PEDIATRICS Vol. 117 No. 2 February 2006, pp. 340-348 (doi:10.1542/peds.2005-0333)
Persistent Bacteremia and Severe Thrombocytopenia Caused by Coagulase-Negative Staphylococcus in a Neonatal Intensive Care Unit
a Division of Neonatology, Department of Pediatrics, Children's and Women's Health Centre of British Columbia, University of British Columbia, Vancouver, British Columbia, Canada
b Division of Infectious and Immunological Diseases, Department of Pediatrics, Children's and Women's Health Centre of British Columbia, University of British Columbia, Vancouver, British Columbia, Canada
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Coagulase-negative Staphylococcus (CoNS) is the most frequent cause of late-onset sepsis in NICUs, but mortality is rare and morbidity is unusual. We report a new syndrome of CoNS sepsis characterized by significant morbidity and persistent bacteremia despite aggressive antibiotic therapy and no identified focus of infection.
METHODS. We conducted a retrospective review of infants in the NICU with CoNS bacteremia between 2000 and 2002. Statistical analysis included an initial exploratory analysis followed by logistic regression. Microbiological identification of all isolates and molecular typing were performed.
RESULTS. Thirty-one neonates with persistent CoNS bacteremia were compared with 60 randomly selected neonates from a group of 140 with nonpersistent CoNS bacteremia. The clinical manifestations at presentation, gestational ages, and birth weights were similar in the 2 groups. Thrombocytopenia was present in 26 (84%) neonates with persistent CoNS bacteremia but only in 8 (13%) neonates in the nonpersistent group. Central venous catheterization increased the risk for persistent CoNS bacteremia, but 42% of the persistent group was never catheterized. Staphylococcus epidermidis was the most common isolate in both groups. Molecular typing failed to identify a predominant clone.
CONCLUSIONS. The syndrome of persistent CoNS septicemia is remarkable for thrombocytopenia and persistence in the absence of central venous catheterization. Clinical manifestations at presentation and demographic characteristics did not discriminate between the persistent and nonpersistent groups. We did not identify the emergence of a particularly virulent clone, but it is possible that some strains of CoNS have acquired the capacity to persist under different conditions.
Key Words: neonatal sepsis • Staphylococcus epidermidis • DNA fingerprinting
Abbreviations: CoNS—coagulase-negative Staphylococcus • VLBW—very low birth weight • PN—parenteral nutrition • WCC—white cell count • PFGE—pulsed-field gel electrophoresis • RAPD—random amplified polymorphic DNA
Coagulase-negative Staphylococcus (CoNS) is the most frequent cause of late-onset sepsis in NICUs.1–4 Most studies have shown that infections with CoNS are not associated with significant mortality or morbidity.2,5 This may be attributable to a substantial number of contaminations being reported as CoNS bacteremias, with conclusions biased accordingly. However, studies that have used clinical and laboratory parameters of sepsis in conjunction with positive blood cultures to define CoNS sepsis have also shown that the mortality and complications associated with CoNS are much lower than from other Gram-positive or Gram-negative organisms.2,3,5 Historically, CoNS has been considered to have a relatively low virulence with easy eradication of bacteremia. This coupled with growing concerns about inducing antibiotic resistance has prompted a concerted effort to minimize the use of antibiotics, especially vancomycin, in this setting.2,5–8 This notion may not hold true with regard to the very low birth weight (VLBW) NICU population of today.
We observed a striking change in the pattern of CoNS sepsis in our NICU that has been different from published reports and our own previous experience. We report a new syndrome of CoNS sepsis characterized by persistent bacteremia and severe thrombocytopenia despite aggressive antibiotic therapy and absence of any obvious endovascular focus. The aim of the present study was to describe the clinical profile of neonates with persistent CoNS bacteremia in our NICU and to determine whether a unique bacterial clone was associated with the unusual syndrome.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients
We reviewed the medical records of all neonates who were admitted to the NICU at the Children's and Women's Health Centre of British Columbia and had CoNS bacteremia between January 1, 2000, and December 30, 2002. Persistent CoNS bacteremia was defined as 3 or more consecutive positive blood cultures, at least 48 hours apart, during a single sepsis episode. Nonpersistent CoNS bacteremia was defined as 1 to 2 positive blood cultures, at least 48 hours apart, during a single sepsis episode. The demographic profile of neonates who were evaluated included gestational age, birth weight, and age at first positive blood culture. We also noted length of blood culture incubation and antibiotic susceptibility pattern.
The clinical manifestations evaluated included temperature instability (defined as temperature <36.5 or >37.5°C or a change of >1°C in a 24-hour period); respiratory deterioration (defined as increase in O2 requirement or need for escalation of respiratory therapy); and increased number of episodes of apnea, bradycardia, and/or oxygen desaturations at presentation. Feeding intolerance was defined as significant aspiration of retained gastric fluid or abdominal distension that required cessation of feeding for at least 24 hours. The risk factors for sepsis that were evaluated included endotracheal intubation, central indwelling catheterization (peripherally inserted central catheter, central venous line, umbilical artery catheter, or umbilical venous catheter), parenteral nutrition (PN), intravenous lipid emulsions, and use of postnatal steroids and histamine 2 receptor blockers. These are well-documented risk factors for neonatal sepsis.
The peripheral white cell count (WCC) was considered abnormal when it was >20 x 109/L, when the neutrophil count was <1.5 x 109/ L, or when the immature to total neutrophil ratio was >0.2. Thrombocytopenia was defined as a platelet count of <80 x 109/L and severe thrombocytopenia as a platelet count of <30 x 109/L. The WCC and neutrophil count cutoffs were based on what we use in clinical practice for evaluation of sepsis. In view of lower platelet counts in a large percentage of extremely low birth weight infants in the first weeks of life, we used a cutoff of 80 x 109/L rather than 150 x 109/L for the definition of thrombocytopenia. The cutoff for severe thrombocytopenia was based on the cutoff that we use in clinical practice for platelet transfusion in a sick neonate.
Statistical Analysis
Data from all 31 neonates in the persistent group and 60 randomly selected neonates from the 140 nonpersistent group were subjected to statistical analysis. Exploratory analysis was performed using Student's t test on the following variables and reported as group medians/means with standard errors or as percentages: gestational age, birth weight, age at onset of sepsis, presence of endotracheal intubation, central indwelling catheterization and PN, abnormal WCC and platelet counts, hours to incubation of first positive blood culture, and duration of vancomycin therapy. Variables that displayed considerable difference between the 2 groups then were evaluated by logistic regression to examine each variable independent of confounding effects of the others. Variable selection was performed at the 
= .05 level, and model selection was performed using likelihood ratio tests.
Microbiological Evaluation
Bacterial Isolates
Blood cultures were drawn from patients with suspected sepsis and processed in the hospital microbiology laboratory as per regular practice. Isolates from positive blood cultures were stored at –80°C. Of all of the isolates reported as CoNS, additional analysis was performed on 185 randomly selected isolates from 85 patients. All isolates were identified using API Staph test strips following the manufacturer's directions (bioMerieux, Inc, Durham, NC), and an aliquot of organism was frozen in TE buffer at –20°C for batched DNA extraction.
Pulsed-Field Gel Electrophoresis
Pulsed-field gel electrophoresis (PFGE) of SmaI-digested bacterial DNA on 16 isolates was performed as described before.9 DNA macrorestriction fragments were separated in pulsed-field certified agarose (Bio-Rad Laboratories, Hercules, CA) using a clamped homogeneous electric field chamber (Bio-Rad). Gel patterns were compared by eye and with the Molecular Analyst/PC fingerprinting plus software (Bio-Rad Laboratories, Mississauga, Ontario, Canada). Four band differences between patterns were considered diagnostic of different strains; a 1- to 3-band difference was interpreted as representative of subtypes. When more than 1 bacterial isolate with the same banding pattern was detected, the inferred strain was designated by a letter; when a subtype was detected, it was designated as a number after its letter type.
Random Amplified Polymorphic DNA
Random amplified polymorphic DNA (RAPD) analyses were performed on the same 16 isolates as were tested by PFGE. Isolates that previously were stored at –20°C in 1 mL of TE buffer were thawed and centrifuged, TE buffer was decanted, and the pellet was resuspended in 100 µL of lysostaphin buffer (1 mg of lysostaphin [Sigma Aldrich, Oakville, Ontario, Canada] per milliliter of filter-sterilized 25% sucrose in 10 mM TrisCl [pH 7.4]). Samples were incubated at 36°C for 30 to 60 minutes. One milliliter of 1 mg/mL lysozyme (Boehringer Mannheim, Mannheim, Germany) in TE buffer and 20 µL of 50 mg/mL proteinase K (EMD Biosciences, Inc, Madison, WI) were added to each sample and incubated at 36°C for an additional 30 to 60 minutes. A total of 100 µL of 10% SDS was added and shaken. This was followed by phenol chloroform extraction, the final aqueous phase mixed with 10% v/v of 3 M sodium acetate, and the DNA precipitated with isopropanol. The dry DNA precipitate was reconstituted in TE buffer with 0.5 µg/mL RNase (Roche Diagnostics, Laval, Quebec, Canada), and the DNA was quantified to equal 20 ng/µl. RAPD analysis with CNS2 primer GCCCCCAGGGGCACAGT10 then was performed using polymerase chain reaction conditions as described previously.11 Comparison between the PFGE and RAPD results using the same criteria as described for PFGE indicated that the RAPD method concurred well with results from PFGE analyses. An additional 105 isolates therefore were subjected only to RAPD analysis.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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A total of 31 cases of persistent and 140 cases of nonpersistent CoNS bacteremia were identified during the study period. There were 55 neonates with CoNS bacteremia in 2000, 52 in 2001, and 65 in 2002, constituting 9%, 9%, and 12% of all NICU admissions, respectively. Persistent CoNS bacteremia increased from 5.2% and 5.5% in 2000 and 2001, respectively, to 48% in 2002. The median gestational age in the persistent and nonpersistent groups was 27 and 28 weeks, respectively. The gestational age distribution in the 2 groups was as follows: 23 to 26 weeks, 45% of the persistent and 27% of the nonpersistent; 27 to 29 weeks, 32% and 36%, respectively; 30 to 32 weeks, 16% and 18%; 33 to 36 weeks, 6% and 13%; and 37 weeks or more, 0% and 3%, respectively. The corresponding median birth weights were 1049 and 1145 g, respectively. Twenty-seven of 31 neonates in the persistent group had VLBW compared with 45 in the nonpersistent group of 60. The median age at presentation with sepsis was 12 days in the persistent group and 10 days in the nonpersistent group. None of these differences was statistically significant.
The incidence of temperature instability at presentation was 60% in both groups. Twenty (64%) neonates in the persistent group presented with respiratory deterioration compared with 36 (53%) in the nonpersistent group. Increasing episodes of apnea, bradycardia, and/or oxygen desaturations as a manifestation of sepsis was seen in 21 (67%) neonates in the persistent group and 36 (60%) neonates in the nonpersistent group. Nine (29%) neonates in the persistent group had intolerance to feeding compared with 10 (16%) in the nonpersistent group. None of these differences was statistically significant. The possible risk factors and laboratory indices for sepsis of the 2 groups are shown in Table 1.
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Of the 26 neonates in the persistent group with thrombocytopenia, 22 (70%) had severe thrombocytopenia that required platelet transfusions (Fig 1). No platelet transfusions were required in the nonpersistent group. Central indwelling catheters were removed after the second positive blood culture in all but 3 of the patients with persistent cases, and bacteremia persisted from 2 to 22 days despite removal of catheters. The median duration of bacteremia in the persistent group was 12 days (range: 6–24 days) compared with 3 days (range: 2–5 days) in the nonpersistent group. The median number of positive blood cultures was 4 (range: 3–7) in the persistent group and 1 (range: 1–2) in the nonpersistent group. Echocardiography was normal in all 18 neonates who were investigated for endocarditis in the persistent group and included examination of the great vessels.
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All CoNS isolates were resistant in vitro to penicillin and 29 (93%) were resistant to oxacillin, but all were susceptible to vancomycin. All infants were treated initially with vancomycin and cefotaxime. Cefotaxime was discontinued after confirmation of CoNS. Vancomycin levels were measured, and the dose was adjusted to achieve a trough serum concentration of 5 to 10 µg/mL and a peak serum concentration of 25 to 40 µg/mL. A total of 29 (93%) of the 31 neonates with persistent bacteremia had vancomycin serum levels within the therapeutic range. In 28 (90%) neonates with persistent bacteremia, rifampin was added to the antibiotic regimen because of persistent bacteremia and thrombocytopenia, despite appropriate vancomycin levels. In 24 (86%) neonates, rifampin was added to the antibiotic regimen after the third positive blood culture and in 4 (14%) after the second positive blood culture. Five (18%) neonates were subsequently found to have negative blood cultures at initiation of rifampin therapy, and 12 (52%) of the remaining 23 had negative blood cultures within 72 hours of receiving rifampin. Rifampin was not administered to any neonate in the nonpersistent group. The median duration of vancomycin therapy in the persistent group was 22 days (range: 10–42 days) compared with 7 days (range: 1–18 days) in the nonpersistent group. The median duration of rifampin therapy was 16 days (range: 1–35 days). No deaths were related directly to CoNS bacteremia in either group.
To evaluate whether the clinically severe presentation in the persistent group was related to the clinical profile of the neonates, we compared the demographic characteristics, presence of risk factors, and clinical manifestations between the 2 groups using Student's t test. On exploratory analysis, there were substantial differences between the persistent and nonpersistent groups with regard to presence of central venous catheters, PN, and thrombocytopenia (Table 1) as well as the time to recovery of CoNS from first positive blood culture. However, multiple regression analyses revealed only 2 variables that were significantly different between the 2 groups: presence of indwelling vascular catheters with estimated odds ratio of 7.3 (95% confidence interval: 2.3–22.7) and time to positivity of first positive blood culture with estimated odds ratio of 0.81 (95% confidence interval: 0.7–0.9).
Microbiological Assessment
Bacterial isolates for additional examination were evaluated from 30 of 31 patients with persistent bacteremia and from 58 of 60 patients with nonpersistent bacteremia. The identification results of 185 isolates from 112 blood cultures are displayed in Table 2. A total of 83% of patients with persistent bacteremia and 81% of the patients with nonpersistent infection were infected with S epidermidis; of these, 43% and 71%, respectively, had only S epidermidis. A total of 17% of patients with persistent bacteremia and 21% of patients with nonpersistent infection did not have S epidermidis but had other species of CoNS, whereas 40% and 10% of these respective groups had both S epidermidis and other species. An average of 3.5 isolates were isolated per patient in the group with persistent bacteremia and 1.4 organisms per patient with nonpersistent infection. The comparison between PFGE and RAPD determined that the simpler RAPD method was sufficiently discriminatory to detect differences among strains of S epidermidis (Fig 2). Seventy S epidermidis isolates from the persistent group and 62 S epidermidis isolates from the control group were subjected to RAPD analysis. Fourteen distinct RAPD types (A, B, C, D, E, H, J, K, N, P, Q, R, T, and V) and 2 subtypes (E2 and E3) were identified. Eight types were found in both the persistent and the nonpersistent groups (A, B, C, D, E, E2, H, and T). A total of 14 patients had unique RAPD patterns, 8 of which were among the persistent group. The results in Table 3 show that RAPD types that were detected in the persistent and control groups over the examined time period did not indicate any common clones. In many cases, the greater the number of blood cultures taken from a patient, the larger the variation in strains and species of CoNS isolated. Patient P10 had 4 blood cultures taken over a period of 17 days with isolation of 3 different strains of S epidermidis and 3 different CoNS species.
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ladder; lane 2: P25 PFGE pattern A; lane 3: C25 unique; lane 4: P05 B; lane 5: P17 C2; lane 6: P20 H; lane 7: P18 C; lane 8: P19 C; lane 9: P19 E2; lane 10: C01 unique; lane 11: P20 E; lane 12: P18 E2; lane 13: P16 E; lane 14: P18 S hominis M; lane 15: P17 S hominis N. B, DNA fingerprinting of CoNS by RAPD analysis with CNS2 primer. Lanes 1 and 17: 1-kb DNA ladders; lane 2: P25 RAPD pattern A; lane 3: C25 unique; lane 4: P05 B; lane 5: P17 C; lane 6: P20 H; lane 7: P18 C; lane 8: P19 C; lane 9: P19 E2; lane 10: C01 G; lane 11: P20 E; lane 12: P18 E2; lane 13: P16 E3; lane 14: P18 S hominis M; lane 15: P17 S hominis M; lane 16: negative control.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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CoNS are the most common pathogens involved in nosocomial sepsis in NICUs.1,2,9,12–14; however, mortality is rare, and significant morbidity is unusual.2 A large 10-year prospective study of Australasian neonatal units recently reported that CoNS are relative benign and recommended that overly vigorous attempts to reduce the incidence of CoNS using prophylactic vancomycin is not advisable. Karlowicz et al5 showed that although CoNS was the most prevalent pathogen in late-onset sepsis in a group of VLBW infants, the low frequency of fulminant sepsis suggests that avoiding empiric vancomycin therapy until culture results and susceptibilities are known is a reasonable approach to management of late-onset sepsis.
In contrast to published studies, we describe a new syndrome of CoNS sepsis with significant morbidity and persistent bacteremia. The overall incidence of sepsis, in particular CoNS sepsis, during the 3-year period described was similar to previous years, suggesting that the increase in persistent bacteremia depicts a change in the pattern of CoNS sepsis rather than an increase in infection rates.
Chapman et al15 reported that 16% of cases were persistent in their series of CoNS bacteremia, which is much lower than the 48% noted in our series in 2002, although they defined persistent bacteremia as recovery of CoNS >24 hours after adequate antibiotic therapy was begun, as compared with our more stringent requirement of 3 consecutive positive cultures. Patrick et al16 reported that 33% of cases were persistent in a series of CoNS bacteremia; their definition was bacteremia for >6 days. We did not observe any mortality despite persistent CoNS bacteremia, a finding that is consistent with the relatively benign course reported in various studies.2,5
The atypical persistent bacteremia, with overt signs of septicemia and thrombocytopenia that we observed, could have been attributed to the clinical status of the neonates, to an unusual feature of the infecting organism, or to a change in patient care practice. No obvious changes in patient care practice in this time period could be linked to the persistent bacteremia. We examined the clinical profile of the neonates to ascertain the various risk factors for persistent sepsis as compared with the nonpersistent group. The median gestational age and birth weight at onset of sepsis were similar to those reported by others,15–18 and there was no significant difference in the 2 groups, suggesting that the persistence was not related to extreme prematurity or VLBW.
Seventeen (55%) neonates in the persistent group had central vascular catheters at the onset of bacteremia. Only 11(18%) neonates in the nonpersistent group had a central catheter. In the persistent group, the bacteremia persisted despite removal of the catheters. This suggests that the catheters may have been responsible for establishing the infection but other factors were involved in its persistence. Moreover, 45% of neonates in the persistent group did not have a central catheter. Although bacteremia without indwelling catheters has been reported,15,19 the persistence and the morbidity in our series are remarkable. In most cases in our series, the central vascular catheter was removed after the second positive culture, but in 3 neonates, they were removed after the third positive blood culture; delay was attributed to problems with vascular access. Because successful treatment of CoNS bacteremia without catheter removal is extremely difficult to achieve, we believe that it is prudent to remove the catheter after the second consecutive positive blood culture or after 4 days of bacteremia despite adequate antibiotic therapy.20,21
PN is a significant risk factor in CoNS sepsis22,23; all except 1 of our neonates with persistent bacteremia were receiving PN at onset of CoNS bacteremia. Stoll et al9 noted a direct correlation between duration of PN and risk for late-onset sepsis. Okada et al24 reported impaired bactericidal activity against CoNS in infants who were on long-term PN. Shiro et al25 noted potentiation of S epidermidis catheter-related bacteremia during lipid infusion. However, 48 (78%) neonates in the nonpersistent group were also receiving PN, although use of PN in the persistent group was marginally higher; this difference was not significant on regression analysis. Shama et al26 suggested better clearance of bacteremia after discontinuation of PN during the first 48 hours of antibiotic therapy, although this may have been attributable to use of rifampin in addition to vancomycin in their study.
The similar frequency of clinical manifestations in the nonpersistent and persistent groups suggests that the neonates in the nonpersistent group had true bacteremia rather than a positive blood culture as a result of contamination. Thus, the nonpersistent group seemed appropriate for clinical comparison with the persistent group.
The incidence and the severity of thrombocytopenia among our persistently bacteremic group were very high. The incidence of thrombocytopenia in previously reported series of CoNS bacteremia is much lower than our persistently bacteremic group despite our more stringent definition of thrombocytopenia. The persistence and the severity of thrombocytopenia in our persistent group was striking as demonstrated by the need for frequent and multiple platelet transfusions in 70% of these neonates. Villari et al27 reported that dissemination of resistant clones may have played an important part in CoNS outbreaks such as ours. Our results do not indicate a predominant bacterial clone; however, the prevalent organisms may have changed phenotypically in some subtle way and perhaps acquired the capacity for prolonged endovascular survival. Alternatively, the bacteria could have acquired tolerance to vancomycin, particularly if they are persisting in a biofilm form at some endovascular site.28 Reduced susceptibility to vancomycin, without emergence of a predominant clone, as has been reported for Methicillin-resistant Staphylococcus aureus, may also explain the therapeutic failure with vancomycin.29
None of the neonates who were evaluated by echocardiography showed evidence of endocarditis. Chapman et al15 noted similar results. However, this does not rule out the possibility of an endovascular septic focus that was too small to be detected by available imaging techniques, causing persistent bacteremia and severe thrombocytopenia. All efforts to identify such potential foci were unsuccessful.
The first blood culture was noted to be positive in the persistent group after a median incubation time of 15 hours and after 18.5 hours in the nonpersistent group. This contrasts with situations in which a single positive blood culture with CoNS is obtained and incubation periods are prolonged, suggesting a possibility of contamination. The neonates in the persistent group were bacteremic for a median duration of 13 days, which is more than double the duration reported by Chapman et al.15
All of the CoNS isolates were resistant to penicillin, and 93% were resistant to oxacillin. There has been a worldwide effort to decrease the use of vancomycin in neonates to minimize antibiotic resistance, but the level of oxacillin resistance in our group justifies the use of vancomycin as a first-line antibiotic when CoNS is identified. Moreover, in the majority of our cases, the persistence of bacteremia despite adequate vancomycin levels and in vitro vancomycin susceptibility necessitated the addition of rifampicin. Several authors have suggested the adjunctive use of rifampin in clearing persistent CoNS bacteremia, sometimes even in the presence of indwelling catheters.26,30,31 The success of this combination may be attributable to rifampin's potent serum bactericidal activity as well as its capacity to exert intraleukocytic killing.
Presence of central indwelling catheters, intubation, PN, duration of vancomycin therapy, and thrombocytopenia seemed significantly different in the 2 groups on exploratory analysis, but on regression analysis, the only significant findings were related to shorter duration of incubation of first positive blood culture and presence of indwelling catheters in the persistent group. The duration of vancomycin therapy and incidence of thrombocytopenia were excluded from the regression model to allow satisfactory evaluation of the pertinent risk factors. The former highlights the persistence and the duration of bacteremia, and the latter is a reflection of significant morbidity in the persistent group.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This study describes an unusual outbreak of CoNS sepsis with significant morbidity characterized by persistent bacteremia and severe thrombocytopenia. Comparison between the persistent and nonpersistent groups did not suggest that a difference in the profile of neonates was responsible for the unusual presentation. Microbiological and molecular analyses did not reveal the presence of a resistant or virulent clone. Our series and a recent published report of invasive staphylococcal disease as a result of CoNS with 5% mortality19 suggest that CoNS sepsis in neonates may not be as benign as has been historically perceived. A. Anderson Berry, Department of Pediatrics, University of Utah, Salt Lake City, Utah, has also experienced persistent bacteremia with CoNS in the NICU with significant morbidity (personal communications), suggesting that this new syndrome of CoNS sepsis is a significant emerging concern. This comes at a time of renewed pressure to minimize vancomycin usage, especially in NICUs. Additional research is required to identify putative molecular determinants and pathogenetic mechanisms of the bacteria that are causing this new syndrome and gain insight into patterns of care that might be modified to minimize the problem.
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ACKNOWLEDGMENTS |
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This study was supported by grants from the Canadian Bacterial Diseases Network and the Canadian Cystic Fibrosis Foundation (to D.P.S.).
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FOOTNOTES |
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Accepted May 2, 2005.
Address correspondence to Horacio Osiovich, MD, Division of Neonatology, Room 1R11, Children's and Women's Health Centre of British Columbia, 4480 Oak St, Vancouver, BC, Canada V6H 3V4. E-mail: hosiovich{at}cw.bc.ca
The authors have indicated they have no financial relationships relevant to this article to disclose.
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