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Original Research: CYSTIC FIBROSIS |

Respiratory Microbiology of Patients With Cystic Fibrosis in the United States, 1995 to 2005 FREE TO VIEW

Samiya Razvi, MD; Lynne Quittell, MD; Ase Sewall, PhD; Hebe Quinton, PhD; Bruce Marshall, MD; Lisa Saiman, MD, MPH
Author and Funding Information

Affiliations: From the Department of Pediatrics (Drs. Razvi, Quittell, and Saiman), Columbia University, New York, NY; Morgan Stanley Children's Hospital of New York-Presbyterian (Drs. Razvi, Quittell, and Saiman), New York, NY; Sewall, Inc (Dr. Sewall), Bethesda, MD; the Department of Medicine (Dr. Quinton), Dartmouth Medical School, Hanover, NH; and the Cystic Fibrosis Foundation (Dr. Marshall), Bethesda, MD.

Correspondence to: Lisa Saiman, MD, MPH, Columbia University, Department of Pediatrics, 650 West 168th St, PH 4 West, Room 470, New York, NY 10032; e-mail: LS5@columbia.edu

*Currently at the Department of Pediatrics, Children's Hospital at Cleveland Clinic, Cleveland, OH.


Funding/Support: This study was funded by the US Cystic Fibrosis Foundation.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;136(6):1554-1560. doi:10.1378/chest.09-0132
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Background:  Numerous improvements in diagnostic and therapeutic strategies for patients with cystic fibrosis (CF) have occurred during the past 2 decades. We hypothesized that these changes could impact trends in respiratory microbiology.

Methods:  Data from the Cystic Fibrosis Foundation Patient Registry were used to examine trends in the incidence and prevalence of bacterial pathogens isolated from patients with CF in the United States from 1995 to 2005.

Results:  The number of patients with CF in the patient registry increased from 19,735 in 1995 to 23,347 in 2005. During the study period, the reported annual prevalence of Pseudomonas aeruginosa significantly declined from 60.4% in 1995 to 56.1% in 2005 (p < 0.001). The decline was most marked in children 6 to 10 years old (48.2 to 36.1%) and adolescents 11 to 17 years old (68.9 to 55.5%). Both the incidence (21.7% in 1995 and 33.2% in 2005) and prevalence (37.0% in 1995 and 52.4% in 2005) of methicillin-susceptible Staphylococcus aureus significantly increased and the age-specific prevalence was highest in patients 6 to 17 years old. The prevalence of methicillin-resistant S aureus increased from 0.1% in 1995 to 17.2% in 2005 and from 2002 to 2005 was highest in adolescents 11 to 17 years old. Both the prevalence and incidence of Burkholderia cepacia complex declined, while the prevalence of Haemophilus influenzae, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans increased.

Conclusions:  Data from the patient registry suggest that the epidemiology of bacterial pathogens in patients with CF changed during the study period. Future studies should continue to monitor changing trends and define the association between these trends and care practices in CF.

Figures in this Article

In patients with cystic fibrosis (CF), respiratory tract infections begin in early childhood, and methicillin-susceptible Staphylococcus aureus (MSSA), nontypeable Haemophilus influenzae, and Pseudomonas aeruginosa are the most common pathogens seen during the first decade of life. Infections with P aeruginosa and Burkholderia cepacia complex are associated with a decline in lung function and predict morbidity and mortality in CF patients,1 and methicillin-resistant S aureus (MRSA), Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans are increasingly identified as potential pathogens in patients with CF.24

During the past 2 decades, improvements have been made in diagnostic and therapeutic strategies for patients with CF. Changes include the following: improved nutrition5; the use of dornase alpha6,7; long-term suppressive therapy for patients infected with P aeruginosa with inhaled antibiotics8 and oral azithromycin9; the widespread implementation of standardized microbiology laboratory protocols to enhance the recovery and identification of CF pathogens,10,11 which is monitored during accreditation visits by the Cystic Fibrosis Foundation (CFF) center directors committee; increased surveillance for respiratory pathogens by the use of quarterly cultures10; emphasis on infection control practices10,11; and the use of antibiotics for early eradication of P aeruginosa.1214 In addition, heightened awareness of CF among pediatric health-care professionals and the implementation of newborn screening programs have lead to an earlier diagnosis of CF and a better understanding of the respiratory tract flora of young, often asymptomatic infants.1517

We hypothesized that changes in care could impact the respiratory microbiology of patients with CF. Thus, we analyzed data from the CFF Patient Registry18 to examine longitudinal trends in the epidemiology of CF respiratory pathogens in the United States.

Study Design and CFF Patient Registry

We performed a retrospective review of the CFF Patient Registry to examine trends in the reported epidemiology of bacterial pathogens from 1995 to 2005. The CFF Patient Registry is a national database of the demographic and clinical characteristics of patients cared for at approximately 169 accredited CF care centers and affiliate programs in the United States. The CFF generates annual center-specific and aggregate reports, including the age-specific prevalence of specific pathogens.

Over time, the CFF has revised data-collection strategies to evaluate potential changes in the epidemiology of respiratory pathogens. In 1996, specific data fields were added for S maltophilia, A xylosoxidans, and MRSA; prior to 1996, these organisms could be added as free text. Until 1993, only one respiratory tract culture per patient was submitted annually. Results of quarterly cultures were submitted in aggregate in 1994 and as separate culture results from 1998 to 2002. Since 2003, all culture results are submitted.

The Columbia University institutional review board approved this study. Since 2003, the institutional review board of each CF center has approved the submission of data to the CFF and the use of deidentified data for secondary analyses of the database.

Study Cohort and Case Definitions

The study cohort included patients with a confirmed diagnosis of CF19 with at least one respiratory tract culture result in the CFF Patient Registry from January 1995 to December 2005. Cultures could be negative or positive for pathogens of interest; reported as normal flora; and obtained from sputum, throat swabs, and/or BAL fluid. Data from patients who died during the study period or from patients prior to lung, heart-lung, and/or liver transplantation were included.

An incident case for a pathogen of interest was defined as a patient with a positive culture for that pathogen isolated for the first time during the study period. To limit misclassification, culture results from 1985 to 1994 were reviewed to ensure that previous respiratory tract cultures had not been positive. For example, a patient without previously positive cultures for MSSA until 1998, was considered to be an incident case of MSSA in 1998. A prevalent case for a pathogen of interest was defined as a patient with a positive culture for that pathogen during the study years. For example, a patient with positive cultures for P aeruginosa from 1990 to 1996 would be considered a prevalent case in the study years 1995 and 1996. In addition, because of changes in taxonomy, the database was analyzed by both genus and species (eg, maltophilia and cepacia).

Statistical Analysis

Overall, annual and age-specific prevalence and incidence rates were determined for P aeruginosa, MSSA, MRSA, nontypeable H influenzae, B cepacia complex, S maltophilia, and A xylosoxidans. Age categories similar to those used in the annual CFF Patient Registry (0 to 1 year old, 2 to 5 years old, 6 to 10 years old, 11 to 17 years old, 18 to 25 years old, and >25 years old) were used to examine age-specific trends. To calculate age-specific rates for incident cases, the age of patients at the time of the first positive culture was used. To calculate age-specific prevalence rates, the age of patients on December 31 of each study year was used.

To evaluate potential biases introduced by changes in data collection that were implemented during the study period, two strategies were used to calculate annual rates. In strategy 1, regardless of the number of cultures obtained from an individual patient, the incidence and prevalence of the pathogens of interest were estimated by using the results of a single negative or positive culture (ie, the culture obtained closest to each patient's date of birth). In strategy 2, annual rates were determined by using all available culture results.

To assess annual changes in the overall and age-specific incidence and prevalence, trend analyses for each pathogen were performed by utilizing logistic regressions with the year being the independent variable. Trend analyses represented a linearized annual relative change from baseline prevalence or incidence. Thus, an odds ratio of 1.02 represented an increase of 2% per year and an odds ratio of 0.98 represented a decrease of 2% per year.

Study Cohort

The number of patients with CF in the CFF Patient Registry increased from 19,735 in 1995 to 23,347 in 2005, while the median age increased from 13.1 years in 1995 to 15.1 years in 2005. The proportion of patients with data from at least one culture report ranged from 87% to 91% each year.

Prevalence and Incidence of Respiratory Pathogens

During the study period, the proportion of patients with three or more cultures per year sent to the CFF Patient Registry increased from 0.1% to 55.8% (Table 1). As shown for P aeruginosa, MSSA, and H influenzae, the prevalence rates calculated by strategy 1 (ie, using one culture result per year per patient) were consistently lower than the rates calculated by strategy 2 (ie, using all available culture results each year). Similar trends were noted in the estimated prevalence rates of other study pathogens and in the incidence rates of all pathogens of interest. Strategy 2 was used for subsequent analyses.

Table Graphic Jump Location
Table 1 Annual Prevalence Rates of P aeruginosa, MSSA, and H influenzae Determined by Results From One Culture vs All Available Cultures, 1995 to 2005

*Includes subjects who harbored both MSSA and MRSA.

The relative annual percentage change in the age-specific prevalence and incidence of CF pathogens during the study period is shown in Table 2. The age-specific prevalence rates of respiratory pathogens for the previous year are available annually on the CFF Web site (http://www.cff.org/UploadedFiles/research/ClinicalResearch/2007-Patient-Registry-Report.pdf).

Table Graphic Jump Location
Table 2 Annual Percent Change in the Prevalence and Incidence of CF Pathogens by Age Strata, 1995 to 2005
P aeruginosa

As reported to the CFF Patient Registry the prevalence of P aeruginosa significantly declined from 60.4% in 1995 to 56.1% in 2005 (p<0.001) [Table 2]. The age-specific prevalence of P aeruginosa significantly decreased among all age strata except among infants 0 to 1 year old in whom the prevalence of P aeruginosa increased during the study period (Fig 1, Table 2).

Figure Jump LinkFigure 1 Prevalence of P aeruginosa among patients with CF from different age strata, from 1995 to 2005. The prevalence of P aeruginosa among patients with CF in the United States representing six age strata is shown. These data reflect an analysis of the US CFF Patient Registry.Grahic Jump Location

The overall incidence of P aeruginosa did not change (Table 2). However, the incidence of this pathogen significantly increased among infants 0 to 1 year old from 21.5% in 1995 to 27.0% in 2005 (p<0.001) and significantly increased among children 2 to 5 years old (p = 0.041). In contrast, the incidence of P aeruginosa decreased among older children and adolescents and was unchanged among adults.

H influenzae

The overall prevalence of nontypeable H influenzae increased (Table 2), while the incidence remained stable (10.3% in 1995; 10.6% in 2005). The greatest increase in the prevalence and incidence of this pathogen occurred among young children; the prevalence of H influenzae increased during the study period among infants 0 to 1 year old from 15.2% to 27.1%, and among children 2 to 5 years old from 22.2% to 34.1%. The incidence of this pathogen also significantly increased among infants and children while declining in adolescents and adults (Table 2).

MSSA and MRSA

The reported prevalence of MSSA increased during the study period (Fig 2, Table 2) as did the incidence, which increased from 21.7% in 1995 to 33.2% in 2005. The age-specific prevalence of MSSA was highest among children 6 to 10 years old in whom the occurrence of this pathogen significantly increased from 39.5% to 63.0% (p<0.001), and among adolescents 11 to 17 years old in whom the occurrence of this pathogen increased from 42.0% to 61.0% (p<0.001). Prevalence rates for adults 18 to 25 years old were lower, but increased from 37.9% to 46.1% (p<0.001). Prevalence rates among adults >25 years old did not change during the study period. The incidence of MSSA significantly increased within all age strata, except among older adults.

Figure Jump LinkFigure 2 Prevalence of MSSA and MRSA in patients with CF, from 1995 to 2005. The prevalence of MSSA, MRSA, or both among patients with CF in the United States is shown. These data reflect an analysis of the US CFF Patient Registry.Grahic Jump Location

Similarly, the reported prevalence of MRSA significantly increased from 2.1% in 1996 to 17.2% in 2005 (p<0.001) [Fig 2], while the incidence increased from 2.0% to 6.9%. Significant increases in prevalence and incidence occurred in all age strata (Table 2). However, while the prevalence of MRSA was highest among adults 18 to 25 years old from 1996 (2.9%) to 2001 (8.3%), the prevalence was highest among adolescents 11 to 17 years old from 2002 (10.8%) to 2005 (20.9%).

B cepacia complex

During the study period, the reported prevalence of B cepacia complex significantly declined from 3.6% to 3.1% (p<0.001) [Fig 3, Table 2]. The incidence also significantly declined from 1.3% to 0.8% (p<0.001). The age-specific prevalence rates of B cepacia complex were generally highest among adults 18 to 25 years old, but declined from 8.0% in 1995 to 5.2% in 2005. Significant declines in incidence also occurred among persons 11 to 17 years old, those 18 to 25 years old, and those >25 years old (Table 2).

Figure Jump LinkFigure 3 Incidence and prevalence rates of B cepacia complex in patients with CF, from 1995 to 2005. Please note the change in the y-axis. The incidence and prevalence of B cepacia complex among patients with CF in the United States is shown. These data reflect an analysis of the US CFF Patient Registry.Grahic Jump Location
S maltophilia and A xylosoxidans

Both the overall prevalence and incidence of S maltophilia increased during the years studied (Table 2). The prevalence increased from 4.0% in 1996 to 12.4% in 2005, and the incidence increased from 2.8% to 6.4%. From 1995 to 1998, the highest prevalence rates of S maltophilia were noted among adults >25 years old (5.3% in 1995 to 6.9% in 1998), but from 1999 to 2005, the highest prevalence rates were noted among adolescents 11 to 17 years old (7.8% in 1999 to 15.8% in 2005). Similarly, from 1995 to 2005, the prevalence of A xylosoxidans increased from 1.9% to 6.0%, while the incidence increased from 1.6% to 2.6% (Table 2). The highest prevalence rates of A xylosoxidans were noted among the adult subgroups which increased from 3.4% in 1996 among adults >25 years old to 8.1% in 2005 among those 18 to 25 years old.

The data in the CFF Patient Registry provide a unique opportunity to assess potential changes in the epidemiology of respiratory pathogens in CF patients. Over the past decade, a decreased prevalence of P aeruginosa and B cepacia complex was noted, while the prevalence of H influenzae, MSSA, MRSA, S maltophilia, and A xylosoxidans increased. However, it is important to interpret these trends with caution. Changing trends may reflect true epidemiologic changes in the CF patient population, and may reflect improved laboratory detection strategies and/or more frequent culturing of the respiratory tract.

The last published analyses of respiratory microbiology data from the CFF Patient Registry were performed in 1990 and described the age-specific prevalence of the bacterial pathogens from 12,284 patients.20 This previous study reported data from approximately 79% of patients seen at CF centers and described the predominance of P aeruginosa with an overall prevalence of 60.7%. Prevalence rates of S aureus and nontypeable H influenzae were lower (28.3% and 5.5%, respectively) than the rates reported in the current study (52.4% and 17.3%, respectively). The overall prevalence of B cepacia complex was comparable (3.2%). However, this previous study was most likely biased toward sicker patients as only patients who produced sputum were included in the analysis. In addition, the prevalence of pathogens could have been underestimated as only one culture per patient per year was submitted to the CFF Patient Registry for analysis.

The current epidemiologic trends noted in the CFF Patient Registry data regarding the prevalence of P aeruginosa may reflect changes in care practices. Despite more frequent cultures, the prevalence of P aeruginosa decreased, particularly among children and adolescents 6 to 17 years of age. This observation may be suggestive of the impact of antibiotic eradication strategies for this pathogen.13,14 Refinement of the genus Pseudomonas and improved identification of non-aeruginosa species such as Pseudomonas fluorescens and Pseudomonas fluorescens21 are unlikely to account for the decreased prevalence of P aeruginosa as, on average, only 33 cultures per year (range, 1 to 70 cultures per year) were reported with non-aeruginosa pseudomonads during the study period.

The increasing prevalence of both MSSA and MRSA may reflect both increased microbiological surveillance and improved laboratory techniques, including testing all S aureus strains for resistance to methicillin. As noted in the Epidemiology Study of CF,22 care sites that performed more frequent respiratory cultures and used complete protocols for microbiological processing had higher rates of S aureus. Currently, 82% of the laboratories serving CF care sites are using selective media for S aureus, which would be expected to increase detection.11 Furthermore, it is estimated that as many as half of patients with CF harbor MRSA transiently, making it likely that increasing the frequency of cultures would improve the detection of transient colonization.23 However, the increasing prevalence of MRSA in patients with CF could be attributed to the acquisition of community-acquired MRSA (CA-MRSA) strains.24 The potential for acquisition of CA-MRSA strains among children and adolescents with CF is particularly intriguing given the increased prevalence of CA-MRSA noted in pediatric populations throughout the United States. Additional studies are needed in the CF population to continue to assess the potential for adverse outcomes due to MRSA and to distinguish hospital-acquired MRSA vs CA-MRSA.

Since the mid-1980s, the CF community has emphasized infection control strategies for patients harboring B cepacia complex to prevent patient-to-patient transmission.10 The decline in incidence and prevalence noted in the CFF Patient Registry data for B cepacia complex may reflect successful implementation of these strategies, although studies continue to demonstrate shared clones of Burkholderia species25 and incomplete adoption of infection control recommendations.26 In addition, the widespread use of the B cepacia complex Reference Laboratory and Repository, which provides speciation of B cepacia complex by molecular techniques,4 could have reduced incidence and prevalence rates by providing more accurate identification of other genuses (eg, Pandorea or Ralstonia) and minimizing the misidentification of these genuses as Burkholderia species. Nevertheless, declining trends are potentially even more reassuring in view of several factors that could be predicted to increase incidence and prevalence. These factors include the following: increased life expectancy of patients with CF; increased frequency of respiratory tract cultures; and use of selective media for B cepacia complex by nearly all laboratories in the United States.11

Standardized microbiology laboratory techniques could also impact the epidemiology of other bacterial pathogens. Since the 1980s, selective media for nontypeable H influenzae, prolonged incubation, and identification of all microorganisms in CF specimens, particularly non-lactose-fermenting, Gram-negative bacilli such as S maltophilia or A xylosoxidans, have been increasingly implemented.11,22 However, as studies have demonstrated the inaccuracies of bacterial identification by automated systems, molecular strategies are being increasingly used for these potential pathogens as well.4,10

Notably, both S maltophilia and A xylosoxidans are now more common in patients with CF than are Burkholderia species. As described for MRSA,27 the transient colonization of patients with CF with S maltophilia has been documented. Thus, increasing the frequency of cultures could increase the detection of S maltophilia. In addition, increased antibiotic use, including aerosolized antibiotics, has been shown to be a risk factor for S maltophilia.28 Notably, epidemiologic studies29 using the CFF Patient Registry have not shown a decline in lung function associated with S maltophilia. Similar studies have not yet been conducted to assess the clinical impact of A xylosoxidans in CF patients.

Our study had some limitations. We did not assess transient colonization vs chronic infection or assess the impact of CF center or region of the country. As described above, several changes in data collection (eg, new data fields for potential pathogens), clinical practice (eg, recommendations for quarterly cultures), and microbiological processing (eg, selective media) were instituted during the study period that could have resulted in the increased detection of the organisms of interest. There were several changes in bacterial taxonomy that could have influenced epidemiologic trends as staff submitting data to the CFF Patient Registry gained familiarity with new nomenclature. It is possible that rates of MSSA were inaccurate if staff coded MRSA as both S aureus and MRSA, but this was unlikely to be a widespread practice as few patients had both pathogens. We did not assess ascertainment bias due to increased culturing of more severely ill patients. During the study period, external validation of the data was not performed. Finally, our findings may not be generalizable outside of the United States.

From 1995 to 2005, the data from the CFF Patient Registry indicated that the epidemiology of respiratory microbiology in patients with CF has changed. Future studies are needed to monitor these changing trends and to better define the association among these trends, care practices, and clinical outcomes in CF patients.

CA-MRSA

community-acquired methicillin-resistant Staphylococcus aureus

CF

cystic fibrosis

CFF

Cystic Fibrosis Foundation

MRSA

methicillin-resistant Staphylococcus aureus

MSSA

methicillin-susceptible Staphylococcus aureus

Author contributions: Drs. Razvi, Quittell, Marshall, and Saiman have made substantial contributions to the conception and design of the study and Drs. Razvi, Quittell, Sewall, Quinton, Marshall, and Saiman made substantial contributions to the analysis and interpretation of data. Drs. Razvi and Saiman drafted the submitted article and Drs. Razvi, Quittell, Sewall, Quinton, Marshall, and Saiman revised it critically for important intellectual content. Drs. Razvi, Quittell, Sewall, Quinton, Marshall, and Saiman have provided final approval of the version to be published.

Financial/nonfinancial disclosures: Dr. Quittell has received grant funding from the CFF and served as a consultant to Novartis and received an honorarium. Dr. Quinton has received grant funding from the CFF. Dr. Marshall has no conflicts of interest to disclose. Dr. Saiman has received grant funding from the CFF, Chiesi Pharmaceuticals, and Bayer Pharmaceuticals and received honorarium from Chiesi, Novartis, Gilead, Transave Pharmaceuticals, and Smith Kline Beecham. Dr. Razvi has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The CFF Patient Registry data set is made possible through the dedicated work of the Clinic Coordinators at CF Centers across the United States. The authors thank Dr. Jeff Wagener for helpful conversations about the data analysis.

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Goss CH, Rosenfeld M. Update on cystic fibrosis epidemiology. Curr Opin Pulm Med. 2004;10:510-514. [PubMed]
 
LiPuma JJ. Expanding microbiology of pulmonary infection in cystic fibrosis. Pediatr Infect Dis J. 2000;19:473-474. [PubMed]
 
LiPuma JJ. Burkholderia and emerging pathogens in cystic fibrosis. Semin Respir Crit Care Med. 2003;24:681-692. [PubMed]
 
Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689. [PubMed]
 
Paul K, Rietschel E, Ballmann M, et al. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am J Respir Crit Care Med. 2004;169:719-725. [PubMed]
 
Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168:918-951. [PubMed]
 
Ramsey BW, Dorkin HL, Eisenberg JD, et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993;328:1740-1746. [PubMed]
 
Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected withPseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290:1749-1756. [PubMed]
 
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Zhou J, Garber E, Desai M, et al. Compliance of clinical microbiology laboratories in the United States with current recommendations for processing respiratory tract specimens from patients with cystic fibrosis. J Clin Microbiol. 2006;44:1547-1549. [PubMed]
 
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Figures

Figure Jump LinkFigure 1 Prevalence of P aeruginosa among patients with CF from different age strata, from 1995 to 2005. The prevalence of P aeruginosa among patients with CF in the United States representing six age strata is shown. These data reflect an analysis of the US CFF Patient Registry.Grahic Jump Location
Figure Jump LinkFigure 2 Prevalence of MSSA and MRSA in patients with CF, from 1995 to 2005. The prevalence of MSSA, MRSA, or both among patients with CF in the United States is shown. These data reflect an analysis of the US CFF Patient Registry.Grahic Jump Location
Figure Jump LinkFigure 3 Incidence and prevalence rates of B cepacia complex in patients with CF, from 1995 to 2005. Please note the change in the y-axis. The incidence and prevalence of B cepacia complex among patients with CF in the United States is shown. These data reflect an analysis of the US CFF Patient Registry.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Annual Prevalence Rates of P aeruginosa, MSSA, and H influenzae Determined by Results From One Culture vs All Available Cultures, 1995 to 2005

*Includes subjects who harbored both MSSA and MRSA.

Table Graphic Jump Location
Table 2 Annual Percent Change in the Prevalence and Incidence of CF Pathogens by Age Strata, 1995 to 2005

References

Emerson J, Rosenfeld M, McNamara S, et al. Pseudomonas aeruginosaand other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34:91-100. [PubMed] [CrossRef]
 
Goss CH, Rosenfeld M. Update on cystic fibrosis epidemiology. Curr Opin Pulm Med. 2004;10:510-514. [PubMed]
 
LiPuma JJ. Expanding microbiology of pulmonary infection in cystic fibrosis. Pediatr Infect Dis J. 2000;19:473-474. [PubMed]
 
LiPuma JJ. Burkholderia and emerging pathogens in cystic fibrosis. Semin Respir Crit Care Med. 2003;24:681-692. [PubMed]
 
Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689. [PubMed]
 
Paul K, Rietschel E, Ballmann M, et al. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am J Respir Crit Care Med. 2004;169:719-725. [PubMed]
 
Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168:918-951. [PubMed]
 
Ramsey BW, Dorkin HL, Eisenberg JD, et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993;328:1740-1746. [PubMed]
 
Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected withPseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290:1749-1756. [PubMed]
 
Saiman L, Siegel J. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. Infect Control Hosp Epidemiol. 2003;24:S6-S52. [PubMed]
 
Zhou J, Garber E, Desai M, et al. Compliance of clinical microbiology laboratories in the United States with current recommendations for processing respiratory tract specimens from patients with cystic fibrosis. J Clin Microbiol. 2006;44:1547-1549. [PubMed]
 
Gibson RL, Emerson J, McNamara S, et al. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Respir Crit Care Med. 2003;167:841-849. [PubMed]
 
Taccetti G, Campana S, Festini F, et al. Early eradication therapy againstPseudomonas aeruginosain cystic fibrosis patients. Eur Respir J. 2005;26:458-461. [PubMed]
 
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