4 (5)	18 (14)
SIRS and sepsis	27 (6)	2 (3)	4 (3)
SIRS and respiratory failure	9 (2)	5 (6)	0 (0)
SIRS and respiratory failure and sepsis	28 (6)	3 (4)	5 (4)
Total systemic complications	479	77	127

In sub‐group analyses, 269 children had meningococcal meningitis and 470 children had pneumococcal meningitis. Of the children with meningococcal meningitis, 31.2% had a meningitis‐associated condition: 26.4% had a systemic complication, 2.6% had a focal infection, and 2.2% had both conditions. The most common associated conditions in children with meningococcal meningitis were respiratory failure (18.6%; n = 50), sepsis (9.3%; n = 25), and SIRS (7.1%; n = 19). In children with pneumococcal meningitis, 32.3% had a meningitis‐associated complication: 24.7% had a systemic complication, 5.3% had a focal infection, and 2.3% had both conditions. The most common associated conditions in children with pneumococcal meningitis were sepsis (20.4%; n = 96), respiratory failure (11.3%; n = 53), and pneumonia (4.7%; n = 22); mastoiditis was present in 2.3% (n = 11) of children with pneumococcal meningitis. Respiratory failure was more common in meningococcal meningitis (18.6%) than in pneumococcal meningitis (11.3%; P = 0.006). In contrast, sepsis was less common in meningococcal meningitis (9.3%) than in pneumococcal meningitis (20.4%; P < 0.001).

Hospital Charges

Overall, the median charges per hospital ranged from $20,158 to $53,823. In‐hospital charges for children with bacterial meningitis with and without any identified associated conditions are presented in Table 2. In multivariate analyses, the presence of systemic conditions, associated focal infections, or both conditions was independently associated with significantly higher total in‐hospital charges (Table 2). When conditions were considered individually, bone and joint infections (213% increase; 95% CI, 113‐260%), endocarditis (108% increase; 95% CI, 23‐258%), and pneumonia (107% increase; 95% CI, 58‐171%) were associated with the highest increases in total hospital charges (Figure 3). In contrast, SIRS and mastoiditis were not associated with higher hospital charges (Figure 3).

Table 2.Comparison of Total Hospital Charges and Length of Stay by Complication Type

	Charges		LOS
	Median, $ (IQR)	Adjusted Increase,* % (95% CI)	Median, days (IQR)	Adjusted Increase,* % (95% CI)
Abbreviations: CI, confidence interval; IQR, interquartile range. * Adjusted for age category, race, sex, vancomycin receipt, and adjuvant corticosteroid therapy. P value <0.001 for all comparisons.
None (n = 1,745)	$27,110 (15,823‐48,307)	Reference**	9 (6‐14)	Reference
Systemic (n = 423)	$66,690 (39,546136,756)	136 (108269)	14 (923)	72 (5196)
Focal Infection (n = 95)	$58,016 (29,056125,813)	118 (77168)	13 (928)	78 (40126)
Both (n = 56)	$130,744 (62,397299,288)	351 (237503)	21.5 (1245)	211 (142303)

Figure 3

LOS

The median LOS was 9 days (IQR, 6‐15 days); 5% of children had a LOS >42 days. Table 2 summarizes difference in LOS by the presence and absence of systemic conditions and focal infections. In multivariate analyses, the presence of systemic conditions, associated focal infections, or both conditions was independently associated with a significantly longer LOS (Table 2). When conditions were considered individually, endocarditis (152% increase; 95% CI, 60‐300%) and pneumonia (136% increase; 95% CI, 85‐201%) were associated with the greatest adjusted increases in LOS (Figure 4); only mastoiditis was not associated with an increased LOS compared with those without complications.

Figure 4

Discussion

To our knowledge, this is the first study to examine bacterial meningitis‐associated conditions in children and their impact on in‐hospital resource utilization. We found that 25% of the cohort of children with bacterial meningitis suffered from at least one focal infection or systemic complication. This represents a significant invasive disease burden among children with bacterial meningitis who do not have underlying comorbid conditions. Younger children were more likely to have systemic complications when compared with older children, specifically due to a higher frequency of sepsis in children <1 year. Older children were more likely to have an associated focal infection, specifically due to an increase in mastoiditis and osteomyelitis in children >1 year. Only 2% of children had more than 1 focal infection, while 24% of children had more than 1 systemic complication.

Importantly, the presence of a systemic complication in a child with bacterial meningitis increased their in‐hospital adjusted charges by 136%. The presence of a focal infection increased in‐hospital adjusted charges by 118%. A child with both a systemic complication and a focal infection and had a 351% increase in in‐hospital adjusted charges.

The presence of systemic complications or associated focal infections was significantly associated with higher in‐hospital charges and longer hospital LOS. Most individual meningitis‐associated conditions included in this study were associated with higher in‐hospital charges with the exception of SIRS and mastoiditis. All individual meningitis‐associated conditions were associated with a longer LOS except mastoiditis. This finding is not surprising as the LOS for children with mastoiditis is typically shorter than for children with bacterial meningitis. Glikich et al.14 reported a mean LOS of approximately 8 days for children with mastoiditis. As meningitis in the context of mastoiditis is likely caused by direct extension of infection, patients with meningitis and mastoiditis likely required extended hospitalization to treat meningitis rather than mastoiditis. In contrast, patients with meningitis occurring in the context of metastatic dissemination of infection (eg, endocarditis, pneumonia) often have hemodynamic instability requiring prolonged intensive care support.

A study of children with sepsis found that increasing severity of illness was associated with greater hospital resource utilization.15 Our study shows that this may also be true in children with bacterial meningitis. We found that in children with bacterial meningitis, having systemic complications or an associated focal infection was associated with greater in‐hospital resource utilization. This finding may therefore indicate greater in‐hospital morbidity among children with a bacterial meningitis‐associated condition. Since mortality rates for bacterial meningitis are low in children, in‐hospital morbidity may be a better indicator of disease burden.

Our data show that, in contrast to adults, bacterial meningitis in children is not typically associated with other focal infections. Some focal complications such as mastoiditis and osteomyelitis disproportionately affect older children. These complications are typically accompanied by overt clinical manifestations. Therefore, we believe that the evaluation for the presence of concomitant focal infections can be guided by clinical examination findings and that routine radiologic evaluation for focal complications may not be necessary. Additionally, focal infections tend to occur in the absence of concomitant systemic complications. Of the 151 children with at least 1 associated focal infection, only 37% had a systemic complication. Bacterial meningitis may lie on a continuum of invasive disease depending on the virulence factors of the invading pathogen as well as specific host factors. Understanding the epidemiology of these associated conditions can enhance our understanding of the pathogenesis of bacterial meningitis in children. Understanding why some children suffer from septicemia rather than bacteremia may help in developing novel therapeutics.

There are several limitations to our study. First, since we identified focal infections and systemic complications using billing charges and ICD‐9 discharge diagnosis codes, it was impossible to determine when these conditions represented true complications of bacterial meningitis and when they represented the primary source of infection. Therefore, some of our primary outcomes may represent the cause of meningitis rather than a direct complication. We attempted to minimize such misclassification by limiting the cohort to those with a primary discharge diagnosis of bacterial meningitis though such misclassification is still possible.

Second, the use of ICD‐9 codes to accurately identify systemic complications and associated focal infections is a potential limitation. For example, respiratory failure, defined as the requirement of endotracheal intubation in our study, may not capture children receiving non‐invasive mechanical ventilation (eg, bilevel positive airway pressure). If use of noninvasive ventilation strategies did not depend exclusively on illness severity, our study would underestimate the frequency of respiratory failure. Furthermore, there may be inconsistencies among pediatric physicians in coding conditions such as SIRS and sepsis. Even in the clinical setting, a uniform definition of SIRS and sepsis is problematic due to physiologic differences between adults and children of varying age groups.16 An international panel of pediatricians proposed age‐specific definitions for sepsis and SIRS, while acknowledging the paucity of evidence to support some of their recommendations.16 None of the proposed definitions could be applied using administrative data. Limitations in the use of ICD‐9 discharge diagnosis codes to identify children with bacterial meningitis were discussed previously.1

Third, only free‐standing children's hospitals were included in the analysis. It is likely that many children with uncomplicated bacterial meningitis are treated at community hospitals or smaller academic centers. Our study may overestimate the rate of bacterial meningitis‐associated focal infections and systemic complications since participating hospitals serve as regional referral centers. To address the potential for such referral bias, we repeated the analysis while restricting the cohort to those children who had a lumbar puncture performed at the treating facility. No difference in frequency of associated conditions or in‐hospital resource utilization was found between children transferred and children not transferred. Finally, the PHIS database reports billed charge data rather than cost data. Billed data may overestimate the actual economic impact of bacterial meningitis‐associated complications since payers often reimburse at lesser rates. Resource utilization may also vary widely between hospitals and geographic locations as previously shown.15

In conclusion, bacterial meningitis remains an important cause of morbidity in children. Systemic complications such as sepsis and respiratory failure are common. Respiratory failure occurred more commonly among patients with meningococcal meningitis while sepsis occurred more commonly among patients with pneumococcal meningitis. While focal complications are uncommon, children >5 years of age are more likely than younger children to have concomitant mastoiditis or osteomyelitis. The presence of both systemic and focal complications is associated with substantially greater resource utilization than either complication alone.

Dr. Shah had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. Study concept and design: Shah, Mongelluzzo; acquisition of data: Shah, Mohamad; analysis and interpretation of data: Mongelluzzo, Mohamad, Ten Have, Shah; drafting of the manuscript: Mongelluzzo; critical revision of the manuscript for important intellectual content: Mongelluzzo, Mohamad, Ten Have, Shah; statistical analysis: Shah, Mongelluzzo, Ten Have; obtained funding: Shah, Mongelluzzo; administrative, technical, or material support: Shah; study supervision: Shah.

A 57‐year‐old man with Hepatitis B and C was scheduled for an outpatient computed tomography (CT)‐guided biopsy of the left lobe of the liver for grading and staging of his liver disease at an outside hospital. Complete metabolic profile (CMP), complete blood count (CBC) and international normalized ratio (INR) were performed and were normal. Following his liver biopsy, the patient became hypotensive and developed shock. He received fluid resuscitation. Clinical exam and an abdominal x‐ray failed to identify a hepatic or intraperitoneal source of bleeding to explain the cause of hypotension. A chest radiograph showed an enlarged cardiac silhouette with clear lung fields. An electrocardiogram (ECG) demonstrated (Figure 1) 1‐mm ST segment elevation in the anterior leads. An emergent echocardiogram showed a significant pericardial effusion with echocardiographic evidence of cardiac tamponade. The patient underwent emergent pericardiocentesis with removal of 400 mL of hemorrhagic fluid. The etiology of the hemorrhagic fluid was thought to be due to myocardial injury secondary to the liver biopsy. Subsequently, the histopathology of the liver biopsy reported (Figure 2) features suggestive of cirrhosis of the liver. Additional tissues from the biopsy included pericardium, myocardium and coronary artery. The patient was transferred to our institution for a cardiac catheterization and coronary angiogram to evaluate his coronary anatomy. The coronary angiogram was normal without any evidence of dye extravasation. A follow‐up echocardiogram and CT scan of the chest showed residual pericardial and pleural fluid. The remainder of the hospital stay was uneventful and he was discharged on day 7 in good condition. He was doing well a month later at the time of his follow‐up visit.0, 0

Figure 1

Figure 2

Discussion

Serious complications of liver biopsy occur in less than 1% of biopsied patients and include intraperitoneal1 or intrahepatic hemorrhage,2, 3 pneumothorax, hemothorax, hemobilia,1 and injury to the gall bladder, colon, kidney and lung. Other rare complications of percutaneous liver biopsy include biliary ascites, bile pleuritis, bile peritonitis, subcutaneous emphysema, pneumoperitoneum, subphrenic abscess, carcinoid crisis, anaphylaxis after biopsy of an echinococcal cyst, pancreatitis due to hemobilia, and breakage of the biopsy needle.1, 4, 5 Bleeding is more common in the elderly and in patients with cirrhosis and liver cancer.1, 6 The most common cause of shock in a patient after liver biopsy is hypovolemia from intrahepatic or intraperitoneal bleeding. The incidence of such complications may be higher than commonly appreciated as these complications are likely underreported.

Ultrasound (US)‐guided and CT‐guided techniques are 2 common methods for performing liver biopsy. US‐guided and CT‐guided liver biopsy each have their own benefits and limitations. The CT‐guided biopsy provides an excellent resolution of the liver architecture and is done from the epigastric region, but uses a static view. The US‐guided liver biopsy, on the other hand, is done from the mid‐axillary intercostal line and is performed with real‐time images.

Our patient's complication was presumably caused by accidental passage of the biopsy needle from the liver into the pericardium during respiratory movements. The coronary artery tissue was most likely not an epicardial vessel as supported by the normal angiogram without evidence of coronary artery perforation.

Our patient had an inadvertent biopsy of cardiac tissue during a liver biopsy resulting in a hemorrhagic pericardial effusion and tamponade. Cardiac tamponade as a complication of liver biopsy and intrathoracic percutaneous procedures has been described, although this has very rarely been reported.7, 8 Fortunately, the patient's coronary artery anatomy was normal and he did well without surgical intervention.

Unusual procedural complications are reported in the literature with the intention of increasing awareness and improving patient safety. Percutaneous liver biopsy is performed to stage and grade liver disease for assessment and treatment. However, as with any invasive procedure, there are potential risks and complications. In patients who present with hypotension and shock following liver biopsy, myocardial injury with cardiac tamponade should be considered in the differential diagnosis.

A 57‐year‐old man with Hepatitis B and C was scheduled for an outpatient computed tomography (CT)‐guided biopsy of the left lobe of the liver for grading and staging of his liver disease at an outside hospital. Complete metabolic profile (CMP), complete blood count (CBC) and international normalized ratio (INR) were performed and were normal. Following his liver biopsy, the patient became hypotensive and developed shock. He received fluid resuscitation. Clinical exam and an abdominal x‐ray failed to identify a hepatic or intraperitoneal source of bleeding to explain the cause of hypotension. A chest radiograph showed an enlarged cardiac silhouette with clear lung fields. An electrocardiogram (ECG) demonstrated (Figure 1) 1‐mm ST segment elevation in the anterior leads. An emergent echocardiogram showed a significant pericardial effusion with echocardiographic evidence of cardiac tamponade. The patient underwent emergent pericardiocentesis with removal of 400 mL of hemorrhagic fluid. The etiology of the hemorrhagic fluid was thought to be due to myocardial injury secondary to the liver biopsy. Subsequently, the histopathology of the liver biopsy reported (Figure 2) features suggestive of cirrhosis of the liver. Additional tissues from the biopsy included pericardium, myocardium and coronary artery. The patient was transferred to our institution for a cardiac catheterization and coronary angiogram to evaluate his coronary anatomy. The coronary angiogram was normal without any evidence of dye extravasation. A follow‐up echocardiogram and CT scan of the chest showed residual pericardial and pleural fluid. The remainder of the hospital stay was uneventful and he was discharged on day 7 in good condition. He was doing well a month later at the time of his follow‐up visit.0, 0

Figure 1

Figure 2

Discussion

Serious complications of liver biopsy occur in less than 1% of biopsied patients and include intraperitoneal1 or intrahepatic hemorrhage,2, 3 pneumothorax, hemothorax, hemobilia,1 and injury to the gall bladder, colon, kidney and lung. Other rare complications of percutaneous liver biopsy include biliary ascites, bile pleuritis, bile peritonitis, subcutaneous emphysema, pneumoperitoneum, subphrenic abscess, carcinoid crisis, anaphylaxis after biopsy of an echinococcal cyst, pancreatitis due to hemobilia, and breakage of the biopsy needle.1, 4, 5 Bleeding is more common in the elderly and in patients with cirrhosis and liver cancer.1, 6 The most common cause of shock in a patient after liver biopsy is hypovolemia from intrahepatic or intraperitoneal bleeding. The incidence of such complications may be higher than commonly appreciated as these complications are likely underreported.

Ultrasound (US)‐guided and CT‐guided techniques are 2 common methods for performing liver biopsy. US‐guided and CT‐guided liver biopsy each have their own benefits and limitations. The CT‐guided biopsy provides an excellent resolution of the liver architecture and is done from the epigastric region, but uses a static view. The US‐guided liver biopsy, on the other hand, is done from the mid‐axillary intercostal line and is performed with real‐time images.

Our patient's complication was presumably caused by accidental passage of the biopsy needle from the liver into the pericardium during respiratory movements. The coronary artery tissue was most likely not an epicardial vessel as supported by the normal angiogram without evidence of coronary artery perforation.

Our patient had an inadvertent biopsy of cardiac tissue during a liver biopsy resulting in a hemorrhagic pericardial effusion and tamponade. Cardiac tamponade as a complication of liver biopsy and intrathoracic percutaneous procedures has been described, although this has very rarely been reported.7, 8 Fortunately, the patient's coronary artery anatomy was normal and he did well without surgical intervention.

Unusual procedural complications are reported in the literature with the intention of increasing awareness and improving patient safety. Percutaneous liver biopsy is performed to stage and grade liver disease for assessment and treatment. However, as with any invasive procedure, there are potential risks and complications. In patients who present with hypotension and shock following liver biopsy, myocardial injury with cardiac tamponade should be considered in the differential diagnosis.

A 57‐year‐old man with Hepatitis B and C was scheduled for an outpatient computed tomography (CT)‐guided biopsy of the left lobe of the liver for grading and staging of his liver disease at an outside hospital. Complete metabolic profile (CMP), complete blood count (CBC) and international normalized ratio (INR) were performed and were normal. Following his liver biopsy, the patient became hypotensive and developed shock. He received fluid resuscitation. Clinical exam and an abdominal x‐ray failed to identify a hepatic or intraperitoneal source of bleeding to explain the cause of hypotension. A chest radiograph showed an enlarged cardiac silhouette with clear lung fields. An electrocardiogram (ECG) demonstrated (Figure 1) 1‐mm ST segment elevation in the anterior leads. An emergent echocardiogram showed a significant pericardial effusion with echocardiographic evidence of cardiac tamponade. The patient underwent emergent pericardiocentesis with removal of 400 mL of hemorrhagic fluid. The etiology of the hemorrhagic fluid was thought to be due to myocardial injury secondary to the liver biopsy. Subsequently, the histopathology of the liver biopsy reported (Figure 2) features suggestive of cirrhosis of the liver. Additional tissues from the biopsy included pericardium, myocardium and coronary artery. The patient was transferred to our institution for a cardiac catheterization and coronary angiogram to evaluate his coronary anatomy. The coronary angiogram was normal without any evidence of dye extravasation. A follow‐up echocardiogram and CT scan of the chest showed residual pericardial and pleural fluid. The remainder of the hospital stay was uneventful and he was discharged on day 7 in good condition. He was doing well a month later at the time of his follow‐up visit.0, 0

Figure 1

Figure 2

Discussion

Serious complications of liver biopsy occur in less than 1% of biopsied patients and include intraperitoneal1 or intrahepatic hemorrhage,2, 3 pneumothorax, hemothorax, hemobilia,1 and injury to the gall bladder, colon, kidney and lung. Other rare complications of percutaneous liver biopsy include biliary ascites, bile pleuritis, bile peritonitis, subcutaneous emphysema, pneumoperitoneum, subphrenic abscess, carcinoid crisis, anaphylaxis after biopsy of an echinococcal cyst, pancreatitis due to hemobilia, and breakage of the biopsy needle.1, 4, 5 Bleeding is more common in the elderly and in patients with cirrhosis and liver cancer.1, 6 The most common cause of shock in a patient after liver biopsy is hypovolemia from intrahepatic or intraperitoneal bleeding. The incidence of such complications may be higher than commonly appreciated as these complications are likely underreported.

Ultrasound (US)‐guided and CT‐guided techniques are 2 common methods for performing liver biopsy. US‐guided and CT‐guided liver biopsy each have their own benefits and limitations. The CT‐guided biopsy provides an excellent resolution of the liver architecture and is done from the epigastric region, but uses a static view. The US‐guided liver biopsy, on the other hand, is done from the mid‐axillary intercostal line and is performed with real‐time images.

Our patient's complication was presumably caused by accidental passage of the biopsy needle from the liver into the pericardium during respiratory movements. The coronary artery tissue was most likely not an epicardial vessel as supported by the normal angiogram without evidence of coronary artery perforation.

Our patient had an inadvertent biopsy of cardiac tissue during a liver biopsy resulting in a hemorrhagic pericardial effusion and tamponade. Cardiac tamponade as a complication of liver biopsy and intrathoracic percutaneous procedures has been described, although this has very rarely been reported.7, 8 Fortunately, the patient's coronary artery anatomy was normal and he did well without surgical intervention.

Unusual procedural complications are reported in the literature with the intention of increasing awareness and improving patient safety. Percutaneous liver biopsy is performed to stage and grade liver disease for assessment and treatment. However, as with any invasive procedure, there are potential risks and complications. In patients who present with hypotension and shock following liver biopsy, myocardial injury with cardiac tamponade should be considered in the differential diagnosis.

Classically, infections have been categorized as either community‐acquired (CAI) or nosocomial in origin. Until recently, this scheme was thought adequate to capture the differences in the microbiology and outcomes in the corresponding scenarios. However, recent evidence suggests that this distinction may no longer be valid. For example, with the spread and diffusion of healthcare delivery beyond the confines of the hospital along with the increasing use of broad spectrum antibiotics both in and out of the hospital, pathogens such as methicillin‐resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA), traditionally thought to be confined to the hospital, are now seen in patients presenting from the community to the emergency department (ED).1, 2 Reflecting this shift in epidemiology, some national guidelines now recognize healthcare‐associated infection (HCAI) as a distinct entity.3 The concept of HCAI allows the clinician to identify patients who, despite suffering a community onset infection, still may be at risk for a resistant bacterial pathogen. Recent studies in both bloodstream infection and pneumonia have clearly demonstrated that those with HCAI have distinct microbiology and outcomes relative to those with pure CAI.47

Most work focusing on establishing HCAI has not addressed skin and soft tissue infections. These infections, although not often fatal, account for an increasing number of admissions to the hospital.8, 9 In addition, they may be associated with substantial morbidity and cost.8 Given that many pathogens such as S. aureus, which may be resistant to typical antimicrobials used in the ED, are also major culprits in complicated skin and skin structure infections (cSSSI), the HCAI paradigm may apply in cSSSI. Furthermore, because of these patterns of increased resistance, HCA‐cSSSI patients, similar to other HCAI groups, may be at an increased risk of being treated with initially inappropriate antibiotic therapy.7, 10

Since in the setting of other types of infection inappropriate empiric treatment has been shown to be associated with increased mortality and costs,7, 1015 and since indirect evidence suggests a similar impact on healthcare utilization among cSSSI patients,8 we hypothesized that among a cohort of patients hospitalized with a cSSSI, the initial empiric choice of therapy is independently associated with hospital length of stay (LOS). We performed a retrospective cohort study to address this question.

Methods

Results

Of the 717 patients with culture‐positive cSSSI admitted during the study period, 527 (73.5%) were classified as HCAI. The most common reason for classification as an HCAI was recent hospitalization. Among those with an HCA‐cSSSI, 405 (76.9%) received appropriate empiric treatment, with nearly one‐quarter receiving inappropriate initial coverage. Those receiving inappropriate antibiotic were more likely to be African American, and had a higher likelihood of having end‐stage renal disease (ESRD) than those with appropriate coverage (Table 1). While those patients treated appropriately had higher rates of both cellulitis and abscess as the presenting infection, a substantially higher proportion of those receiving inappropriate initial treatment had a decubitus ulcer (29.5% vs. 10.9%, P <0.001), a device‐associated infection (42.6% vs. 28.6%, P = 0.004), and had evidence of bacteremia (68.9% vs. 57.8%, P = 0.028) than those receiving appropriate empiric coverage (Table 2).

The pathogens recovered from the appropriately and inappropriately treated groups are listed in Figure 1. While S. aureus overall was more common among those treated appropriately, the frequency of MRSA did not differ between the groups. Both E. faecalis and E. faecium were recovered more frequently in the inappropriate group, resulting in a similar pattern among the vancomycin‐resistant enterococcal species. Likewise, P. aeruginosa, P. mirabilis, and A. baumannii were all more frequently seen in the group treated inappropriately than in the group getting appropriate empiric coverage. A mixed infection was also more likely to be present among those not exposed (16.5%) than among those exposed (7.5%) to appropriate early therapy (P = 0.001) (Figure 1).

Figure 1

In terms of processes of care and outcomes (Table 3), commensurate with the higher prevalence of abscess in the appropriately treated group, the rate of I&D was significantly higher in this cohort (36.8%) than in the inappropriately treated (23.0%) group (P = 0.005). Need for initial ICU care did not differ as a function of appropriateness of therapy (P = 0.635).

The unadjusted mortality rate was low overall and did not vary based on initial treatment (Table 3). In a generalized linear model with the log‐transformed LOS as the dependent variable, adjusting for multiple potential confounders, initial inappropriate antibiotic therapy had an attributable incremental increase in the hospital LOS of 1.8 days (95% CI, 1.42.3) (Table 4).

Because bacteremia is known to be an effect modifier of the relationship between the empiric choice of antibiotic and infection outcomes, we further explored its role in the HCAI cSSSI on the outcomes of interest (Table 5). Similar to the effect detected in the overall cohort, treatment with inappropriate therapy was associated with an increase in the hospital LOS, but not hospital mortality in those with bacteremia, though this phenomenon was observed only among patients with secondary bacteremia, and not among those without (Table 5).

Discussion

This retrospective analysis provides evidence that inappropriate empiric antibiotic therapy for HCA‐cSSSI independently prolongs hospital LOS. The impact of inappropriate initial treatment on LOS is independent of many important confounders. In addition, we observed that this effect, while present among patients with secondary bacteremia, is absent among those without a blood stream infection.

To the best of our knowledge, ours is the first cohort study to examine the outcomes associated with inappropriate treatment of a HCAI cSSSI within the context of available microbiology data. Edelsberg et al.8 examined clinical and economic outcomes associated with the failure of the initial treatment of cSSSI. While not specifically focusing on HCAI patients, these authors noted an overall 23% initial therapy failure rate. Among those patients who failed initial therapy, the risk of hospital death was nearly 3‐fold higher (adjusted odds ratio [OR], 2.91; 95% CI, 2.343.62), and they incurred the mean of 5.4 additional hospital days, compared to patients treated successfully with the initial regimen.8 Our study confirms Edelsberg et al.'s8 observation of prolonged hospital LOS in association with treatment failure, and builds upon it by defining the actual LOS increment attributable to inappropriate empiric therapy. It is worth noting that the study by Edelsberg et al.,8 however, lacked explicit definition of the HCAI population and microbiology data, and used treatment failure as a surrogate marker for inappropriate treatment. It is likely these differences between our two studies in the underlying population and exposure definitions that account for the differences in the mortality data between that study and ours.

It is not fundamentally surprising that early exposure to inappropriate empiric therapy alters healthcare resource utilization outcomes for the worse. Others have demonstrated that infection with a resistant organism results in prolongation of hospital LOS and costs. For example, in a large cohort of over 600 surgical hospitalizations requiring treatment for a gram‐negative infection, antibiotic resistance was an independent predictor of increased LOS and costs.15 These authors quantified the incremental burden of early gram‐negative resistance at over $11,000 in hospital costs.15 Unfortunately, the treatment differences for resistant and sensitive organisms were not examined.15 Similarly, Shorr et al. examined risk factors for prolonged hospital LOS and increased costs in a cohort of 291 patients with MRSA sterile site infection.17 Because in this study 23% of the patients received inappropriate empiric therapy, the authors were able to examine the impact of this exposure on utilization outcomes.17 In an adjusted analysis, inappropriate initial treatment was associated with an incremental increase in the LOS of 2.5 days, corresponding to the unadjusted cost differential of nearly $6,000.17 Although focusing on a different population, our results are consistent with these previous observations that antibiotic resistance and early inappropriate therapy affect hospital utilization parameters, in our case by adding nearly 2 days to the hospital LOS.

Our study has a number of limitations. First, as a retrospective cohort study it is prone to various forms of bias, most notably selection bias. To minimize the possibility of such, we established a priori case definitions and enrolled consecutive patients over a specific period of time. Second, as in any observational study, confounding is an issue. We dealt with this statistically by constructing a multivariable regression model; however, the possibility of residual confounding remains. Third, because some of the wound and ulcer cultures likely were obtained with a swab and thus represented colonization, rather than infection, we may have over‐estimated the rate of inappropriate therapy, and this needs to be followed up in future prospective studies. Similarly, we may have over‐estimated the likelihood of inappropriate therapy among polymicrobial and mixed infections as well, given that, for example, a gram‐negative organism may carry a different clinical significance when cultured from blood (infection) than when it is detected in a decubitus ulcer (potential colonization). Fourth, because we limited our cohort to patients without deep‐seated infections, such as necrotizing fasciitis, other procedures were not collected. This omission may have led to either over‐estimation or under‐estimation of the impact of inappropriate therapy on the outcomes of interest.

The fact that our cohort represents a single large urban academic tertiary care medical center may limit the generalizability of our results only to centers that share similar characteristics. Finally, similar to most other studies of this type, ours lacks data on posthospitalization outcomes and for this reason limits itself to hospital outcomes only.

In summary, we have shown that, similar to other populations with HCAI, a substantial proportion (nearly 1/4) of cSSSI patients with HCAI receive inappropriate empiric therapy for their infection, and this early exposure, though not affecting hospital mortality, is associated with a significant prolongation of the hospitalization by as much as 2 days. Studies are needed to refine decision rules for risk‐stratifying patients with cSSSI HCAI in order to determine the probability of infection with a resistant organism. In turn, such instruments at the bedside may assure improved utilization of appropriately targeted empiric therapy that will both optimize individual patient outcomes and reduce the risk of emergence of antimicrobial resistance.

Classically, infections have been categorized as either community‐acquired (CAI) or nosocomial in origin. Until recently, this scheme was thought adequate to capture the differences in the microbiology and outcomes in the corresponding scenarios. However, recent evidence suggests that this distinction may no longer be valid. For example, with the spread and diffusion of healthcare delivery beyond the confines of the hospital along with the increasing use of broad spectrum antibiotics both in and out of the hospital, pathogens such as methicillin‐resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA), traditionally thought to be confined to the hospital, are now seen in patients presenting from the community to the emergency department (ED).1, 2 Reflecting this shift in epidemiology, some national guidelines now recognize healthcare‐associated infection (HCAI) as a distinct entity.3 The concept of HCAI allows the clinician to identify patients who, despite suffering a community onset infection, still may be at risk for a resistant bacterial pathogen. Recent studies in both bloodstream infection and pneumonia have clearly demonstrated that those with HCAI have distinct microbiology and outcomes relative to those with pure CAI.47

Most work focusing on establishing HCAI has not addressed skin and soft tissue infections. These infections, although not often fatal, account for an increasing number of admissions to the hospital.8, 9 In addition, they may be associated with substantial morbidity and cost.8 Given that many pathogens such as S. aureus, which may be resistant to typical antimicrobials used in the ED, are also major culprits in complicated skin and skin structure infections (cSSSI), the HCAI paradigm may apply in cSSSI. Furthermore, because of these patterns of increased resistance, HCA‐cSSSI patients, similar to other HCAI groups, may be at an increased risk of being treated with initially inappropriate antibiotic therapy.7, 10

Since in the setting of other types of infection inappropriate empiric treatment has been shown to be associated with increased mortality and costs,7, 1015 and since indirect evidence suggests a similar impact on healthcare utilization among cSSSI patients,8 we hypothesized that among a cohort of patients hospitalized with a cSSSI, the initial empiric choice of therapy is independently associated with hospital length of stay (LOS). We performed a retrospective cohort study to address this question.

Methods

Results

Of the 717 patients with culture‐positive cSSSI admitted during the study period, 527 (73.5%) were classified as HCAI. The most common reason for classification as an HCAI was recent hospitalization. Among those with an HCA‐cSSSI, 405 (76.9%) received appropriate empiric treatment, with nearly one‐quarter receiving inappropriate initial coverage. Those receiving inappropriate antibiotic were more likely to be African American, and had a higher likelihood of having end‐stage renal disease (ESRD) than those with appropriate coverage (Table 1). While those patients treated appropriately had higher rates of both cellulitis and abscess as the presenting infection, a substantially higher proportion of those receiving inappropriate initial treatment had a decubitus ulcer (29.5% vs. 10.9%, P <0.001), a device‐associated infection (42.6% vs. 28.6%, P = 0.004), and had evidence of bacteremia (68.9% vs. 57.8%, P = 0.028) than those receiving appropriate empiric coverage (Table 2).

The pathogens recovered from the appropriately and inappropriately treated groups are listed in Figure 1. While S. aureus overall was more common among those treated appropriately, the frequency of MRSA did not differ between the groups. Both E. faecalis and E. faecium were recovered more frequently in the inappropriate group, resulting in a similar pattern among the vancomycin‐resistant enterococcal species. Likewise, P. aeruginosa, P. mirabilis, and A. baumannii were all more frequently seen in the group treated inappropriately than in the group getting appropriate empiric coverage. A mixed infection was also more likely to be present among those not exposed (16.5%) than among those exposed (7.5%) to appropriate early therapy (P = 0.001) (Figure 1).

Figure 1

In terms of processes of care and outcomes (Table 3), commensurate with the higher prevalence of abscess in the appropriately treated group, the rate of I&D was significantly higher in this cohort (36.8%) than in the inappropriately treated (23.0%) group (P = 0.005). Need for initial ICU care did not differ as a function of appropriateness of therapy (P = 0.635).

The unadjusted mortality rate was low overall and did not vary based on initial treatment (Table 3). In a generalized linear model with the log‐transformed LOS as the dependent variable, adjusting for multiple potential confounders, initial inappropriate antibiotic therapy had an attributable incremental increase in the hospital LOS of 1.8 days (95% CI, 1.42.3) (Table 4).

Because bacteremia is known to be an effect modifier of the relationship between the empiric choice of antibiotic and infection outcomes, we further explored its role in the HCAI cSSSI on the outcomes of interest (Table 5). Similar to the effect detected in the overall cohort, treatment with inappropriate therapy was associated with an increase in the hospital LOS, but not hospital mortality in those with bacteremia, though this phenomenon was observed only among patients with secondary bacteremia, and not among those without (Table 5).

Discussion

This retrospective analysis provides evidence that inappropriate empiric antibiotic therapy for HCA‐cSSSI independently prolongs hospital LOS. The impact of inappropriate initial treatment on LOS is independent of many important confounders. In addition, we observed that this effect, while present among patients with secondary bacteremia, is absent among those without a blood stream infection.

To the best of our knowledge, ours is the first cohort study to examine the outcomes associated with inappropriate treatment of a HCAI cSSSI within the context of available microbiology data. Edelsberg et al.8 examined clinical and economic outcomes associated with the failure of the initial treatment of cSSSI. While not specifically focusing on HCAI patients, these authors noted an overall 23% initial therapy failure rate. Among those patients who failed initial therapy, the risk of hospital death was nearly 3‐fold higher (adjusted odds ratio [OR], 2.91; 95% CI, 2.343.62), and they incurred the mean of 5.4 additional hospital days, compared to patients treated successfully with the initial regimen.8 Our study confirms Edelsberg et al.'s8 observation of prolonged hospital LOS in association with treatment failure, and builds upon it by defining the actual LOS increment attributable to inappropriate empiric therapy. It is worth noting that the study by Edelsberg et al.,8 however, lacked explicit definition of the HCAI population and microbiology data, and used treatment failure as a surrogate marker for inappropriate treatment. It is likely these differences between our two studies in the underlying population and exposure definitions that account for the differences in the mortality data between that study and ours.

It is not fundamentally surprising that early exposure to inappropriate empiric therapy alters healthcare resource utilization outcomes for the worse. Others have demonstrated that infection with a resistant organism results in prolongation of hospital LOS and costs. For example, in a large cohort of over 600 surgical hospitalizations requiring treatment for a gram‐negative infection, antibiotic resistance was an independent predictor of increased LOS and costs.15 These authors quantified the incremental burden of early gram‐negative resistance at over $11,000 in hospital costs.15 Unfortunately, the treatment differences for resistant and sensitive organisms were not examined.15 Similarly, Shorr et al. examined risk factors for prolonged hospital LOS and increased costs in a cohort of 291 patients with MRSA sterile site infection.17 Because in this study 23% of the patients received inappropriate empiric therapy, the authors were able to examine the impact of this exposure on utilization outcomes.17 In an adjusted analysis, inappropriate initial treatment was associated with an incremental increase in the LOS of 2.5 days, corresponding to the unadjusted cost differential of nearly $6,000.17 Although focusing on a different population, our results are consistent with these previous observations that antibiotic resistance and early inappropriate therapy affect hospital utilization parameters, in our case by adding nearly 2 days to the hospital LOS.

Our study has a number of limitations. First, as a retrospective cohort study it is prone to various forms of bias, most notably selection bias. To minimize the possibility of such, we established a priori case definitions and enrolled consecutive patients over a specific period of time. Second, as in any observational study, confounding is an issue. We dealt with this statistically by constructing a multivariable regression model; however, the possibility of residual confounding remains. Third, because some of the wound and ulcer cultures likely were obtained with a swab and thus represented colonization, rather than infection, we may have over‐estimated the rate of inappropriate therapy, and this needs to be followed up in future prospective studies. Similarly, we may have over‐estimated the likelihood of inappropriate therapy among polymicrobial and mixed infections as well, given that, for example, a gram‐negative organism may carry a different clinical significance when cultured from blood (infection) than when it is detected in a decubitus ulcer (potential colonization). Fourth, because we limited our cohort to patients without deep‐seated infections, such as necrotizing fasciitis, other procedures were not collected. This omission may have led to either over‐estimation or under‐estimation of the impact of inappropriate therapy on the outcomes of interest.

The fact that our cohort represents a single large urban academic tertiary care medical center may limit the generalizability of our results only to centers that share similar characteristics. Finally, similar to most other studies of this type, ours lacks data on posthospitalization outcomes and for this reason limits itself to hospital outcomes only.

In summary, we have shown that, similar to other populations with HCAI, a substantial proportion (nearly 1/4) of cSSSI patients with HCAI receive inappropriate empiric therapy for their infection, and this early exposure, though not affecting hospital mortality, is associated with a significant prolongation of the hospitalization by as much as 2 days. Studies are needed to refine decision rules for risk‐stratifying patients with cSSSI HCAI in order to determine the probability of infection with a resistant organism. In turn, such instruments at the bedside may assure improved utilization of appropriately targeted empiric therapy that will both optimize individual patient outcomes and reduce the risk of emergence of antimicrobial resistance.

Classically, infections have been categorized as either community‐acquired (CAI) or nosocomial in origin. Until recently, this scheme was thought adequate to capture the differences in the microbiology and outcomes in the corresponding scenarios. However, recent evidence suggests that this distinction may no longer be valid. For example, with the spread and diffusion of healthcare delivery beyond the confines of the hospital along with the increasing use of broad spectrum antibiotics both in and out of the hospital, pathogens such as methicillin‐resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA), traditionally thought to be confined to the hospital, are now seen in patients presenting from the community to the emergency department (ED).1, 2 Reflecting this shift in epidemiology, some national guidelines now recognize healthcare‐associated infection (HCAI) as a distinct entity.3 The concept of HCAI allows the clinician to identify patients who, despite suffering a community onset infection, still may be at risk for a resistant bacterial pathogen. Recent studies in both bloodstream infection and pneumonia have clearly demonstrated that those with HCAI have distinct microbiology and outcomes relative to those with pure CAI.47

Most work focusing on establishing HCAI has not addressed skin and soft tissue infections. These infections, although not often fatal, account for an increasing number of admissions to the hospital.8, 9 In addition, they may be associated with substantial morbidity and cost.8 Given that many pathogens such as S. aureus, which may be resistant to typical antimicrobials used in the ED, are also major culprits in complicated skin and skin structure infections (cSSSI), the HCAI paradigm may apply in cSSSI. Furthermore, because of these patterns of increased resistance, HCA‐cSSSI patients, similar to other HCAI groups, may be at an increased risk of being treated with initially inappropriate antibiotic therapy.7, 10

Since in the setting of other types of infection inappropriate empiric treatment has been shown to be associated with increased mortality and costs,7, 1015 and since indirect evidence suggests a similar impact on healthcare utilization among cSSSI patients,8 we hypothesized that among a cohort of patients hospitalized with a cSSSI, the initial empiric choice of therapy is independently associated with hospital length of stay (LOS). We performed a retrospective cohort study to address this question.

Methods

Results

Of the 717 patients with culture‐positive cSSSI admitted during the study period, 527 (73.5%) were classified as HCAI. The most common reason for classification as an HCAI was recent hospitalization. Among those with an HCA‐cSSSI, 405 (76.9%) received appropriate empiric treatment, with nearly one‐quarter receiving inappropriate initial coverage. Those receiving inappropriate antibiotic were more likely to be African American, and had a higher likelihood of having end‐stage renal disease (ESRD) than those with appropriate coverage (Table 1). While those patients treated appropriately had higher rates of both cellulitis and abscess as the presenting infection, a substantially higher proportion of those receiving inappropriate initial treatment had a decubitus ulcer (29.5% vs. 10.9%, P <0.001), a device‐associated infection (42.6% vs. 28.6%, P = 0.004), and had evidence of bacteremia (68.9% vs. 57.8%, P = 0.028) than those receiving appropriate empiric coverage (Table 2).

The pathogens recovered from the appropriately and inappropriately treated groups are listed in Figure 1. While S. aureus overall was more common among those treated appropriately, the frequency of MRSA did not differ between the groups. Both E. faecalis and E. faecium were recovered more frequently in the inappropriate group, resulting in a similar pattern among the vancomycin‐resistant enterococcal species. Likewise, P. aeruginosa, P. mirabilis, and A. baumannii were all more frequently seen in the group treated inappropriately than in the group getting appropriate empiric coverage. A mixed infection was also more likely to be present among those not exposed (16.5%) than among those exposed (7.5%) to appropriate early therapy (P = 0.001) (Figure 1).

Figure 1

In terms of processes of care and outcomes (Table 3), commensurate with the higher prevalence of abscess in the appropriately treated group, the rate of I&D was significantly higher in this cohort (36.8%) than in the inappropriately treated (23.0%) group (P = 0.005). Need for initial ICU care did not differ as a function of appropriateness of therapy (P = 0.635).

The unadjusted mortality rate was low overall and did not vary based on initial treatment (Table 3). In a generalized linear model with the log‐transformed LOS as the dependent variable, adjusting for multiple potential confounders, initial inappropriate antibiotic therapy had an attributable incremental increase in the hospital LOS of 1.8 days (95% CI, 1.42.3) (Table 4).

Because bacteremia is known to be an effect modifier of the relationship between the empiric choice of antibiotic and infection outcomes, we further explored its role in the HCAI cSSSI on the outcomes of interest (Table 5). Similar to the effect detected in the overall cohort, treatment with inappropriate therapy was associated with an increase in the hospital LOS, but not hospital mortality in those with bacteremia, though this phenomenon was observed only among patients with secondary bacteremia, and not among those without (Table 5).

Discussion

This retrospective analysis provides evidence that inappropriate empiric antibiotic therapy for HCA‐cSSSI independently prolongs hospital LOS. The impact of inappropriate initial treatment on LOS is independent of many important confounders. In addition, we observed that this effect, while present among patients with secondary bacteremia, is absent among those without a blood stream infection.

To the best of our knowledge, ours is the first cohort study to examine the outcomes associated with inappropriate treatment of a HCAI cSSSI within the context of available microbiology data. Edelsberg et al.8 examined clinical and economic outcomes associated with the failure of the initial treatment of cSSSI. While not specifically focusing on HCAI patients, these authors noted an overall 23% initial therapy failure rate. Among those patients who failed initial therapy, the risk of hospital death was nearly 3‐fold higher (adjusted odds ratio [OR], 2.91; 95% CI, 2.343.62), and they incurred the mean of 5.4 additional hospital days, compared to patients treated successfully with the initial regimen.8 Our study confirms Edelsberg et al.'s8 observation of prolonged hospital LOS in association with treatment failure, and builds upon it by defining the actual LOS increment attributable to inappropriate empiric therapy. It is worth noting that the study by Edelsberg et al.,8 however, lacked explicit definition of the HCAI population and microbiology data, and used treatment failure as a surrogate marker for inappropriate treatment. It is likely these differences between our two studies in the underlying population and exposure definitions that account for the differences in the mortality data between that study and ours.

It is not fundamentally surprising that early exposure to inappropriate empiric therapy alters healthcare resource utilization outcomes for the worse. Others have demonstrated that infection with a resistant organism results in prolongation of hospital LOS and costs. For example, in a large cohort of over 600 surgical hospitalizations requiring treatment for a gram‐negative infection, antibiotic resistance was an independent predictor of increased LOS and costs.15 These authors quantified the incremental burden of early gram‐negative resistance at over $11,000 in hospital costs.15 Unfortunately, the treatment differences for resistant and sensitive organisms were not examined.15 Similarly, Shorr et al. examined risk factors for prolonged hospital LOS and increased costs in a cohort of 291 patients with MRSA sterile site infection.17 Because in this study 23% of the patients received inappropriate empiric therapy, the authors were able to examine the impact of this exposure on utilization outcomes.17 In an adjusted analysis, inappropriate initial treatment was associated with an incremental increase in the LOS of 2.5 days, corresponding to the unadjusted cost differential of nearly $6,000.17 Although focusing on a different population, our results are consistent with these previous observations that antibiotic resistance and early inappropriate therapy affect hospital utilization parameters, in our case by adding nearly 2 days to the hospital LOS.

Our study has a number of limitations. First, as a retrospective cohort study it is prone to various forms of bias, most notably selection bias. To minimize the possibility of such, we established a priori case definitions and enrolled consecutive patients over a specific period of time. Second, as in any observational study, confounding is an issue. We dealt with this statistically by constructing a multivariable regression model; however, the possibility of residual confounding remains. Third, because some of the wound and ulcer cultures likely were obtained with a swab and thus represented colonization, rather than infection, we may have over‐estimated the rate of inappropriate therapy, and this needs to be followed up in future prospective studies. Similarly, we may have over‐estimated the likelihood of inappropriate therapy among polymicrobial and mixed infections as well, given that, for example, a gram‐negative organism may carry a different clinical significance when cultured from blood (infection) than when it is detected in a decubitus ulcer (potential colonization). Fourth, because we limited our cohort to patients without deep‐seated infections, such as necrotizing fasciitis, other procedures were not collected. This omission may have led to either over‐estimation or under‐estimation of the impact of inappropriate therapy on the outcomes of interest.

The fact that our cohort represents a single large urban academic tertiary care medical center may limit the generalizability of our results only to centers that share similar characteristics. Finally, similar to most other studies of this type, ours lacks data on posthospitalization outcomes and for this reason limits itself to hospital outcomes only.

In summary, we have shown that, similar to other populations with HCAI, a substantial proportion (nearly 1/4) of cSSSI patients with HCAI receive inappropriate empiric therapy for their infection, and this early exposure, though not affecting hospital mortality, is associated with a significant prolongation of the hospitalization by as much as 2 days. Studies are needed to refine decision rules for risk‐stratifying patients with cSSSI HCAI in order to determine the probability of infection with a resistant organism. In turn, such instruments at the bedside may assure improved utilization of appropriately targeted empiric therapy that will both optimize individual patient outcomes and reduce the risk of emergence of antimicrobial resistance.

Staphylococcus aureus (S. aureus) is well recognized as a major cause of nosocomial and healthcare‐associated pneumonia (HCAP). These infections are associated with substantial morbidity and mortality, and generate high medical costs.14 The significance of S. aureus in community‐acquired pneumonia (CAP) is less clear. Historically, S. aureus has not been considered a common pathogen in CAP, usually arising in association with or following influenza or an influenza‐like syndrome.58 However, with the increasing prevalence of methicillin‐resistant S. aureus (MRSA) as a cause of HCAPand most recently, serious community‐acquired non‐pulmonary infectionsinterest in this pathogen and its impact beyond the hospital have been expanding. During the 2003 to 2004 influenza season, 15 cases of influenza‐associated MRSA CAP were identified.6 In January 2007, the US Centers for Disease Control and Prevention (CDC) received reports of an additional 10 cases of severe MRSA CAP, resulting in six deaths, among previously healthy children and adults in Louisiana and Georgia.7 Kallen et al.9 recently reported 51 cases from 19 states between November 2006 and April 2007. To the best of our knowledge, these reports represent the largest case series describing MRSA in CAP.

Earlier studies have suggested a relationship between the outcome of S. aureus infection and the presence of various patient and strain characteristics.1013 Most observations regarding the adverse impact of MRSA on patient outcomes have arisen from analyses of cohorts of patients with either mixed infections, bacteremias, or nosocomial infection. There is little information on outcomes in patients with S. aureus CAP. To address this issue, we conducted a retrospective study of patients with culture‐proven S. aureus pneumonia admitted to a large urban hospital.

Materials and Methods

Sample Selection

The source population for the study consisted of all admissions to Henry Ford Hospital between January 2005 and May 2008 (study period) Patients were included in the study sample if they had: (1) a discharge diagnosis (principal or secondary) of pneumonia (International Classification of Diseases 9th Edition, Clinical Modification [ICD‐9‐CM] diagnosis codes 481.X 486.X) on their discharge summary or in their medical record; (2) a positive chest x‐ray (ie, infiltrate, consolidation, pleural effusion) within 48 hours of hospital admission; (3) an abnormal temperature (>38.3C [101.0F] or <36C [96.8F]), an abnormal white blood count (WBC) (>12,000/mm³ or <4,000/mm³), or increased sputum production on their day of hospital admission; and (4) a positive blood or respiratory culture for S. aureus within 48 hours of hospital admission.

Among these identified patients, those with probable HCAP were excluded from the study sample, based on evidence of: (1) hospitalization for 2 days during the 90‐day period preceding the index hospitalization; (2) admission to hospital from a nursing home or long‐term care facility; (3) hemodialysis 30 days prior to hospital admission; (4) receipt of cancer chemotherapy, IV antibiotic therapy, or wound care 30 days prior to hospital admission; or (5) receipt of an immunosuppressant at the time of hospital admission. All remaining patients were assumed to have CAP.

Results

There were 282 admissions to Henry Ford Hospital between January 2005 and May 2008 of patients with pneumonia who had positive blood or respiratory cultures for S. aureus within 48 hours of admission. (The total number of admissions over this period of patients with a principal diagnosis of pneumonia was 3894). Twelve patients had a negative chest x‐ray or negative clinical findings for pneumonia on the day of hospital admission and were excluded from the analysis. An additional 142 (53%) patients had evidence of HCAP and were excluded from the analysis. The final study sample therefore consisted of 128 patients with S. aureus CAP; their demographic and clinical characteristics are presented in Table 1.

Mean (SD) age of study subjects was 60 (17.0) years; 72% were nonwhite, and 58% were males. Prevalence of selected comorbidities, including acute renal failure, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, diabetes, myocardial infarction, and peripheral vascular disease was high (>20%). Mean (SD) CURB score at admission was 1.8 (1.1); scores did not differ significantly between MRSA vs. MSSA patients. Eight patients (6%) had evidence of positive S. aureus cultures in the year prior to admission.

A total of 55 (43%) patients had positive MRSA cultures within the first 48 hours of admission, while the remainder (n = 73 [57%]) had cultures positive for MSSA. Among the 55 patients with MRSA, 23 (42%) had USA300 MRSA strains that produced PVL toxin. Only 18% of MRSA patients had MICs to vancomycin of 1 g/mL; most remaining patients (73%) had 1.5 g/mL MIC values. Thirty‐one patients (24%) died prior to hospital discharge (Table 2). Eighty‐eight (69%) patients received mechanical ventilation, and 79% were admitted to ICU; 25% of patients underwent thoracic surgery for pneumonia. Mean (SD) length of stay in hospital was 17.0 (15.7) days, and mean (SD) total charges per hospitalization were $127,922 ($154,605). (Mean length of stay in hospital was 5.8 days for all 3894 patients with a principal discharge diagnosis of pneumonia, and mean total charges were $29,448).

Notwithstanding the fact that patients with MRSA were more than twice as likely to receive inappropriate initial therapy (44% for MRSA vs. 18% for MSSA; odds ratio [OR], 3.57; 95% confidence interval [CI], 1.607.97; P = 0.0015), there were no statistically significant differences in in‐hospital mortality (26% for MSSA vs. 22% for MRSA; P = 0.678), surgery for pneumonia (26% vs. 24%; P = 0.838), or admission to ICU (82% vs. 74%; P = 0.382). Patients with MSSA CAP were more likely to receive mechanical ventilation (77% vs. 58%; P = 0.034). Mean (SD) total charges per admission did not differ between patients with MSSA vs. MRSA CAP ($135,784 [$170,046] vs $117,489 [$132,164], respectively [P = 0.510]). (30‐day mortality following hospital discharge was 24% for MRSA CAP patients and 30% for MSSA CAP patients.)

Among patients with MRSA CAP, there were no notable differences in outcomes between those with strains with the PVL toxin vs. those without it (Table 2). Mean (SD) length of stay in hospital, however, was significantly longer among the former patients (25 [22.6] days vs. 13 [7.7] days for those without PVL toxin; P = 0.020). Reflecting this difference, mean (SD) total charges per admission were $76,909 higher among MRSA patients with PVL‐positive strains vs. those with PVL‐negative strains ($162,124 [$186,923] vs. $85,215 [$57,957] respectively; P = 0.066).

Among MRSA patients with MICs to vancomycin of 1.5 g/mL, 17% died in hospital, 20% underwent surgery for pneumonia, 60% received mechanical ventilation, and 75% were admitted to ICU. Mean (SD) total charges per admission were $104,514 ($112,606) (Table 2).

Discussion

To the best of our knowledge, this is the largest observational study to date of outcomes in patients with S. aureus CAP. Our results indicate that MRSA represents almost one‐half of all such infections, with USA300 strains accounting for a substantial proportion of these cases. In addition, for most outcome measures, there were no significant differences between patients with MSSA vs. MRSA CAP. In patients with MRSA CAP, however, those with PVL‐positive strains had longer stays in the hospital and had higher total costs of hospitalization.

Our study highlights the significant clinical and economic burden of S. aureus CAP. In the US, the mortality rate in patients hospitalized with CAP is about 8%, while mean length of stay is approximately 5 days (it was 5.8 days in our institution among all patients with CAP). In contrast, we found that most patients with S. aureus CAP were admitted to ICU, and that nearly one in four died during hospitalization. One possible explanation for these findings is that patients with S. aureus CAP may often receive inappropriate initial antibiotic therapy, a major predictor of adverse outcome in infection. The overall rate of inappropriate treatment, however, was low in our study (although we note that optimal antibiotic treatment is not clearly defined for the USA300 strain, and as a result, we assumed that vancomycin would be appropriate for all MRSA infections). A more likely explanation for our findings is the severity of CAP associated with S. aureus, whether MRSA or MSSA. Given the nature of S. aureus infections, the need for prevention (and potentially, development of a vaccine) remains crucial.

While MRSA has been studied extensively as a cause of bacteremia, as well as HCAP and VAP, it has not been well studied in CAP. Patients with MRSA bacteremia have been shown to have a higher mortality risk and higher healthcare costs than those with MSSA infections, and a meta‐analysis of 31 studies of patients with S. aureus bloodstream infections demonstrated a significant increase in mortality among patients with MRSA vs. MSSA bacteremia.1820 Outcomes when comparing MRSA and MSSA in VAP are slightly more variable. A higher rate of mortality has been reported in patients with pneumonia caused by MRSA vs. MSSA, but others found no difference after controlling for potential confounders.21, 22 We found that case fatality, surgery for pneumonia, ICU admission, length of stay, and total hospital charges do not differ significantly between patients with MRSA vs. MSSA CAP. This suggests that appreciation of the burden of MRSA can only be done in the context of the syndrome in question, and that conclusions from analyses of bacteremia and VAP may not be generalizable to CAP.

In the US, an increasing number of community‐associated infections are due to MRSA. Skin and skin structure infections comprise the majority of community‐associated MRSA infections and are caused by a single pulsed field type, termed USA300. These strains are believed to have distinctive virulence and epidemiologic characteristics. USA300 isolates typically are resistant only to beta‐lactam and macrolide antimicrobial agents and contain genes for the PVL toxin, which typically are not present in strains of healthcare‐associated MRSA.23 Recent studies of acute pneumonia with animal models and in humans have suggested that the PVL toxinalone or in combination with other virulence factorsis associated with the development of necrotizing pneumonia.2430 In our study, 23 patients with MRSA CAP had strains that contained PVL toxin, and these patients had longer stays in hospital and higher total hospital charges than those with MRSA CAP not containing the PVL toxin. This is an important finding, as length of stay is an important proxy for morbidity and case severity. This also extends the finding of previous case studies reporting that MRSA CAP with PVL toxin is associated with worse outcomes.2430 Moreover, we clearly document that PVL‐positive strains are emerging as a cause of pulmonary infection in broader clinical scenarios. As such, physicians must remain vigilant for this toxin‐producing strain. The full extent of the impact of PVL‐positive strains in our study is unknown, as we cannot ascertain whether morbidity was worse because of the PVL toxin itself, or because most patients were not treated with clindamycin or linezolid, which inhibit toxin production.

We failed to observe a correlation between MICs to vancomycin and the outcomes we studied. The clinical significance of reduced susceptibility of S. aureus to vancomycin remains a controversial issue. In our study, there was no significant association between MICs to vancomycin and mortality, need for surgery, ICU admission, length of stay, or total hospital charges. Sakoulas et al.11 reported that as vancomycin MICs for MRSA isolates rose within the susceptible range from 0.5 mcg/mL to 2.0 mcg/mL, so too did the number of clinical failures among bacteremic patients receiving vancomycin. Moise‐Broder et al.31 reported a similar finding in a study of 63 patients with MRSA bacteremia, of whom 45 failed or were intolerant of vancomycin therapy. In a more recent report, Soriano et al.12 prospectively evaluated 414 episodes of bacteremia. The authors concluded that mortality in patients with MRSA bacteremia is significantly higher when the empiric antimicrobial agent is inappropriate and when vancomycin is used to treat infections involving strains with MICs >1.0 mcg/mL. In pneumonia, Hidayat et al.13 reported that patients with infections due to pathogens with higher MICs to vancomycin had a higher rate of mortality than those with lower MICs. Our findings likely differ from this report because of the proportion of subjects with PVL‐positive strains, and because of the skew in the distribution of vancomycin MICs. More specifically, the majority of patients had higher MIC strains, clustered around 1.5 mg/L, leaving us with few lower MIC strains and fewer strains with MICs of 2.0 mcg/mL for comparison, and therefore limited statistical power to assess the relationship between MICs and outcomes.

There were no clinical features that clearly distinguished patients with MRSA vs. MSSA CAP. This suggests that if physicians hope to ensure that patients with MRSA CAP receive appropriate initial antibiotic therapy, they cannot base therapeutic decision‐making (ie, use of an anti‐MRSA treatment) on clinical criteria. Presently, national guidelines recommend diagnostic testing only if the results might affect clinical decisions (eg, antimicrobial management).32 Furthermore, the IDSA/ATS guidelines recommend sputum cultures along with blood cultures and other diagnostic tests only in select cases (eg, those with severe disease). Since beginning optimal therapy quickly can reduce mortality in pneumonia,33 our results indicate a need for both rapid diagnostic tests to identify patients with MRSA, and reevaluation of current recommendations for diagnostic testing in CAP.

Our study has several important limitations. First, its retrospective design exposes it to many forms of bias. Second, because the diagnosis of pneumonia can be challenging, we required that all patients have both clinical and radiologic evidence of the disease. However, we may have thereby excluded some admissions for S. aureus pneumonia among the over 3000 pneumonia admissions to our hospital during the study period.

Third, we only included patients with culture evidence of infection. This was necessary by design, but as a result we may have failed to identify some patients with S. aureus infections because of the limitations of respiratory culture technology. Patients on general practice units often do not get cultured, and accordingly we may have missed those with milder disease caused by S. aureus.

Fourth, we used only one method of MIC testing to determine vancomycin susceptibility. It would have been of interest to have used automated dilution testing also and to have compared both methods. Comparison of laboratory methods was not among our study objectives, and most of the earlier studies examining epidemiology and outcomes used a single laboratory testing method only.

Finally, since the study was conducted at a large urban teaching hospital in a city with a long history of issues with MRSA and resistance, the generalizability of our results may be limited.

In summary, our study provides further evidence that S. aureus is an important pathogen in CAP. MRSA CAP has few obvious characteristics that differentiate it from MSSA CAP. MRSA and MSSA CAP are both very serious infections that should be treated aggressively to avoid poor outcomes.

Staphylococcus aureus (S. aureus) is well recognized as a major cause of nosocomial and healthcare‐associated pneumonia (HCAP). These infections are associated with substantial morbidity and mortality, and generate high medical costs.14 The significance of S. aureus in community‐acquired pneumonia (CAP) is less clear. Historically, S. aureus has not been considered a common pathogen in CAP, usually arising in association with or following influenza or an influenza‐like syndrome.58 However, with the increasing prevalence of methicillin‐resistant S. aureus (MRSA) as a cause of HCAPand most recently, serious community‐acquired non‐pulmonary infectionsinterest in this pathogen and its impact beyond the hospital have been expanding. During the 2003 to 2004 influenza season, 15 cases of influenza‐associated MRSA CAP were identified.6 In January 2007, the US Centers for Disease Control and Prevention (CDC) received reports of an additional 10 cases of severe MRSA CAP, resulting in six deaths, among previously healthy children and adults in Louisiana and Georgia.7 Kallen et al.9 recently reported 51 cases from 19 states between November 2006 and April 2007. To the best of our knowledge, these reports represent the largest case series describing MRSA in CAP.

Earlier studies have suggested a relationship between the outcome of S. aureus infection and the presence of various patient and strain characteristics.1013 Most observations regarding the adverse impact of MRSA on patient outcomes have arisen from analyses of cohorts of patients with either mixed infections, bacteremias, or nosocomial infection. There is little information on outcomes in patients with S. aureus CAP. To address this issue, we conducted a retrospective study of patients with culture‐proven S. aureus pneumonia admitted to a large urban hospital.

Materials and Methods

Sample Selection

The source population for the study consisted of all admissions to Henry Ford Hospital between January 2005 and May 2008 (study period) Patients were included in the study sample if they had: (1) a discharge diagnosis (principal or secondary) of pneumonia (International Classification of Diseases 9th Edition, Clinical Modification [ICD‐9‐CM] diagnosis codes 481.X 486.X) on their discharge summary or in their medical record; (2) a positive chest x‐ray (ie, infiltrate, consolidation, pleural effusion) within 48 hours of hospital admission; (3) an abnormal temperature (>38.3C [101.0F] or <36C [96.8F]), an abnormal white blood count (WBC) (>12,000/mm³ or <4,000/mm³), or increased sputum production on their day of hospital admission; and (4) a positive blood or respiratory culture for S. aureus within 48 hours of hospital admission.

Among these identified patients, those with probable HCAP were excluded from the study sample, based on evidence of: (1) hospitalization for 2 days during the 90‐day period preceding the index hospitalization; (2) admission to hospital from a nursing home or long‐term care facility; (3) hemodialysis 30 days prior to hospital admission; (4) receipt of cancer chemotherapy, IV antibiotic therapy, or wound care 30 days prior to hospital admission; or (5) receipt of an immunosuppressant at the time of hospital admission. All remaining patients were assumed to have CAP.

Results

There were 282 admissions to Henry Ford Hospital between January 2005 and May 2008 of patients with pneumonia who had positive blood or respiratory cultures for S. aureus within 48 hours of admission. (The total number of admissions over this period of patients with a principal diagnosis of pneumonia was 3894). Twelve patients had a negative chest x‐ray or negative clinical findings for pneumonia on the day of hospital admission and were excluded from the analysis. An additional 142 (53%) patients had evidence of HCAP and were excluded from the analysis. The final study sample therefore consisted of 128 patients with S. aureus CAP; their demographic and clinical characteristics are presented in Table 1.

Mean (SD) age of study subjects was 60 (17.0) years; 72% were nonwhite, and 58% were males. Prevalence of selected comorbidities, including acute renal failure, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, diabetes, myocardial infarction, and peripheral vascular disease was high (>20%). Mean (SD) CURB score at admission was 1.8 (1.1); scores did not differ significantly between MRSA vs. MSSA patients. Eight patients (6%) had evidence of positive S. aureus cultures in the year prior to admission.

A total of 55 (43%) patients had positive MRSA cultures within the first 48 hours of admission, while the remainder (n = 73 [57%]) had cultures positive for MSSA. Among the 55 patients with MRSA, 23 (42%) had USA300 MRSA strains that produced PVL toxin. Only 18% of MRSA patients had MICs to vancomycin of 1 g/mL; most remaining patients (73%) had 1.5 g/mL MIC values. Thirty‐one patients (24%) died prior to hospital discharge (Table 2). Eighty‐eight (69%) patients received mechanical ventilation, and 79% were admitted to ICU; 25% of patients underwent thoracic surgery for pneumonia. Mean (SD) length of stay in hospital was 17.0 (15.7) days, and mean (SD) total charges per hospitalization were $127,922 ($154,605). (Mean length of stay in hospital was 5.8 days for all 3894 patients with a principal discharge diagnosis of pneumonia, and mean total charges were $29,448).

Notwithstanding the fact that patients with MRSA were more than twice as likely to receive inappropriate initial therapy (44% for MRSA vs. 18% for MSSA; odds ratio [OR], 3.57; 95% confidence interval [CI], 1.607.97; P = 0.0015), there were no statistically significant differences in in‐hospital mortality (26% for MSSA vs. 22% for MRSA; P = 0.678), surgery for pneumonia (26% vs. 24%; P = 0.838), or admission to ICU (82% vs. 74%; P = 0.382). Patients with MSSA CAP were more likely to receive mechanical ventilation (77% vs. 58%; P = 0.034). Mean (SD) total charges per admission did not differ between patients with MSSA vs. MRSA CAP ($135,784 [$170,046] vs $117,489 [$132,164], respectively [P = 0.510]). (30‐day mortality following hospital discharge was 24% for MRSA CAP patients and 30% for MSSA CAP patients.)

Among patients with MRSA CAP, there were no notable differences in outcomes between those with strains with the PVL toxin vs. those without it (Table 2). Mean (SD) length of stay in hospital, however, was significantly longer among the former patients (25 [22.6] days vs. 13 [7.7] days for those without PVL toxin; P = 0.020). Reflecting this difference, mean (SD) total charges per admission were $76,909 higher among MRSA patients with PVL‐positive strains vs. those with PVL‐negative strains ($162,124 [$186,923] vs. $85,215 [$57,957] respectively; P = 0.066).

Among MRSA patients with MICs to vancomycin of 1.5 g/mL, 17% died in hospital, 20% underwent surgery for pneumonia, 60% received mechanical ventilation, and 75% were admitted to ICU. Mean (SD) total charges per admission were $104,514 ($112,606) (Table 2).

Discussion

To the best of our knowledge, this is the largest observational study to date of outcomes in patients with S. aureus CAP. Our results indicate that MRSA represents almost one‐half of all such infections, with USA300 strains accounting for a substantial proportion of these cases. In addition, for most outcome measures, there were no significant differences between patients with MSSA vs. MRSA CAP. In patients with MRSA CAP, however, those with PVL‐positive strains had longer stays in the hospital and had higher total costs of hospitalization.

Our study highlights the significant clinical and economic burden of S. aureus CAP. In the US, the mortality rate in patients hospitalized with CAP is about 8%, while mean length of stay is approximately 5 days (it was 5.8 days in our institution among all patients with CAP). In contrast, we found that most patients with S. aureus CAP were admitted to ICU, and that nearly one in four died during hospitalization. One possible explanation for these findings is that patients with S. aureus CAP may often receive inappropriate initial antibiotic therapy, a major predictor of adverse outcome in infection. The overall rate of inappropriate treatment, however, was low in our study (although we note that optimal antibiotic treatment is not clearly defined for the USA300 strain, and as a result, we assumed that vancomycin would be appropriate for all MRSA infections). A more likely explanation for our findings is the severity of CAP associated with S. aureus, whether MRSA or MSSA. Given the nature of S. aureus infections, the need for prevention (and potentially, development of a vaccine) remains crucial.

While MRSA has been studied extensively as a cause of bacteremia, as well as HCAP and VAP, it has not been well studied in CAP. Patients with MRSA bacteremia have been shown to have a higher mortality risk and higher healthcare costs than those with MSSA infections, and a meta‐analysis of 31 studies of patients with S. aureus bloodstream infections demonstrated a significant increase in mortality among patients with MRSA vs. MSSA bacteremia.1820 Outcomes when comparing MRSA and MSSA in VAP are slightly more variable. A higher rate of mortality has been reported in patients with pneumonia caused by MRSA vs. MSSA, but others found no difference after controlling for potential confounders.21, 22 We found that case fatality, surgery for pneumonia, ICU admission, length of stay, and total hospital charges do not differ significantly between patients with MRSA vs. MSSA CAP. This suggests that appreciation of the burden of MRSA can only be done in the context of the syndrome in question, and that conclusions from analyses of bacteremia and VAP may not be generalizable to CAP.

In the US, an increasing number of community‐associated infections are due to MRSA. Skin and skin structure infections comprise the majority of community‐associated MRSA infections and are caused by a single pulsed field type, termed USA300. These strains are believed to have distinctive virulence and epidemiologic characteristics. USA300 isolates typically are resistant only to beta‐lactam and macrolide antimicrobial agents and contain genes for the PVL toxin, which typically are not present in strains of healthcare‐associated MRSA.23 Recent studies of acute pneumonia with animal models and in humans have suggested that the PVL toxinalone or in combination with other virulence factorsis associated with the development of necrotizing pneumonia.2430 In our study, 23 patients with MRSA CAP had strains that contained PVL toxin, and these patients had longer stays in hospital and higher total hospital charges than those with MRSA CAP not containing the PVL toxin. This is an important finding, as length of stay is an important proxy for morbidity and case severity. This also extends the finding of previous case studies reporting that MRSA CAP with PVL toxin is associated with worse outcomes.2430 Moreover, we clearly document that PVL‐positive strains are emerging as a cause of pulmonary infection in broader clinical scenarios. As such, physicians must remain vigilant for this toxin‐producing strain. The full extent of the impact of PVL‐positive strains in our study is unknown, as we cannot ascertain whether morbidity was worse because of the PVL toxin itself, or because most patients were not treated with clindamycin or linezolid, which inhibit toxin production.

We failed to observe a correlation between MICs to vancomycin and the outcomes we studied. The clinical significance of reduced susceptibility of S. aureus to vancomycin remains a controversial issue. In our study, there was no significant association between MICs to vancomycin and mortality, need for surgery, ICU admission, length of stay, or total hospital charges. Sakoulas et al.11 reported that as vancomycin MICs for MRSA isolates rose within the susceptible range from 0.5 mcg/mL to 2.0 mcg/mL, so too did the number of clinical failures among bacteremic patients receiving vancomycin. Moise‐Broder et al.31 reported a similar finding in a study of 63 patients with MRSA bacteremia, of whom 45 failed or were intolerant of vancomycin therapy. In a more recent report, Soriano et al.12 prospectively evaluated 414 episodes of bacteremia. The authors concluded that mortality in patients with MRSA bacteremia is significantly higher when the empiric antimicrobial agent is inappropriate and when vancomycin is used to treat infections involving strains with MICs >1.0 mcg/mL. In pneumonia, Hidayat et al.13 reported that patients with infections due to pathogens with higher MICs to vancomycin had a higher rate of mortality than those with lower MICs. Our findings likely differ from this report because of the proportion of subjects with PVL‐positive strains, and because of the skew in the distribution of vancomycin MICs. More specifically, the majority of patients had higher MIC strains, clustered around 1.5 mg/L, leaving us with few lower MIC strains and fewer strains with MICs of 2.0 mcg/mL for comparison, and therefore limited statistical power to assess the relationship between MICs and outcomes.

There were no clinical features that clearly distinguished patients with MRSA vs. MSSA CAP. This suggests that if physicians hope to ensure that patients with MRSA CAP receive appropriate initial antibiotic therapy, they cannot base therapeutic decision‐making (ie, use of an anti‐MRSA treatment) on clinical criteria. Presently, national guidelines recommend diagnostic testing only if the results might affect clinical decisions (eg, antimicrobial management).32 Furthermore, the IDSA/ATS guidelines recommend sputum cultures along with blood cultures and other diagnostic tests only in select cases (eg, those with severe disease). Since beginning optimal therapy quickly can reduce mortality in pneumonia,33 our results indicate a need for both rapid diagnostic tests to identify patients with MRSA, and reevaluation of current recommendations for diagnostic testing in CAP.

Our study has several important limitations. First, its retrospective design exposes it to many forms of bias. Second, because the diagnosis of pneumonia can be challenging, we required that all patients have both clinical and radiologic evidence of the disease. However, we may have thereby excluded some admissions for S. aureus pneumonia among the over 3000 pneumonia admissions to our hospital during the study period.

Third, we only included patients with culture evidence of infection. This was necessary by design, but as a result we may have failed to identify some patients with S. aureus infections because of the limitations of respiratory culture technology. Patients on general practice units often do not get cultured, and accordingly we may have missed those with milder disease caused by S. aureus.

Fourth, we used only one method of MIC testing to determine vancomycin susceptibility. It would have been of interest to have used automated dilution testing also and to have compared both methods. Comparison of laboratory methods was not among our study objectives, and most of the earlier studies examining epidemiology and outcomes used a single laboratory testing method only.

Finally, since the study was conducted at a large urban teaching hospital in a city with a long history of issues with MRSA and resistance, the generalizability of our results may be limited.

In summary, our study provides further evidence that S. aureus is an important pathogen in CAP. MRSA CAP has few obvious characteristics that differentiate it from MSSA CAP. MRSA and MSSA CAP are both very serious infections that should be treated aggressively to avoid poor outcomes.

Staphylococcus aureus (S. aureus) is well recognized as a major cause of nosocomial and healthcare‐associated pneumonia (HCAP). These infections are associated with substantial morbidity and mortality, and generate high medical costs.14 The significance of S. aureus in community‐acquired pneumonia (CAP) is less clear. Historically, S. aureus has not been considered a common pathogen in CAP, usually arising in association with or following influenza or an influenza‐like syndrome.58 However, with the increasing prevalence of methicillin‐resistant S. aureus (MRSA) as a cause of HCAPand most recently, serious community‐acquired non‐pulmonary infectionsinterest in this pathogen and its impact beyond the hospital have been expanding. During the 2003 to 2004 influenza season, 15 cases of influenza‐associated MRSA CAP were identified.6 In January 2007, the US Centers for Disease Control and Prevention (CDC) received reports of an additional 10 cases of severe MRSA CAP, resulting in six deaths, among previously healthy children and adults in Louisiana and Georgia.7 Kallen et al.9 recently reported 51 cases from 19 states between November 2006 and April 2007. To the best of our knowledge, these reports represent the largest case series describing MRSA in CAP.

Earlier studies have suggested a relationship between the outcome of S. aureus infection and the presence of various patient and strain characteristics.1013 Most observations regarding the adverse impact of MRSA on patient outcomes have arisen from analyses of cohorts of patients with either mixed infections, bacteremias, or nosocomial infection. There is little information on outcomes in patients with S. aureus CAP. To address this issue, we conducted a retrospective study of patients with culture‐proven S. aureus pneumonia admitted to a large urban hospital.

Materials and Methods

Sample Selection

The source population for the study consisted of all admissions to Henry Ford Hospital between January 2005 and May 2008 (study period) Patients were included in the study sample if they had: (1) a discharge diagnosis (principal or secondary) of pneumonia (International Classification of Diseases 9th Edition, Clinical Modification [ICD‐9‐CM] diagnosis codes 481.X 486.X) on their discharge summary or in their medical record; (2) a positive chest x‐ray (ie, infiltrate, consolidation, pleural effusion) within 48 hours of hospital admission; (3) an abnormal temperature (>38.3C [101.0F] or <36C [96.8F]), an abnormal white blood count (WBC) (>12,000/mm³ or <4,000/mm³), or increased sputum production on their day of hospital admission; and (4) a positive blood or respiratory culture for S. aureus within 48 hours of hospital admission.

Among these identified patients, those with probable HCAP were excluded from the study sample, based on evidence of: (1) hospitalization for 2 days during the 90‐day period preceding the index hospitalization; (2) admission to hospital from a nursing home or long‐term care facility; (3) hemodialysis 30 days prior to hospital admission; (4) receipt of cancer chemotherapy, IV antibiotic therapy, or wound care 30 days prior to hospital admission; or (5) receipt of an immunosuppressant at the time of hospital admission. All remaining patients were assumed to have CAP.

Results

There were 282 admissions to Henry Ford Hospital between January 2005 and May 2008 of patients with pneumonia who had positive blood or respiratory cultures for S. aureus within 48 hours of admission. (The total number of admissions over this period of patients with a principal diagnosis of pneumonia was 3894). Twelve patients had a negative chest x‐ray or negative clinical findings for pneumonia on the day of hospital admission and were excluded from the analysis. An additional 142 (53%) patients had evidence of HCAP and were excluded from the analysis. The final study sample therefore consisted of 128 patients with S. aureus CAP; their demographic and clinical characteristics are presented in Table 1.

Mean (SD) age of study subjects was 60 (17.0) years; 72% were nonwhite, and 58% were males. Prevalence of selected comorbidities, including acute renal failure, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, diabetes, myocardial infarction, and peripheral vascular disease was high (>20%). Mean (SD) CURB score at admission was 1.8 (1.1); scores did not differ significantly between MRSA vs. MSSA patients. Eight patients (6%) had evidence of positive S. aureus cultures in the year prior to admission.

A total of 55 (43%) patients had positive MRSA cultures within the first 48 hours of admission, while the remainder (n = 73 [57%]) had cultures positive for MSSA. Among the 55 patients with MRSA, 23 (42%) had USA300 MRSA strains that produced PVL toxin. Only 18% of MRSA patients had MICs to vancomycin of 1 g/mL; most remaining patients (73%) had 1.5 g/mL MIC values. Thirty‐one patients (24%) died prior to hospital discharge (Table 2). Eighty‐eight (69%) patients received mechanical ventilation, and 79% were admitted to ICU; 25% of patients underwent thoracic surgery for pneumonia. Mean (SD) length of stay in hospital was 17.0 (15.7) days, and mean (SD) total charges per hospitalization were $127,922 ($154,605). (Mean length of stay in hospital was 5.8 days for all 3894 patients with a principal discharge diagnosis of pneumonia, and mean total charges were $29,448).

Notwithstanding the fact that patients with MRSA were more than twice as likely to receive inappropriate initial therapy (44% for MRSA vs. 18% for MSSA; odds ratio [OR], 3.57; 95% confidence interval [CI], 1.607.97; P = 0.0015), there were no statistically significant differences in in‐hospital mortality (26% for MSSA vs. 22% for MRSA; P = 0.678), surgery for pneumonia (26% vs. 24%; P = 0.838), or admission to ICU (82% vs. 74%; P = 0.382). Patients with MSSA CAP were more likely to receive mechanical ventilation (77% vs. 58%; P = 0.034). Mean (SD) total charges per admission did not differ between patients with MSSA vs. MRSA CAP ($135,784 [$170,046] vs $117,489 [$132,164], respectively [P = 0.510]). (30‐day mortality following hospital discharge was 24% for MRSA CAP patients and 30% for MSSA CAP patients.)

Among patients with MRSA CAP, there were no notable differences in outcomes between those with strains with the PVL toxin vs. those without it (Table 2). Mean (SD) length of stay in hospital, however, was significantly longer among the former patients (25 [22.6] days vs. 13 [7.7] days for those without PVL toxin; P = 0.020). Reflecting this difference, mean (SD) total charges per admission were $76,909 higher among MRSA patients with PVL‐positive strains vs. those with PVL‐negative strains ($162,124 [$186,923] vs. $85,215 [$57,957] respectively; P = 0.066).

Among MRSA patients with MICs to vancomycin of 1.5 g/mL, 17% died in hospital, 20% underwent surgery for pneumonia, 60% received mechanical ventilation, and 75% were admitted to ICU. Mean (SD) total charges per admission were $104,514 ($112,606) (Table 2).

Discussion

To the best of our knowledge, this is the largest observational study to date of outcomes in patients with S. aureus CAP. Our results indicate that MRSA represents almost one‐half of all such infections, with USA300 strains accounting for a substantial proportion of these cases. In addition, for most outcome measures, there were no significant differences between patients with MSSA vs. MRSA CAP. In patients with MRSA CAP, however, those with PVL‐positive strains had longer stays in the hospital and had higher total costs of hospitalization.

Our study highlights the significant clinical and economic burden of S. aureus CAP. In the US, the mortality rate in patients hospitalized with CAP is about 8%, while mean length of stay is approximately 5 days (it was 5.8 days in our institution among all patients with CAP). In contrast, we found that most patients with S. aureus CAP were admitted to ICU, and that nearly one in four died during hospitalization. One possible explanation for these findings is that patients with S. aureus CAP may often receive inappropriate initial antibiotic therapy, a major predictor of adverse outcome in infection. The overall rate of inappropriate treatment, however, was low in our study (although we note that optimal antibiotic treatment is not clearly defined for the USA300 strain, and as a result, we assumed that vancomycin would be appropriate for all MRSA infections). A more likely explanation for our findings is the severity of CAP associated with S. aureus, whether MRSA or MSSA. Given the nature of S. aureus infections, the need for prevention (and potentially, development of a vaccine) remains crucial.

While MRSA has been studied extensively as a cause of bacteremia, as well as HCAP and VAP, it has not been well studied in CAP. Patients with MRSA bacteremia have been shown to have a higher mortality risk and higher healthcare costs than those with MSSA infections, and a meta‐analysis of 31 studies of patients with S. aureus bloodstream infections demonstrated a significant increase in mortality among patients with MRSA vs. MSSA bacteremia.1820 Outcomes when comparing MRSA and MSSA in VAP are slightly more variable. A higher rate of mortality has been reported in patients with pneumonia caused by MRSA vs. MSSA, but others found no difference after controlling for potential confounders.21, 22 We found that case fatality, surgery for pneumonia, ICU admission, length of stay, and total hospital charges do not differ significantly between patients with MRSA vs. MSSA CAP. This suggests that appreciation of the burden of MRSA can only be done in the context of the syndrome in question, and that conclusions from analyses of bacteremia and VAP may not be generalizable to CAP.

In the US, an increasing number of community‐associated infections are due to MRSA. Skin and skin structure infections comprise the majority of community‐associated MRSA infections and are caused by a single pulsed field type, termed USA300. These strains are believed to have distinctive virulence and epidemiologic characteristics. USA300 isolates typically are resistant only to beta‐lactam and macrolide antimicrobial agents and contain genes for the PVL toxin, which typically are not present in strains of healthcare‐associated MRSA.23 Recent studies of acute pneumonia with animal models and in humans have suggested that the PVL toxinalone or in combination with other virulence factorsis associated with the development of necrotizing pneumonia.2430 In our study, 23 patients with MRSA CAP had strains that contained PVL toxin, and these patients had longer stays in hospital and higher total hospital charges than those with MRSA CAP not containing the PVL toxin. This is an important finding, as length of stay is an important proxy for morbidity and case severity. This also extends the finding of previous case studies reporting that MRSA CAP with PVL toxin is associated with worse outcomes.2430 Moreover, we clearly document that PVL‐positive strains are emerging as a cause of pulmonary infection in broader clinical scenarios. As such, physicians must remain vigilant for this toxin‐producing strain. The full extent of the impact of PVL‐positive strains in our study is unknown, as we cannot ascertain whether morbidity was worse because of the PVL toxin itself, or because most patients were not treated with clindamycin or linezolid, which inhibit toxin production.

We failed to observe a correlation between MICs to vancomycin and the outcomes we studied. The clinical significance of reduced susceptibility of S. aureus to vancomycin remains a controversial issue. In our study, there was no significant association between MICs to vancomycin and mortality, need for surgery, ICU admission, length of stay, or total hospital charges. Sakoulas et al.11 reported that as vancomycin MICs for MRSA isolates rose within the susceptible range from 0.5 mcg/mL to 2.0 mcg/mL, so too did the number of clinical failures among bacteremic patients receiving vancomycin. Moise‐Broder et al.31 reported a similar finding in a study of 63 patients with MRSA bacteremia, of whom 45 failed or were intolerant of vancomycin therapy. In a more recent report, Soriano et al.12 prospectively evaluated 414 episodes of bacteremia. The authors concluded that mortality in patients with MRSA bacteremia is significantly higher when the empiric antimicrobial agent is inappropriate and when vancomycin is used to treat infections involving strains with MICs >1.0 mcg/mL. In pneumonia, Hidayat et al.13 reported that patients with infections due to pathogens with higher MICs to vancomycin had a higher rate of mortality than those with lower MICs. Our findings likely differ from this report because of the proportion of subjects with PVL‐positive strains, and because of the skew in the distribution of vancomycin MICs. More specifically, the majority of patients had higher MIC strains, clustered around 1.5 mg/L, leaving us with few lower MIC strains and fewer strains with MICs of 2.0 mcg/mL for comparison, and therefore limited statistical power to assess the relationship between MICs and outcomes.

There were no clinical features that clearly distinguished patients with MRSA vs. MSSA CAP. This suggests that if physicians hope to ensure that patients with MRSA CAP receive appropriate initial antibiotic therapy, they cannot base therapeutic decision‐making (ie, use of an anti‐MRSA treatment) on clinical criteria. Presently, national guidelines recommend diagnostic testing only if the results might affect clinical decisions (eg, antimicrobial management).32 Furthermore, the IDSA/ATS guidelines recommend sputum cultures along with blood cultures and other diagnostic tests only in select cases (eg, those with severe disease). Since beginning optimal therapy quickly can reduce mortality in pneumonia,33 our results indicate a need for both rapid diagnostic tests to identify patients with MRSA, and reevaluation of current recommendations for diagnostic testing in CAP.

Our study has several important limitations. First, its retrospective design exposes it to many forms of bias. Second, because the diagnosis of pneumonia can be challenging, we required that all patients have both clinical and radiologic evidence of the disease. However, we may have thereby excluded some admissions for S. aureus pneumonia among the over 3000 pneumonia admissions to our hospital during the study period.

Third, we only included patients with culture evidence of infection. This was necessary by design, but as a result we may have failed to identify some patients with S. aureus infections because of the limitations of respiratory culture technology. Patients on general practice units often do not get cultured, and accordingly we may have missed those with milder disease caused by S. aureus.

Fourth, we used only one method of MIC testing to determine vancomycin susceptibility. It would have been of interest to have used automated dilution testing also and to have compared both methods. Comparison of laboratory methods was not among our study objectives, and most of the earlier studies examining epidemiology and outcomes used a single laboratory testing method only.

Finally, since the study was conducted at a large urban teaching hospital in a city with a long history of issues with MRSA and resistance, the generalizability of our results may be limited.

In summary, our study provides further evidence that S. aureus is an important pathogen in CAP. MRSA CAP has few obvious characteristics that differentiate it from MSSA CAP. MRSA and MSSA CAP are both very serious infections that should be treated aggressively to avoid poor outcomes.