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(Chest. 2004;125:410-417.)
© 2004 American College of Chest Physicians

Epidemiology of Nosocomial Pneumonia in Infants After Cardiac Surgery*

Linhua Tan, MD; Xiaonan Sun, MD; Xiongkai Zhu, MD; Zewei Zhang, MD; Jianhua Li, MD and Qiang Shu, MD, PhD

* From the Departments of Surgical Intensive Care Unit (Dr. Tan) and Cardiothoracic Surgery (Drs. Zhu, Zhang, Li, and Shu), Affiliated Children’s Hospital; and Affiliated Sir Run Run Shaw Hospital (Dr. Sun), School of Medicine, Zhejiang University, Hangzhou, China.

Correspondence to: Linhua Tan, MD, Director, Department of Surgical Intensive Care Unit, Affiliated Children’s Hospital, School of Medicine, Zhejiang University, No. 57# Zhu Gan Xiang, Hangzhou, China 310003; e-mail: suntan{at}mail.hz.zj.cn


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Background: The pattern of nosocomial pneumonia (NP) in infants in a pediatric surgical ICU after cardiac surgery may differ from that seen in adult ICUs.

Study objectives: The primary aim of this study was to describe the epidemiology of NP in infants after cardiac surgery and, secondarily, to describe the changes of the distribution and antibiotic resistance of the pathogen during the last 3 years.

Methods: Data were collected between June 1999 and June 2002 from 311 consecutive infants who underwent open-heart surgery in our hospital. We retrospectively analyzed the distribution and antibiotic resistance pattern of all the pathogenic microbial isolates cultured from lower respiratory tract aspirations.

Results: Of 311 infants, 67 patients (21.5%) acquired NP after cardiac surgery. The incidence of NP was more frequently associated with complex congenital heart defect (CHD) compared to simple CHD (43% vs 15.9%, {chi}2 = 22.47, p < 0.0001). The proportion of late-onset NP was higher in patients with complex CHD ({chi}2 = 6.02, p = 0.014). A total of 79 pathogenic microbial strains were isolated. Gram-negative bacilli (GNB) were the most frequent isolates (68 isolates, 86.1%), followed by fungi (6 isolates, 7.6%) and Gram-positive cocci (5 isolates, 6.3%). The main GNB were Acinetobacter baumanii (11 isolates, 13.9%), Pseudomonas aeruginosa (10 isolates, 12.7%); other commonly seen GNB were Flavobacterium meningosepticum (7 isolates, 8.9%), Klebsiella pneumoniae (7 isolates, 8.9%), Escherichia coli (6 isolates, 7.6%), and Xanthomonas maltophilia (5 isolates, 6.2%). The most commonly seen Gram-positive cocci were Staphylococcus aureus (2 isolates, 2.5%) and Staphylococcus epidermidis (2 isolates, 2.5%). The frequent fungi were Candida albicans (5 isolates, 6.3%). Most GNB were sensitive to cefoperazone-sulbactum, piperacillin-tazobactam, imipenem, ciprofloxacin, amikacin. The bacteria producing extended spectrum ß-lactamases were mainly from K pneumoniae and E coli; the susceptibility of ESBL-producing strains to imipenem was 100%. There were one case of methicillin-resistant S aureus (MRSA) and 1 case of methicillin-resistant S epidermidis; their susceptibility to vancomycin, gentamycin, and ciprofloxacin were 100%. From 1999 to 2002 in infants with NP after open-heart surgery, there was a trend of increasing frequency of multiresistant GNB such as A baumanii, P aeruginosa, and K pneumoniae. However, no remarkable changes of distribution were found in Gram-positive cocci and fungi in the 3-year period. Early onset episodes of NP were frequently caused by Haemophilus influenzae, methicillin-sensitive S aureus, and other susceptible Enterobacteriaceae. Conversely, in patients who acquired late-onset NP, P aeruginosa, A baumannii, other multiresistant GNB, MRSA, and fungi were the predominant organisms.

Conclusions: The pattern of pathogens and their antibiotic-resistance patterns in NP in infants after cardiac surgery had not shown an increasing prevalence of Gram-positive pathogens as reported by several adult ICUs. GNB still remained the most common pathogens during the last 3 years in our hospital. There was a trend of increasing antibiotic resistance in these isolates.

Key Words: antibiotic resistance • cardiac surgery • epidemiology • infant • nosocomial pneumonia


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Pediatric cardiovascular surgical ICUs differ from adult ICUs in a number of ways, apart from the age of their patients. First, they frequently lack the physical barriers between patients now commonly present in adult ICUs. Second, a smaller proportion of patients have irreversible diseases as often seen in adults.1 The majority of children in pediatric cardiovascular surgical ICUs will, if successfully treated, return to a normal productive life. Nosocomial pneumonia (NP) represents an important cause of morbidity and mortality in this population2 and increases hospital costs. The overall mortality attributed to NP has been estimated at 11%.3 The prior administration of antibiotics, particularly broad-spectrum antibiotics such as third-generation cephalosporins, has recently become recognized as an important risk factor for NP caused by antibiotic-resistant Gram-negative bacilli (GNB).4 5 6 7 This report describes the epidemiology of NP in infants after cardiac surgery. Special emphasis will be directed toward the trend of the changing distribution of the pathogen and its antibiotic resistance pattern during the last 3 years.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Setting
This was a retrospective study using prospectively collected data performed at the pediatric cardiovascular surgical ICU in a 580-bed teaching children’s hospital.

Patients
Data were collected on 311 consecutive infants (age, 8 days to 12 months) with congenital heart defect (CHD) who underwent open-heart surgery in our hospital between June 1999 and June 2002.

Sampling
Surveillance Samples:
All patients were monitored for NP after cardiac surgery by clinical standards and also by quantitative cultures of endotracheal aspirate. The technique of endotracheal aspiration was a simplified nonbronchoscopic diagnostic procedure (a blind procedure via a sterile suction catheter).

Diagnostic Samplings:
NP was considered ICU associated if it developed 48 h after ICU admission or within 48 h of discharge from the unit, unless the clinical evidence strongly suggested otherwise. NP was defined8 as the presence of a new or progressive radiographic infiltrate developed in conjunction with one of the following: radiographic evidence of pulmonary abscess formation (ie, cavitation within preexisting pulmonary infiltrates); histologic evidence of pneumonia in lung tissue; presence of a positive quantitative culture of a sample of secretions from the lower respiratory tract; or two of the following clinical criteria in the absence of an alternative explanation for the pulmonary infiltrates: fever, leukocytosis, and purulent tracheal aspirate. In this report, the time of onset of NP (< 5 days or >= 5 days after ICU admission) was used to define as early-onset or late-onset NP.

Microbiological Methods
NP was diagnosed based on result of a quantitative culture yielding >= 105 cfu/mL. Quantitative cultures of the bronchial aspirate were performed in all cases, used to differentiate low concentration contaminants of endotracheal tube-colonizing organisms from higher concentration pathogenic organisms. After identifying the pathogenic microbial isolates, in vitro antibiotic resistance to commonly used antibiotics was determined following the annually published National Committee for Clinical Laboratory Standards.9

Statistical Analysis
{chi}2 statistics was used for categorical variables; when not appropriate, Fisher exact test was used. Differences between groups were considered to be significant for variables yielding a p value < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Demographic Variables
A total of 311 consecutive infants with CHD who underwent open-heart surgery were enrolled in the study. Sixty-seven patients (including 28 patients with complex CHD and 39 patients with simple CHD; Table 1 ) acquired NP. The incidence rate of NP was 21.5%. NP more frequently occurred in patients with complex CHD compared to simple CHD (43% vs 15.9%, {chi}2 = 22.47, p < 0.0001) [Table 2 ]. The proportion of late-onset NP was higher in patients with complex CHD ({chi}2 = 6.02, p = 0.014) [Fig 1 ].


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  		Table 1. Underlying CHD of Patients With NP*

 

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  		Table 2. Different Incidence Rate of NP in Patients Between Complex CHD and Simple CHD

 


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  		Figure 1. The proportion of early and late-onset NP in two underlying cardiac conditions. The upper pie represents 39 patients with simple CHD and NP, and the lower pie represents 28 patients with complex CHD and NP. Percentage within the pies represent the proportion of early onset pneumonia (open area) compared to late-onset pneumonia (shaded area). The proportion of late-onset pneumonia was higher in patients with complex CHD ({chi}2 = 6.02, p = 0.014).

 
Distribution of Pathogens
As depicted in Table 3 , from June 1999 to June 2002, among 311 consecutive infants, 79 pathogenic microbial strains were isolated from endotracheal aspirates in 67 NP cases. Among all isolates, GNB were the most prevalent pathogens (68 isolates, 86.1%), followed by fungi (6 isolates, 7.6%) and Gram-positive cocci (5 isolates, 6.3%). The most frequent GNB were Acinetobacter baumanii (11 isolates, 13.9%), Pseudomonas aeruginosa (10 isolates, 12.7%); other commonly seen GNB were Flavobacterium meningosepticum (7 isolates, 8.9%), Klebsiella pneumoniae (7 isolates, 8.9%), Escherichia coli (6 isolates, 7.6%), and Xanthomonas maltophilia (5 isolates, 6.2%). The most frequent Gram-positive cocci were Staphylococcus aureus (two isolates, 2.5%) and Staphylococcus epidermidis (two isolates, 2.5%). The most frequent fungi were Candida albicans (five isolates, 6.3%).


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  		Table 3. Pathogen Distribution (1999 to 2002)

 
Antibiotic Resistance of GNB
Table 4 shows the antibiotic resistance of GNB to commonly used antibiotics. The susceptibility of causative GNB to cefoperazone-sulbactum, piperacillin-tazobactam, imipenem, and ciprofloxacin ranged from 62 to 74%; amikacin and ceftazidime had 50 to 60% susceptibility; other antibiotics such as ticarcillin-clavulanic, cefotaxime, ceftriaxone sodium, gentamycin, and sulfamethoxazole had susceptibility as low as 40%. Imipenem and cefoperazone-sulbactum had susceptibility to A baumanii as high as 82%. P aeruginosa was resistant to most third-generation cephalosporins, amikacin, and sulfamethoxazole. Almost 100% of X maltophilia and F meningosepticum were resistant to imipenem, and they also were resistant to third-generation cephalosporins, aminoglycosides, and sulfamethoxazole. The bacteria producing extended spectrum ß-lactamases (ESBLs) were mainly from K pneumoniae and E coli; approximately 42.9% of K pneumoniae and 33.3% of E coli produced ESBLs; the ESBL-producing strains were resistant to all first-, second-, third-, and fourth-generation cephalosporins and penicillins, but the susceptibility of ESBL-producing strains to imipenem was 100%.


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  		Table 4. Antibiotic Resistance of GNB Against Commonly Used Antibiotics*

 
Antibiotic Resistance of Gram-Positive Cocci
Table 5 depicted the antibiotic resistance of Gram-positive cocci. Gram-positive cocci were susceptible to vancomycin, gentamycin, ciprofloxacin, amikacin, rifampin, and ampicillin-sulbactam, whereas they had relatively higher antibiotic resistance rate to penicillin G, erythromycin, clindamycin, oxacillin sodium, and sulfamethoxazole. There were one case of methicillin-resistant S aureus (MRSA) and 1 case of methicillin-resistant S epidermidis (MRSE); their susceptibility to vancomycin, gentamycin, and ciprofloxacin were 100%.


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  		Table 5. Antibiotic Resistance of Gram-Positive Cocci Against Commonly Used Antibotics

 
Temporary Changes of Pathogen Distribution and Antibiotic Resistance
From June 1999 to June 2002 in our unit, in infants who had NP after open-heart surgery, we observed changes in the distribution of pathogens and antibiotic resistance (Table 6 ). GNB were the most frequent isolates for all species. There was a trend of increasing frequency of A baumanii, P aeruginosa, and K pneumoniae, which have broad antibiotic resistance. The frequency of A baumanii increased from 5.3 to 27.3%, P aeruginosa increased from 5.3 to 15.2%, and K pneumoniae increased from 5.3 to 15.2%. However no remarkable changes in Gram-positive cocci and fungi distribution were observed in the 3-year period.


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  		Table 6. Changes of Pathogen Distribution in 3- Year Period (1999 to 2002)*

 
Impact of Early- or Late-Onset NP on the Type of Microorganisms
Early-onset episodes of NP were caused by Haemophilus influenzae, methicillin-sensitive S aureus (MSSA) and other susceptible Enterobacteriaceae. Conversely, in patients with late-onset NP, P aeruginosa, A baumannii, other multiresistant GNB, MRSA, and fungi were frequently the causes (Table 7 ).


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  		Table 7. The Impact of Early or Late-Onset Pneumonia on the Type of Microorganisms*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Many studies have noted the development of pneumonia was closely associated with severity of the underlying disease.10 11 12 13 In our study, NP in infants after cardiac surgery was more frequently found in patients with underlying complex CHD. This may due to recurrent pneumonia before operation, longer surgical procedure, and prolonged mechanical ventilation after surgery in these patients. Early- onset episodes of NP were caused frequently by H influenzae, MSSA, and other susceptible Enterobacteriaceae, while late-onset episodes were frequently caused by P aeruginosa, A baumannii, other multiresistant GNB, MRSA, and fungi similar to other studies.14 15 16

More recently, however, some investigators have reported that Gram-positive bacteria have become increasingly more common; the percentage of Gram-positive cocci, especially MRSA, MRSE, and enterococci, increased. Meanwhile, the percentage of GNB decreased; for example, former commonly seen GNB, P aeruginosa was less frequent in several adult ICUs.7 17 18 19 20 This has not been found in all ICUs. In this survey, we described the epidemiology of NP in infants after cardiac surgery. The specimens were obtained through endotracheal aspirate via a sterile suction catheter by using a simplified blind procedure to prevent oropharynx contamination. Quantitative cultures of tracheal aspirates were used to differentiate low-concentration contaminants of endotracheal tube colonizing organisms from higher-concentration pathogenic organisms. During the past 3 years, in infants with NP after open-heart surgery, GNB were the most commonly seen isolates, followed by fungi and Gram-positive cocci. In the 3-year period, there was a trend of increasing frequency of A baumanii, P aeruginosa, and K pneumoniae, which were multidrug resistant to antibiotics. However, no remarkable changes of pathogen distribution were observed in Gram-positive cocci and fungi during the past 3 years. These results showed that the spectrum of NP in infants after cardiac surgery had not seen an increasing prevalence of Gram-positive pathogens as reported by several adult ICUs.

Acinetobacter organisms were the prevalent GNB in this population. A baumanii was more widely resistant to antimicrobial agents than other Acinetobacter organisms because of the selective pressure of commonly used third-generation cephalosporins.21 This report suggests imipenem and cefoperazone-sulbactum maybe the first choice for A baumanii, with antimicrobial activity equal to 92%.

P aeruginosa was another predominant pathogen of NP in infants after cardiac surgery. Its antibiotic resistance increases22 and presents clinicians with a real challenge for treatment. The risk of infection by Pseudomonas organisms may be due to the following: immature and low body weight of infants, severe underlying medical and surgical conditions, recurrent pneumonia before surgery, malnutrition, endotracheal intubation or tracheotomy, and prolonged usage of mechanical ventilation. Additional factors include treatment with antacids and/or histamine type 2 blockers that influence gastric pH and cause oropharyngeal and tracheal colonization,23 and previous use of antibiotics especially the extended-spectrum antibiotics that destroy normal intestinal microbial flora.24 This report showed that P aeruginosa had high resistance to ticarcillin-clavulanic, amoxicillin-clavulanate, cefotaxime, ceftriaxone, and sulfamethoxazole, but was sensitive to aminoglycoside, ceftazidime, piperacillin-tazobactam, imipenem, and cefoperazone-sulbactum.

Among multiresistant GNB, X maltophilia is a serious concern25 26 27 28 because it is resistant to imipenem as well as to most ß-lactam antibiotics. This report showed the resistance rate of X maltophilia to imipenem was as high as 100%. In addition, its resistance rate to aminoglycoside, cefotaxime, ceftriaxone, piperacillin-tazobactam was 80%, and approximately 60% resistant to sulfamethoxazole. Cefoperazone-sulbactum, ceftazidime, ciprofloxacin, and ticarcillin-clavulanic can be selected to treat X maltophilia with antimicrobial susceptibility of 80%, 60%, 60%, and 60%, respectively.

F meningosepticum is another frequent multiresistant GNB29 30 in infants after cardiac surgery. Its resistance rates to imipenem, ceftazidime, cefotaxime, and gentamycin were 100%; its resistance rates to amikacin, sulfamethoxazole, ticarcillin-clavulanic, and amoxicillin-clavulanate were all > 80%. The most effective antibiotics selected to treat it are piperacillin-tazobactam, cefoperazone-sulbactum, and ciprofloxacin; their susceptibility rates are 86%, 86%, and 57%, respectively.

Many studies have focused on ESBLs, which are mainly produced by K pneumoniae and E coli,31 32 33 but also on the Enterobacter organisms,34 35 which produce high-level class I cephalosporinase. This report showed these bacteria were also commonly seen in infants after cardiac surgery. K pneumoniae and E coli usually confer resistance to all ß-lactam antibiotics except for imipenem. There could be high mortality if the infection caused by ESBL-producing GNB could not be effectively controlled. The risk factors associated with ESBL-producing GNB infection are as follows: prolonged or prophylactic exposure to antibiotics, long duration of stay in ICU, and use of third-generation cephalosporins. ESBL-producing GNB are broadly resistant to third- and fourth-generation cephalosporins. Alternative antimicrobials that may be considered for use in these patients with ESBL-producing strains include lactamase inhibitor combinations and imipenem. In addition, the Enterobacter organisms easily become resistant to third-generation cephalosporins and lactamase inhibitor combinations through the mechanisms of chromosomal mutations and high-level production of cephalosporinase, but they remain sensitive to imipenem and fourth-generation cephalosporins.

In recent years, bacteremic pneumonia due to MRSA or MRSE is a serious concern of NP.36 The emergence of MRSA and MRSE may due to the following: (1) the character of intrinsic broad antimicrobial resistance of MRSA and MRSE, and (2) the extensive usage of third-generation cephalosporins,34 because these kind of antibiotics not only have weak effects on Gram-positive cocci but also select for emergence of MRSA and MRSE. The resistance of MRSA and MRSE can be induced by the usage of penicillins and cephalosporins. So far, the most effective drug to treat MRSA and MRSE is vancomycin; the rate of vancomycin-resistant staphylococci remains quite rare.6 37 The data of our report showed that in our unit, MRSA and MRSE were all susceptible to vancomycin.

Regarding fungal infection,38 40 it is considered to be caused by extensive use of extended-spectrum antibiotics. This report showed fungi were the second most frequent isolate of pneumonia in infants after cardiac surgery. The main type of fungi was C albicans. The fungal infections may be underreported because routine culture medium is not suitable for the growth of fungi. Furthermore, the growth of fungi generally requires 2 weeks, so there were less fungal isolates cultured in these data. There are difficulties in treating fungal infections because antifungal drugs often are less effective and have severe side effects. When patients are treated with extended-spectrum antibiotics, it is more important to prevent secondary fungal infections than to treat them.

Our study has three limitations. Firstly, the low number of isolates of Gram-positive cocci as well as GNB limits the generalizability of the findings. Similar limitation with the low number of Gram-negative isolates. Secondly, the technique of endotracheal aspiration was a simplified nonbronchoscopic diagnostic procedure (a blind procedure via a sterile suction catheter). Although quantitative culture of aspirates were performed in all cases and the cut-off value was set at 105 cfu/mL, the endotracheal aspirate may be contaminated by organisms colonizing the endotracheal tube. Thirdly, in this study it was regarded as same pathogen if an identical isolate was cultured in a patient within 1 week of another culture and not tested for antibiotic resistance again. It represents a possible limitation because the resistance pattern, even within the same pathogen, may change over a relatively short period of time, particularly in patients receiving antibiotic therapy.

When the patient is suspected of having NP after cardiac surgery, it is essential to carry out the microbial examination of tracheal aspirate as soon as possible. Meanwhile, empiric antibiotic treatment23 should be started. The empiric treatment chosen depends on the microbial spectrum of NP in the ICU and antibiotic resistance pattern, as well as the correct clinical diagnosis. Local epidemiologic data should be considered for the optimal selection of initial antibiotic therapy. Rational use of antibiotics shorten ICU stay, and decrease mortality and hospitalization expenses. Thus, a knowledge of the epidemiology of NP in infants after cardiac surgery has great clinical significance. Even so, it is necessary to distinguish infection from systemic inflammatory reaction syndrome reported in many studies.41 42 In systemic inflammatory reaction syndrome, there is no need for antibiotics.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
The pattern of microbial pathogens in NP in infants after cardiac surgery has not seen an increasing prevalence of Gram-positive pathogens as reported by several adult ICUs. GNB still remains the most common pathogens during the past 3 years in our study. There was a trend of increasing antibiotic resistance of these isolates. Understanding of the epidemiology, changes of pathogen distribution, and antibiotic resistance profile promotes rational use of antibiotics. This is crucial to reduce drug resistance, mortality, and hospital costs. Antimicrobial agents selected for treatment of NP should be effective against any likely pathogen but should not promote the development of further resistance.


   Acknowledgements
 
The authors thank Dr. David McFadden from Loma Linda University Medical Center for helpful comments on the article. The authors also thank Xiaojun He, Caiyun Zhang, Shanshan Shi, for help with data collection, and all of the contributing intensivists and nurses.


   Footnotes
 
Abbreviations: CHD = congenital heart defect; ESBL = extended spectrum ß-lactamase; GNB = Gram-negative bacilli; MRSA = methicillin-resistant Staphylococcus aureus; MRSE = methicillin-resistant Staphylococcus epidermidis; MSSA = methicillin-sensitive Staphylococcus aureus; NP = nosocomial pneumonia

Financial support provided by Science and Technology Committee Fund of Zhejiang Province, China (No. 2003C33022).

Received for publication February 11, 2003. Accepted for publication September 5, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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