Publications by authors named "André Fleer"

30 Publications

  • Page 1 of 1

Reduced expression of PBP-2A by neonatal mecA-positive coagulase-negative staphylococci (CoNS) blood isolates: β-lactams are useful first-line agents for the treatment of neonatal CoNS sepsis, restricting the use of vancomycin.

J Antimicrob Chemother 2012 Jul 21;67(7):1616-8. Epub 2012 Mar 21.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.

Objectives: Vancomycin use for neonatal coagulase-negative staphylococci (CoNS) sepsis is based on a high CoNS carriage rate of mecA, encoding penicillin-binding protein (PBP)-2a, with low affinity for, and associated with resistance to, β-lactam antibiotics. The relationship between mecA gene carriage, phenotypic expression of the gene by PBP-2a production and in vitro resistance to the β-lactam antibiotics oxacillin, cefazolin and amoxicillin/clavulanate was determined for 85 CoNS blood isolates randomly obtained from our collection of isolates from neonates with CoNS sepsis.

Methods: The relationship between mecA gene carriage, phenotypic expression of the gene by PBP-2a production and in vitro resistance to the β-lactam antibiotics oxacillin, cefazolin and amoxicillin/clavulanate was determined for randomly obtained CoNS blood isolates from our collection of isolates from neonates with CoNS sepsis. The mecA gene was detected using multiplex PCR, and PBP-2a expression was determined using a latex agglutination (LA) test (Oxoid). β-Lactam susceptibility was determined using the Phoenix automated system and, in addition, by Etest with interpretation of MIC values according to the reference MIC breakpoints adopted from the CLSI guidelines M100-S20, Infobase™.

Results: Among 85 CoNS blood isolates, 73 (86%) were mecA positive and 12 (14%) were mecA negative. None of the mecA-negative isolates expressed PBP-2a and all were β-lactam susceptible. All mecA-positive CoNS isolates were oxacillin resistant, although most oxacillin MICs were not very high, ranging from 2 to 8 mg/L for the majority of isolates. Only 8/73 (11%) mecA-positive CoNS isolates had oxacillin MICs ≥32 mg/L (range 32 to >256 mg/L). mecA-positive CoNS blood isolates, although fully resistant to oxacillin, were almost universally susceptible to cefazolin and amoxicillin/clavulanate, which was associated with a low expression rate of PBP-2a.

Conclusions: β-Lactam antibiotics are useful for the treatment of neonatal CoNS sepsis, reserving vancomycin for selected cases.
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http://dx.doi.org/10.1093/jac/dks092DOI Listing
July 2012

Shortening the antibiotic course for the treatment of neonatal coagulase-negative staphylococcal sepsis: fine with three days?

Neonatology 2012 17;101(2):101-5. Epub 2011 Sep 17.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.

Background: The incidence of coagulase-negative staphylococcal (CoNS) sepsis is high in neonatal intensive care units (NICUs) and treatment significantly adds to the antibiotic pressure, increasing the threat of resistance. Because infants recover within 24-48 h, blood cultures are negative within 48 h and CRP normalizes within 72 h, we reduced anti-CoNS treatment from 7 to 3 days in infants with uncomplicated CoNS sepsis.

Objectives: The aim of the study was to evaluate the effect of short (3 days) treatment duration for CoNS sepsis.

Methods: All infants with CoNS sepsis from January 2006 to September 2010 were evaluated. Before 2008 the duration of anti-CoNS treatment was 7 days, but in 2008 it was reduced to 3 days, provided that infants recovered within 48 h, CRP value decreased, thrombocytes were normal and central venous catheters were either not present or removed. Clinical results of treatment for 3 days were compared with 7 days of treatment.

Results: There were 142 infants with CoNS sepsis who were eligible for 3 days of antimicrobial treatment duration, 62 (44%) from the period 2006-2008 were treated over 7 days (Group 1) and 80 (56%) from the period 2008-2010 were treated over 3 days (Group 2). Clinical characteristics were not different between the groups. All infants recovered within 48 h and CoNS sepsis did not relapse.

Conclusions: Antibiotic treatment for CoNS sepsis may be shortened to 3 days when clinical improvement is rapid and central lines are not present. Prospective randomized studies are needed to confirm the results of this single-center study. Future studies may reveal the effects on the development of antimicrobial resistance.
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http://dx.doi.org/10.1159/000330600DOI Listing
June 2012

A seven-year survey of management of coagulase-negative staphylococcal sepsis in the neonatal intensive care unit: vancomycin may not be necessary as empiric therapy.

Neonatology 2011 1;100(2):180-5. Epub 2011 Apr 1.

Department of Neonatology, Wilhelmina Children's Hospital, Utrecht, The Netherlands.

Background: The typical empiric therapy for coagulase-negative staphylococcal (CONS) sepsis includes vancomycin. In our neonatal intensive care unit, we have consistently avoided the use of vancomycin to treat CONS sepsis, except for specific cases, and have used instead cefazolin as empiric agent.

Objectives: The clinical outcome of infants with CONS sepsis was evaluated in relation to the susceptibility of CONS blood isolates to cefazolin over a period of 7 years.

Methods: Clinical characteristics, symptoms of sepsis and antibiotic use were studied retrospectively. Susceptibility of CONS blood isolates to cefazolin was determined by E-test.

Results: Of 163 infants with proven CONS sepsis, 121/140 (86%) infants with a cefazolin-susceptible (minimum inhibition concentration (MIC) ≤8 mg/l) and 21/23 (91%) with a cefazolin-resistant (MIC ≥32 mg/l) blood isolate were treated with cefazolin. 21 (13%) infants were switched to vancomycin, in only 3 of them CONS had become resistant to cefazolin. The majority (81%) of the infants with a good response to cefazolin had the indwelling central venous catheter removed, in contrast to only 22% of the infants with cefazolin treatment failure. Median cefazolin MIC values were 0.75-2 mg/l during the study period.

Conclusions: The great majority of infants with CONS sepsis was successfully treated with cefazolin. The use of vancomycin could be restricted to specific cases. Despite the consistent use of cefazolin in neonatal CONS sepsis over an extended period of time, cefazolin MIC values remained low and in the susceptible range. Removal of the central venous catheter in infants with clinical symptoms of sepsis is an important therapeutic measure.
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http://dx.doi.org/10.1159/000324852DOI Listing
January 2012

Prevention of neonatal late-onset sepsis associated with the removal of percutaneously inserted central venous catheters in preterm infants.

Pediatr Crit Care Med 2011 Jul;12(4):445-8

Department of Neonatology, Wilhelmina Children's Hospital, Utrecht, The Netherlands.

Objectives: Indwelling central venous catheters are the most important risk factors for the development of sepsis attributable to coagulase-negative staphylococci among preterm infants admitted to neonatal intensive care units. In addition, removal of a central venous catheter also may cause coagulase-negative staphylococci sepsis, which may be prevented by the short-term administration of an anti-staphylococcal agent during the procedure of removal. The administration of a specific anti-staphylococcal agent (cefazolin) was evaluated for the prevention of central venous catheter removal-associated coagulase-negative staphylococci sepsis.

Design: A prospective, open, randomized, controlled intervention study.

Setting: Twenty-eight-bed neonatal intensive care unit at a tertiary care children's hospital.

Patients: Eighty-eight preterm infants (gestational age <37 wks) admitted to the neonatal intensive care unit with indwelling percutaneously inserted central venous catheters.

Intervention: From April 2007 to January 2010, infants were randomized to receive two doses of cefazolin during removal of the percutaneously inserted central venous catheter (intervention group, n = 44) or no antimicrobial agent (control group, n = 44). Percutaneously inserted central venous catheter removal-associated sepsis was defined as sepsis occurring <48 hrs after removal of the percutaneously inserted central venous catheter.

Measurements And Main Results: Clinical characteristics and central venous catheter duration did not show differences between both groups. Five infants (11%) of the control group developed coagulase-negative staphylococci sepsis <48 hrs after removal of the percutaneously inserted central venous catheter compared to none (0%) in the intervention group (p = .021).

Conclusions: Two doses of the anti-staphylococcal agent cefazolin during the procedure of removal of a percutaneously inserted central venous catheter were effective in the prevention of coagulase-negative staphylococci sepsis. It is recommended to include this regimen in the guidelines on management of central venous catheters in very-low-birth-weight infants.
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http://dx.doi.org/10.1097/PCC.0b013e3182070f5dDOI Listing
July 2011

Antibiotic weight-watching: slimming down on antibiotic use in a NICU.

Acta Paediatr 2010 Dec;99(12):1900-2

Department of Clinical Pharmacy, University Medical Centre Utrecht, The Netherlands.

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http://dx.doi.org/10.1111/j.1651-2227.2010.01957.xDOI Listing
December 2010

Improvement of adherence to hand hygiene practice using a multimodal intervention program in a neonatal intensive care.

J Nurs Care Qual 2011 Jan-Mar;26(1):22-9

Department of Neonatology, Wilhelmina Children's Hospital, Utrecht, the Netherlands.

Nosocomial infections are serious complications among preterm infants admitted to neonatal intensive care units (NICU). Hand hygiene is one of the most effective measures to prevent these infections. This study, performed in a tertiary level NICU, highlights the importance of a multimodal intervention program for adherence to hand hygiene. The compliance with hand hygiene among health care workers of the NICU increased significantly from 23% in the baseline assessment to 50% in the second assessment and the incidence of sepsis decreased from 13.4% to 11.3% after implementation of an intervention program.
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http://dx.doi.org/10.1097/NCQ.0b013e3181ea86e9DOI Listing
January 2013

Variation in antibiotic use in neonatal intensive care units in the Netherlands.

J Antimicrob Chemother 2010 Jun 7;65(6):1270-5. Epub 2010 Apr 7.

Department of Clinical Pharmacy, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands.

Objectives: To examine the variation in quantity and classes of antibiotics used in all 10 tertiary care neonatal intensive care units (NICUs) in the Netherlands during 2005.

Methods: We collected data from all tertiary care NICUs in the Netherlands on clinical and demographic characteristics and the type and quantity of systemic antibiotic use [expressed as defined daily doses (DDD)/100 admissions] in 2005. Antibiotics were ranked by volume of DDDs, and those antibiotics which accounted for 90% of the total volume of use [drug utilization (DU) 90%] were noted.

Results: Antibiotic consumption ranged from 130 to 360 DDD/100 admissions. In total, 9-24 different antibiotics were used, of which 3-10 were in the DU90% segment.

Conclusions: By comparing antibiotic use in Dutch NICUs we found a considerable variation in the number of different antibiotics used and in the total amount of antibiotic use. Further exploration of the opportunities to reach consensus in antibiotic policy, and to increase attention to antibiotic stewardship, is recommended.
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http://dx.doi.org/10.1093/jac/dkq107DOI Listing
June 2010

Liquid chromatography-tandem mass spectrometry assay for the quantification of free and total sialic acid in human cerebrospinal fluid.

J Chromatogr B Analyt Technol Biomed Life Sci 2010 May 18;878(15-16):1098-102. Epub 2010 Mar 18.

Department of Metabolic and Endocrine Diseases, University Medical Centre Utrecht, WKZ and Netherlands Metabolomics Centre, The Netherlands.

Background: Analysis of sialic acid (SA) metabolites in cerebrospinal fluid (CSF) is important for clinical diagnosis. In the present study, a high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS) method for free sialic acid (FSA) and total sialic acid (TSA) in human CSF was validated.

Methods: The method utilized a simple sample-preparation procedure of protein precipitation for FSA and acid hydrolysis for TSA. Negative electrospray ionisation was used to monitor the transitions m/z 308.2-->87.0 (SA) and m/z 311.2--> 90.0 ((13)C(3)-SA). Conjugated sialic acid (CSA) was calculated by subtracting FSA from TSA. We established reference intervals for FSA, TSA and CSA in CSF in 217 control subjects. The method has been applied to patients' samples with known differences in SA metabolites like meningitis (n=6), brain tumour (n=2), leukaemia (n=5), and Salla disease (n=1).

Results: Limit of detection (LOD) was 0.54 microM for FSA and 0.45 mM for TSA. Intra- and inter-assay variation for FSA (21.8 microM) were 4.8% (n=10) and 10.4% (n=40) respectively. Intra- and inter-assay variation for TSA (35.6 microM) were 9.7% (n=10) and 12.8% (n=40) respectively. Tested patients showed values of TSA above established reference value.

Conclusion: The validated method allows sensitive and specific measurement of SA metabolites in CSF and can be applied for clinical diagnoses.
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http://dx.doi.org/10.1016/j.jchromb.2010.03.020DOI Listing
May 2010

Long-term trends in the epidemiology of neonatal sepsis and antibiotic susceptibility of causative agents.

Neonatology 2010 2;97(1):22-8. Epub 2009 Jul 2.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.

Background: In an era with increased maternal antibiotic use, patterns in early- and late-onset sepsis and antibiotic susceptibility may have changed.

Objectives: To identify longitudinal trends in causative microorganisms for neonatal sepsis and analyze antibiotic susceptibility of all blood isolates of infants with sepsis.

Methods: Early- and late-onset sepsis cases from 29 years (1978-2006) were studied retrospectively, in five clusters of 5 years (period I-V) and one cluster of 4 years (period VI), including antibiotic susceptibility profiles of blood isolates during the years 1999-2006.

Results: The incidence of early-onset sepsis decreased (p < 0.01) from 4% during period I (1978-1982) to 1.2% during period VI (2003-2006). 78% of the infants with group B streptococcal (GBS) sepsis were premature during period I, compared to 47% during period VI (p < 0.05). The incidence of early-onset Gram-negative infections remained low during all periods. The incidence of late-onset sepsis, predominantly caused by coagulase-negative staphylococci (CONS) and Staphylococcus aureus, increased since period III from 7.1 to 13.9% in period VI (p < 0.01). Infections due to fungi or yeasts were rare (incidence <0.3%). The majority of CONS blood isolates were oxacillin-resistant, but vancomycin-susceptible. 95% of CONS blood isolates were susceptible for first-generation cephalosporins. Amoxicillin/clavulanic acid-resistant Escherichia coli were infrequent causes of infection.

Conclusions: The incidence of early-onset sepsis mainly caused by GBS decreased. In contrast, the incidence of late-onset sepsis, predominantly caused by CONS, increased significantly. The incidence of fungal and yeast infections remained low. The majority of CONS blood isolates were susceptible for first-generation cephalosporins.
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http://dx.doi.org/10.1159/000226604DOI Listing
March 2010

No efficacy of silver bone cement in the prevention of methicillin-sensitive Staphylococcal infections in a rabbit contaminated implant bed model.

J Orthop Res 2009 Aug;27(8):1002-7

Department of Orthopaedics, Room G05.228, University Medical Center Utrecht, P.O. Box 85500, 3508GA Utrecht, The Netherlands.

Data from literature showed that a new type of metallic silver PMMA cement had good results in infection prophylaxis. This study investigated the in vivo efficacy of silver cement in the prevention of methicillin-sensitive Staphylococcal infections, compared to plain and tobramycin-containing cement. In 48 rabbits, 0.6% silver, 1% silver, plain, or tobramycin PMMA cement was injected into the femoral medullary canal after contamination with 10(5), 10(6), or 10(7) colony forming units (CFU) Staphylococcus aureus. After 14 days, bone was collected for bacteriology and histopathology. All plain and silver cement rabbits were infected, whereas only two tobra rabbits were infected (p < 0.001). The number of bacteria cultured ((10)logCFU) from bone adjacent to the cement, was 6.4 +/- 0.3 and 6.1 +/- 0.3 for the 0.6% and 1% silver rabbits. For the rabbits with plain and tobra cement, this was 6.2 +/- 0.2 (p > 0.95) and 0.0 +/- 0.0 (p < 0.001), respectively. Two tobra rabbits had a positive culture of a distal bone sample. Histological sections of plain, 0.6%, and 1% silver rabbits all showed signs of infection; these signs were absent in the tobra rabbits. Silver and plain cement were not effective in preventing infection, whereas tobra cement was effective. As silver cement predominantly exhibits an antimicrobial effect at the direct cement surface, this cement seems less useful in situations where there are bacteria present in surrounding tissues, like revision surgery. Whether silver cement has relevance in the prevention of bacterial colonization of cement remains to be determined.
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http://dx.doi.org/10.1002/jor.20854DOI Listing
August 2009

Prevalence and impact of respiratory viral infections in young children with cystic fibrosis: prospective cohort study.

Pediatrics 2008 Dec;122(6):1171-6

Cystic Fibrosis Centre and Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Centre Utrecht, PO Box 85090, Office KH 01.419.0, 3508 AB Utrecht, Netherlands.

Objective: We aimed to investigate differences in upper and lower respiratory tract symptoms in relation to respiratory viral infections detected with polymerase chain reaction assays in young children with cystic fibrosis and healthy control subjects.

Methods: In a 6-month winter period, 20 young children with cystic fibrosis and 18 age-matched, healthy, control subjects were contacted twice per week for detection of symptoms of an acute respiratory illness. If any symptom was present, then a home visit was made for physical examination and collection of nasopharyngeal swabs for viral analysis. In addition, parents were instructed to collect nasopharyngeal swabs every 2 weeks.

Results: Children with cystic fibrosis and healthy control subjects had similar frequencies of acute respiratory illnesses (3.8+/-1.0 and 4.2+/-1.7 episodes, respectively). Although there were no significant differences in upper respiratory tract symptoms, the children with cystic fibrosis had longer periods of lower respiratory tract symptoms (22.4+/-22.2 vs 12.8+/-13.8 days) and a higher mean severity score per episode (2.35+/-0.64 vs 1.92+/-0.46). In addition, similar increases in upper respiratory tract symptom scores were associated with significantly greater increases in lower respiratory tract symptom scores in children with cystic fibrosis. No differences in the seasonal occurrences and distributions of respiratory viruses were observed, with picornaviruses and coronaviruses being the most prevalent.

Conclusions: Although there were no differences in the seasonal occurrences and distributions of polymerase chain reaction-detected respiratory viruses, acute respiratory illnesses were frequently associated with increased lower respiratory tract morbidity in young children with cystic fibrosis.
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http://dx.doi.org/10.1542/peds.2007-3139DOI Listing
December 2008

Prophylaxis of infection and effects on osseointegration using a tobramycin-periapatite coating on titanium implants--an experimental study in the rabbit.

J Orthop Res 2009 Jun;27(6):710-6

Department of Orthopaedics, University Medical Center Utrecht, Room G05.228, P.O. Box 85500, Heidelberglaan 100, 3484CX Utrecht, The Netherlands.

No options are available for local antibiotic delivery from uncemented implants. By loading a porous titanium implant with a biomimetic HA-coating (PeriApatite, PA) with antibiotics, we could obtain adequate local antibiotic concentrations and reduce infection susceptibility. This study investigated the efficacy of a tobramycin-loaded PA-coated titanium foam implant in preventing infection, as well as the effects on osseointegration. In 72 New Zealand White rabbits, an uncoated (Ti), PA-coated (PA), or Tobramycin-PA-coated (PA-tobra) titanium foam rod was implanted intramedullary in the left tibiae after contamination of the implant bed with none (control), 10(3), 10(4) or 10(5) CFU Staphylococcus aureus. PA-tobra implants were loaded with 2.4 mg tobramycin. After 28 days analysis was done by bacteriology, histopathology and histomorphometry. Six percent of the contaminated PA-tobra rabbits were infected, whereas this was 53 and 67% for PA and Ti, respectively (p < 0.001). Quantitative cultures were also significantly lower in the PA-tobra group (p = 0.003). None of the control rabbits were infected. Histopathological and histomorphometrical scores were both better for the PA-tobra group, although only significant compared to Ti. No significant differences were observed between PA and Ti rabbits. We conclude that the application of tobramycin to PA-coated titanium foam implants appears to be an effective local antibiotic strategy for uncemented implants for infection prophylaxis and has a beneficial effect on implant fixation, which will result in improved long-term implant survival.
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http://dx.doi.org/10.1002/jor.20808DOI Listing
June 2009

Removal of percutaneously inserted central venous catheters in neonates is associated with the occurrence of sepsis.

Acta Paediatr 2008 Sep 12;97(9):1250-2. Epub 2008 May 12.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.

Background: Clinical signs of sepsis are frequently observed after removal of a percutaneously inserted central venous catheter (PCVC) in neonates admitted at our Neonatal Intensive Care Unit (NICU). To substantiate this finding and to evaluate the effect of antibiotics administered at the time of removal of a PCVC, we conducted a retrospective study among all infants with a PCVC, admitted at our NICU during 2002 and 2005.

Methods: Clinical data, infectious complications and use of antibiotics were studied retrospectively.

Results: A PCVC was inserted in 345 infants. Sepsis occurred in 90/345 (26%) infants, in 50/90 (56%) during indwelling PCVC and in 40/90 (44%) after removal of the PCVC. Of the latter 40 sepsis episodes, 24 (60%) occurred within 5 days after removal of a PCVC with a clustering of 21 cases of sepsis within 72 h after the removal. The remaining 16 episodes occurred after 7 days. Administration of antibiotics during removal of the PCVC significantly reduced the incidence of sepsis: 22/213 (10.3%) cases of sepsis occurred when no antibiotics were administered versus 2/132 (1.5%) cases of sepsis when antibiotics were administered (p = 0.002).

Conclusion: Our study suggests that peripherally inserted central venous catheters are associated with sepsis not only during the indwelling period of the catheter, but also after removal. Administration of antibiotics targeted at the time of removal of the catheter significantly reduced the incidence of sepsis. Future prospective studies are warranted to confirm this observation.
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http://dx.doi.org/10.1111/j.1651-2227.2008.00864.xDOI Listing
September 2008

Toll-like receptor 2 polymorphism is associated with preterm birth.

Pediatr Res 2007 Oct;62(4):474-6

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3508 AB, The Netherlands.

Evidence is increasing for a role of polymorphisms in maternal or fetal innate immune response genes in preterm birth. Toll-like receptors (TLRs) are important receptors in the innate immunity. The genotype distribution of two TLR2 single nucleotide polymorphisms (SNPs) and one TLR4 SNP were determined among 524 neonates and associated with gestational age (GA). Genomic DNA was isolated from prospectively collected blood samples and polymorphisms in TLR2 (T-16934A, RS4696480 and Arg753Gln, RS5743708) and TLR4 (Thr399Ile, RS4986791) were determined using sequence specific primers by PCR. Allele frequencies of two TLR2 SNPs and one TLR4 SNP were analyzed according to prematurity. Analysis among 305 infants, after exclusion of infants born after multiple pregnancy or because of preeclampsia, revealed significantly shorter GAs for infants carrying two polymorphic TLR2 alleles (-16934TA/AA and 753ArgGln/GlnGln) compared with infants carrying one polymorphic and one wild-type allele or two wild-type alleles (median GA 30.6 wk versus 34.1-36.8 wk, respectively, p < 0.02). Carriage of two variant TLR2 alleles potentially leads to aberrant innate immune responses, which may have contributed to very preterm birth.
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http://dx.doi.org/10.1203/PDR.0b013e31813c9401DOI Listing
October 2007

Macrolide-resistant Staphylococcus aureus colonization in cystic fibrosis patients: is there transmission to household contacts?

J Antimicrob Chemother 2007 Sep 29;60(3):665-8. Epub 2007 Jun 29.

Department of Paediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Centre Utrecht, The Netherlands.

Objectives: Patients with cystic fibrosis (CF) are frequently colonized by macrolide-resistant Staphylococcus aureus, a result of maintenance macrolide therapy. As transmission of S. aureus between household contacts is common, we examined the prevalence of macrolide-resistant S. aureus colonization in CF patients on maintenance azithromycin therapy and their household contacts and compared this with the S. aureus macrolide resistance prevalence in the community.

Patients And Methods: Sixty-five CF patients on maintenance macrolide therapy and 194 household contacts were screened for S. aureus colonization by culturing sputa, cough swabs and nasal swabs. Resistance to macrolide, lincosamide and methicillin was determined by disc diffusion tests. The prevalence of macrolide-resistant S. aureus colonization in both groups was compared with figures from a nationwide study into S. aureus carriership and resistance. To assess possible transmission, genotyping of S. aureus was performed using the spa-typing method.

Results: Macrolide resistance among CF patients with S. aureus colonization was 69.6%; 75% of these isolates displayed lincosamide resistance too. Among household contacts, macrolide resistance prevalence did not differ significantly from resistance prevalence in the community (9.6% versus 6.3%; P = 0.358). No methicillin resistance was observed. No identical (macrolide-resistant and -susceptible) S. aureus genotypes were observed between CF patients and their household contacts except for one household, suggesting a probable transmission.

Conclusions: No significant increase in macrolide-resistant S. aureus colonization was observed among household contacts of CF patients on long-term azithromycin therapy. Transmission of macrolide-resistant S. aureus could not be proved by genotyping in the majority of households.
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http://dx.doi.org/10.1093/jac/dkm235DOI Listing
September 2007

Identification of orthopaedic infections using broad-range polymerase chain reaction and reverse line blot hybridization.

J Bone Joint Surg Am 2007 Jun;89(6):1298-305

Department of Orthopaedics, University Medical Center Utrecht, P.O. Box 85500, 3508GA Utrecht, The Netherlands.

Background: Culture remains the gold standard in the diagnosis of bacterial infection, but molecular biological techniques have yielded promising results. In this study, we validated a combined polymerase chain reaction and reverse line blot hybridization protocol for identifying musculoskeletal infections.

Methods: Samples were obtained from seventy-six patients undergoing orthopaedic surgery for various aseptic and septic indications. The diagnosis of infection was based on a review of all available clinical and culture data. In addition to routine culture for aerobic and anaerobic growth, samples were analyzed with a broad-range 16S rRNA polymerase chain reaction and subsequent reverse line blot hybridization with use of twenty-eight group, genus, and species-specific oligonucleotide probes.

Results: An infection was diagnosed on the basis of patient data in thirty-one patients. All but one of the patients with a clinical diagnosis of infection had a positive result of the polymerase chain reaction-reverse line blot hybridization. Five of the forty-five patients in whom an infection was not suspected on the basis of patient data had at least one positive result of the polymerase chain reaction-reverse line blot hybridization. Cultures demonstrated microorganisms in twenty-five patients with an infection and in two patients in whom an infection was not suspected on the basis of the patient data. Staphylococcus aureus was the most common organism grown on culture. The species identified by the polymerase chain reaction-reverse line blot hybridization was in full accordance with that grown on culture in all but one patient.

Conclusions: Polymerase chain reaction-reverse line blot hybridization performed well in detecting and identifying the various bacterial species and was more sensitive than routine culture. It identified Staphylococcus aureus as the most frequently found microorganism. Five patients in whom an infection was not suspected on the basis of the patient data had a positive result of the polymerase chain reaction, which may have been caused by contamination of the samples. However, three of these patients had aseptic loosening of a total hip prosthesis, suggesting the presence of a low-grade bacterial infection that remained undetected by the culture but was detected by the polymerase chain reaction-reverse line blot hybridization.

Level Of Evidence: Diagnostic Level III.
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http://dx.doi.org/10.2106/JBJS.F.00822DOI Listing
June 2007

RSV mediates Pseudomonas aeruginosa binding to cystic fibrosis and normal epithelial cells.

Pediatr Res 2007 Apr;61(4):398-403

Cystic Fibrosis Centre and Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, Netherlands.

Cystic fibrosis lung disease typically has a course of exacerbations and remissions, suggesting that external factors like viral infections can influence this course. Clinical data suggest synergism between respiratory syncytial virus (RSV) infections and Pseudomonas aeruginosa in cystic fibrosis (CF) lung disease. We studied the influence of RSV infection on adherence of P. aeruginosa to IB3-1, HEp-2, and A549 epithelial cell monolayers in vitro. RSV infection of epithelial cells as well as simultaneous addition of RSV and P. aeruginosa to noninfected cells both strongly enhanced the pseudomonal adherence to epithelial cells. The increased adherence varied from 1.2- to 8.2-fold in case of previous RSV infection, and from 1.7- to 16.1-fold in case of simultaneous addition. We observed direct binding of RSV to P. aeruginosa, and blocking of RSV with heparin eliminated the effect on increased adherence. This suggests that RSV possibly acts as a coupling agent between P. aeruginosa and epithelial cells. In conclusion, RSV enhances P. aeruginosa infection of respiratory epithelial cells. It suggests a role of specific viral-bacterial interactions in exacerbations of CF lung disease, which could have important implications on prevention and treatment.
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http://dx.doi.org/10.1203/pdr.0b013e3180332d1cDOI Listing
April 2007

Innate immunity: toll-like receptors and some more. A brief history, basic organization and relevance for the human newborn.

Neonatology 2007 27;92(3):145-57. Epub 2007 Apr 27.

Eijkman-Winkler Institute for Microbiology, Infectious Diseases and Inflammation, Utrecht, The Netherlands.

The discovery of Toll-like receptors (TLRs) as essential components of the innate immune system has greatly advanced our knowledge and understanding of immune responses to infection and how these are regulated. Innate immunity in general and TLRs in particular play a crucial role in the front line of host defenses against microbes, but also are a key element in the proper functioning of the immune system at large in vertebrate animals. The innate immune system has been identified as a collection of factors, both cell-associated and cell-free, that comprises an impressively effective and well-organized system that is capable of immediate recognition of a whole array of microbes and microbial components. The cell-bound TLRs fulfill a central role in the process from pathogen recognition to activation of adaptive immunity. From the cell-free factors the plasma protein mannose-binding lectin (MBL) has been studied most extensively. Associations have already been documented between TLR polymorphisms in man and TLR deficiency in animals and an increased susceptibility to infection. The effect of MBL on infectious disease susceptibility only seems to emerge when host defenses are compromised by a severe underlying condition. The functional state of the various components of innate immunity at birth is largely unknown and only recently a number of studies have assessed this feature of the innate immune system. In addition, for the human newborn the innate immune system may have a broader significance; it may well be the key system determining the course of inflammatory events associated with premature birth, a notion that is emphasized by the recently described association between TLR polymorphisms and prematurity. However, there are still many open questions, particularly about the exact relation between individual TLRs and infectious disease susceptibility and how TLRs cooperate in resistance to infection and in initiating adaptive immune responses. With regard to the human newborn, the most relevant question that needs to be resolved is the precise role of innate immunity in the pathogenesis of prematurity.
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http://dx.doi.org/10.1159/000102054DOI Listing
November 2007

Maintenance azithromycin treatment in pediatric patients with cystic fibrosis: long-term outcomes related to macrolide resistance and pulmonary function.

Pediatr Infect Dis J 2007 Jan;26(1):8-12

Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Maintenance azithromycin therapy may improve pulmonary function in patients with cystic fibrosis (CF) with Pseudomonas aeruginosa infection because of its antiinflammatory properties. However, azithromycin therapy might increase macrolide resistance in Staphylococcus aureus cultured from respiratory secretions. We studied the emergence of macrolide resistance in S. aureus and correlated this to pulmonary function decline in pediatric patients with CF on daily azithromycin therapy.

Methods: Respiratory cultures of 100 patients with CF were analyzed for S. aureus colonization and its resistance pattern before and during 3 years after initiation of azithromycin maintenance therapy. Mean annual change in forced expiratory volume as percent of predicted (FEV1 %) was calculated to compare pulmonary function before and after azithromycin therapy.

Results: Staphylococcal colonization did not significantly decrease after initiation of azithromycin (50% versus 48%). Before start of therapy, 10% of patients with staphylococcal colonization had macrolide-resistant strains. Staphylococcal resistance increased to 83% in the first year; 97% in the second and 100% in the third year after initiation of azithromycin therapy (P < 0.001). Half of macrolide-resistant S. aureus comprised the macrolide-lincosamide-streptogramin phenotype. Percent forced expiratory volume in 1 second improved in the first year after initiation of azithromycin (mean annual change: -4.75% before versus +3.09% after initiation; P < 0.01) but decreased during the second and third years after initiation (-5.15% and -3.65%, respectively). Emergence of macrolide-resistant S. aureus was not related to pulmonary function decline.

Conclusion: Maintenance azithromycin therapy in patients with CF leads to macrolide resistance in nearly all S. aureus carriers. Pulmonary function improvement after initiation of azithromycin therapy seems to be temporary and appears not to be related to macrolide resistance of S. aureus.
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http://dx.doi.org/10.1097/01.inf.0000247109.44249.acDOI Listing
January 2007

Inflammatory mediators for the diagnosis and treatment of sepsis in early infancy.

Pediatr Res 2006 Mar;59(3):457-61

Department of Neonatology, University Medical Center, EA Utrecht, Utrecht, The Netherlands.

Interleukin-6 (IL-6), interleukin-8 (IL-8), and procalcitonin (PCT) are important parameters in the diagnosis of sepsis and for differentiating between viral and bacterial infection in children. We compared the value of IL-6, IL-8, and PCT with C-reactive protein (CRP) in the diagnosis and treatment of late-onset sepsis among infants admitted to the neonatal intensive care unit (group I) and febrile infants admitted to general hospitals from home (group II). Group I was divided into subgroups Ia, positive blood culture (all Gram-positive cocci); Ib, negative blood culture; and Ic, controls. Group II was divided into subgroups IIa, systemic enterovirus infection, and IIb, no enterovirus infection. Enterovirus was identified by real-time (RT) polymerase chain reaction (PCR) and/or by culture in blood and cerebrospinal fluid (CSF). The positive predictive values of IL-6, IL-8, and PCT (78%, 72%, and 83%, respectively) were better than that of CRP (63%) in the diagnosis of neonatal sepsis. After 48 h of antibiotic treatment, IL-6 and IL-8 levels significantly decreased and PCT stabilized in clinically recovered patients, suggesting that these markers may be useful in distinguishing patients in which antibiotic treatment may be discontinued. Among infants of subgroup IIa, 80%-90% had normal values of IL-6, IL-8, and PCT, whereas CRP was increased in 40%. In conclusion, IL-6, IL-8, and PCT are better parameters than CRP in the diagnosis and follow-up of neonatal sepsis due to coagulase-negative staphylococci (CoNS) and in the exclusion of bacterial infection among those with enteroviral infection among febrile infants presenting from home.
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http://dx.doi.org/10.1203/01.pdr.0000200808.35368.57DOI Listing
March 2006

In-line filters in central venous catheters in a neonatal intensive care unit.

J Perinat Med 2006 ;34(1):71-4

Wilhelmina Children's Hospital, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.

Nosocomial sepsis remains an important cause of morbidity in neonatal intensive care units. Central venous catheters (CVCs) and parenteral nutrition (TPN) are major risk factors. In-line filters in the intravenous (IV) administration sets prevent the infusion of particles, which may reduce infectious complications. We randomized infants to in-line filter (for clear fluids and lipid emulsions) or no filter placement. Sepsis, nursing time and costs were assessed. IV sets without filters were changed every 24 h, IV-sets with filters every 96 h. Of 442 infants with a CVC, 228 were randomized to filter placement, 214 to no filter. No differences were found in clinical characteristics, CVC-use, and catheter days. Nosocomial sepsis occurred in 37 (16.2%) infants with filters, in 35 (16.3%) in the group without filter (NS). Nursing time to change the IV-administration sets was 4 min shorter in the filter-group (P<0.05). Costs of materials used were comparable. In conclusion, the incidence of sepsis when using filters was not reduced but the nursing time for changing the intravenous sets was reduced without a difference in costs.
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http://dx.doi.org/10.1515/JPM.2006.009DOI Listing
January 2007

Direct binding of respiratory syncytial virus to pneumococci: a phenomenon that enhances both pneumococcal adherence to human epithelial cells and pneumococcal invasiveness in a murine model.

Pediatr Res 2005 Dec;58(6):1198-203

Department of Pediatric Infectious Diseases, Wilhelmina Children's Hospital, and Eijkman Winkler Institute for Microbiology, Infectious Diseases and Inflammation, University Medical Centre, Utrecht, The Netherlands.

In a previous study we showed that pneumococcal adherence to epithelial cells was enhanced by a preceding respiratory syncytial virus (RSV) infection. RSV-glycoproteins, expressed on the infected cell surface, may play a role in this enhanced pneumococcal binding, by acting as bacterial receptors. In the current study, it was attempted to analyze the capacity of pneumococci to interact directly with RSV virions. By flow-cytometry, a direct interaction between RSV and pneumococci could be detected. Heparin, an inhibitor of RSV infectivity that interacts with RSV protein-G, blocked RSV-pneumococcal binding, indicating that the latter interaction is indeed mediated by protein-G. RSV-pneumococcal complexes showed enhanced adherence to uninfected human epithelial cells, compared with pneumococcal adherence without bound RSV, and this enhancement was also blocked by heparin. In addition, the significance of these findings in vitro was explored in vivo in a murine model. Both mice that were pretreated with RSV at day 4 before pneumococcal challenge and mice infected with both agents simultaneously showed significantly higher levels of bacteraemia than controls. Simultaneous infection with both agents enhanced the development of pneumococcal bacteraemia most strongly. It was hypothesized that direct viral binding is another mechanism by which RSV can induce enhanced pneumococcal binding to epithelial cells, a phenomenon that is translated in vivo by a higher invasiveness of pneumococci when administered simultaneously with RSV to mice. Apparently, RSV acts in this process as a direct coupling particle between bacteria and uninfected epithelial cells, thereby increasing colonization by and enhancing invasiveness of pneumococci.
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http://dx.doi.org/10.1203/01.pdr.0000188699.55279.1bDOI Listing
December 2005

Clinical and epidemiologic characteristics of viral infections in a neonatal intensive care unit during a 12-year period.

Pediatr Infect Dis J 2005 Oct;24(10):901-4

Department of Neonatology, Wilhelmina Children's, The Netherlands.

Background: The incidence of viral infections in patients treated in the neonatal intensive care unit (NICU) is not well-known. We summarized the data of all patients with laboratory-confirmed viral infections admitted at the NICU of our hospital during the period of 1992-2003.

Objectives: To determine the incidence of viral infections among infants hospitalized in a NICU, the associated clinical manifestations and their outcome.

Methods: Retrospective analysis of epidemiologic, virologic and clinical data from infants with proven viral infection. The diagnosis viral infection was confirmed by positive viral culture and/or polymerase chain reaction from clinical samples.

Results: Viral infection was confirmed in 51 of 5396 infants (1%) admitted to the NICU; 20 (39%) had an enterovirus and parechovirus (EV/PEV) infection, 15 (29%) a respiratory syncytial virus (RSV) infection, 5 (10%) a rotavirus infection, 3 (6%) a cytomegalovirus (CMV) infection, 2 (4%) an adenovirus infection, 2 (4%) a parainfluenza virus infection, 2 (4%) a herpes simplex virus infection, 1 (2%) a rhinovirus infection and 1 (2%) a rubella virus infection. Three of the infants presented at birth with symptomatic rubella virus, CMV or herpes simplex virus infection. RSV infection developed mostly in hospitalized infants (60%), and 93% of infections occurred during the winter (November-March). The clinical presentations of EV/PEV disease were sepsis-like illness, prolonged seizures in term infants and gastrointestinal disease in preterm infants. RSV, parainfluenza virus, rhinovirus and CMV caused respiratory disease, predominantly in preterm infants. Gastrointestinal disease was seen only in preterm infants with adenovirus, rotavirus or EV/PEV infection. Mortality and serious sequelae were high in patients infected with EV/PEV (10 and 15%, respectively).

Conclusions: The incidence of viral infection in the NICU was 1%. Enteroviral infections were the most frequently diagnosed infections, occurred often in term infants born at home and presented with sepsis-like illness or seizures. Preterm infants hospitalized from birth mainly developed gastrointestinal disease caused by rotavirus and adenovirus infection or respiratory disease caused by RSV, parainfluenza and CMV infection. Enteroviruses were responsible for the highest mortality and development of serious sequelae.
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http://dx.doi.org/10.1097/01.inf.0000180471.03702.7fDOI Listing
October 2005

Should an infected Nuss bar be removed?

J Pediatr Surg 2005 Apr;40(4):670-3

Department of Pediatric Surgery, Wilhelmina Children's Hospital, University Medical Center, PO Box 85090, 3508AB Utrecht, The Netherlands.

Background: The Nuss procedure is a minimally invasive procedure for correction of pectus excavatum. It involves insertion of a substernal metal bar. A feared complication of any implanted device is infection, which often necessitates removal. The purpose of this report is to describe the authors' experience with infectious complications after the Nuss procedure.

Methods: From February 2000 to July 2002, 102 patients underwent the Nuss procedure in 2 pediatric surgical centers. In a retrospective way, the files of those patients in whom a postoperative infection developed were studied.

Results: Seven patients suffered postoperative infectious complications. Only one bar needed to be removed.

Conclusion: The authors' experience indicates that there is no need for immediate removal of an infected Nuss bar. Most of these infections can be managed conservatively. However, early antibiotic treatment is warranted to ensure salvage of the bar.
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http://dx.doi.org/10.1016/j.jpedsurg.2004.12.005DOI Listing
April 2005

Enhanced adherence of Streptococcus pneumoniae to human epithelial cells infected with respiratory syncytial virus.

Pediatr Res 2004 Jun 21;55(6):972-8. Epub 2004 Apr 21.

Department of Paediatrics Infectious Diseases, Wilhelmina Children's Hospital, Room KE 04.136.2, Lundlaan 6, 3508 AB Utrecht, The Netherlands.

In the present study, we analyzed the effect of a preceding respiratory syncytial virus (RSV) infection of human respiratory epithelial cells on the adherence of Streptococcus pneumoniae tested by means of a cytometric fluorescence assay. Adherence of clinically relevant pneumococcal serotypes 3, 9, 14, 18, 19, and 23 was studied using uninfected and RSV-infected monolayers. To this end, monolayers of both human nasopharyngeal cells (HEp-2) and pneumocyte type II cells (A549) were infected with RSV serotype A. Adherence to uninfected epithelial cells varied between pneumococcal serotypes. After RSV infection of the monolayers, all serotypes showed a strongly (2- to 10- fold) and significantly increased adherence when compared with adherence to uninfected monolayers. Enhanced adherence was observed with both cell lines. By fluorescence and scanning electron microscopy, we observed redistribution of pneumococcal adherence over the epithelial surface due to RSV infection, with dense bacterial accumulations near to epithelial syncytia.
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http://dx.doi.org/10.1203/01.PDR.0000127431.11750.D9DOI Listing
June 2004

Molecular epidemiology of coagulase-negative staphylococci causing sepsis in a neonatal intensive care unit over an 11-year period.

J Clin Microbiol 2004 Mar;42(3):992-5

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.

Coagulase-negative staphylococci (CoNS) are the major causative microorganisms in neonatal nosocomial sepsis. Previous studies have shown that CoNS sepsis in the neonatal intensive care unit (NICU) is caused by predominant molecular types that are widely distributed among both neonates and staff. Some of these molecular types may persist in the NICU for years. The purpose of the present study was to determine the dynamic behavior of CoNS strains causing sepsis over a prolonged period of time by determining the molecular types of all blood isolates from septicemic infants over a period of 11 years (1991 to 2001). The results show that neonatal CoNS sepsis is increasingly caused by a few predominant molecular clusters. The most striking finding was that in recent years one molecular cluster emerged as the predominant cause of neonatal CoNS sepsis, responsible for no less than 31% (20 of 65) of blood isolates in 2001. Antibiotic resistance, particularly beta-lactam resistance, is probably an important selective force considering the high mecA gene carriage of CoNS blood isolates (70 to 92%). We conclude that neonatal CoNS sepsis is increasingly caused by a limited number of predominant molecular CoNS types and that antibiotic resistance is probably a major selective force.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC356815PMC
http://dx.doi.org/10.1128/jcm.42.3.992-995.2004DOI Listing
March 2004

Staphylococcal scalded skin syndrome in two very low birth weight infants.

J Perinat Med 2003 ;31(6):515-9

Department of Neonatology and Microbiology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.

Two premature infants with very low birth weight were diagnosed with staphylococcal scalded skin syndrome (SSSS) during hospitalization in the neonatal intensive care unit. This syndrome which is rare in premature infants, is characterized by blistering and superficial desquamation of the skin and is caused by two epidermolytic toxins (ETA and ETB) produced by Staphylococcus aureus. Staphylococcal scalded skin syndrome usually occurs in young children probably because of inefficient clearance of the epidermolytic toxins from the bloodstream, which causes dysfunction of cell adhesion in the superficial epidermis. Early diagnosis and early treatment with parenterally administered beta-lactamase resistant penicillins are important to prevent life threatening complications of this syndrome.
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http://dx.doi.org/10.1515/JPM.2003.078DOI Listing
April 2004

Does the tonsillar surface flora differ in children with and without tonsillar disease?

Acta Otolaryngol 2003 Sep;123(7):873-8

Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.

Objective: To investigate whether the tonsillar flora differ in children with and without adenotonsillar disease.

Material And Methods: Tonsil surface swabs were taken from 218 children indicated for adenotonsillectomy because of moderate symptoms of recurrent tonsillopharyngitis or adenotonsillar hypertrophy (T+Ads group). Control swabs were taken from 100 children without symptoms of adenotonsillar disease who visited the ophthalmology clinic. Potential respiratory pathogens were identified.

Results: Potential respiratory pathogens were found in 54% of the T+Ads group, compared to 41% of the control group (p = 0.04). Haemophilus influenzae was the commonest pathogen in both groups, being found in 41% of the T+Ads group and 34% of the control group. Moraxella catarrhalis was found more often in the T+Ads group compared to the control group: 7% vs 0% (p = 0.004). H. influenzae was found in 32% of the children with recurrent tonsillitis, compared to 48% of the children with symptoms of tonsillar hypertrophy (p = 0.03).

Conclusions: The prevalence of potential respiratory pathogens on the tonsillar surface of children with moderate symptoms of recurrent tonsillopharyngitis and/or tonsillar hypertrophy differs only slightly from that in children without symptoms of adenotonsillar disease. Variations in the microbial flora do not seem to play an essential role in the predisposition of these children to tonsillar disease.
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http://dx.doi.org/10.1080/00016480310000395DOI Listing
September 2003

Moraxella catarrhalis: from emerging to established pathogen.

Clin Microbiol Rev 2002 Jan;15(1):125-44

Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam EMCR, 3015 GD Rotterdam, The Netherlands.

Moraxella catarrhalis (formerly known as Branhamella catarrhalis) has emerged as a significant bacterial pathogen of humans over the past two decades. During this period, microbiological and molecular diagnostic techniques have been developed and improved for M. catarrhalis, allowing the adequate determination and taxonomic positioning of this pathogen. Over the same period, studies have revealed its involvement in respiratory (e.g., sinusitis, otitis media, bronchitis, and pneumonia) and ocular infections in children and in laryngitis, bronchitis, and pneumonia in adults. The development of (molecular) epidemiological tools has enabled the national and international distribution of M. catarrhalis strains to be established, and has allowed the monitoring of nosocomial infections and the dynamics of carriage. Indeed, such monitoring has revealed an increasing number of B-lactamase-positive M. catarrhalis isolates (now well above 90%), underscoring the pathogenic potential of this organism. Although a number of putative M. catarrhalis virulence factors have been identified and described in detail, their relationship to actual bacterial adhesion, invasion, complement resistance, etc. (and ultimately their role in infection and immunity), has been established in a only few cases. In the past 10 years, various animal models for the study of M. catarrhalis pathogenicity have been described, although not all of these models are equally suitable for the study of human infection. Techniques involving the molecular manipulation of M. catarrhalis genes and antigens are also advancing our knowledge of the host response to and pathogenesis of this bacterial species in humans, as well as providing insights into possible vaccine candidates. This review aims to outline our current knowledge of M. catarrhalis, an organism that has evolved from an emerging to a well-established human pathogen.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC118065PMC
http://dx.doi.org/10.1128/cmr.15.1.125-144.2002DOI Listing
January 2002