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1.  Epidemiology and outcome of major postoperative infections following cardiac surgery: Risk factors and impact of pathogen type 
Major postoperative infections (MPIs) are poorly understood complications of cardiac surgery. We examined the epidemiology, microbiology, and outcome of MPIs occurring after cardiac surgery.
The study cohort was drawn from the Society of Thoracic Surgeon National Cardiac Database and comprised adults who underwent cardiac surgery at 5 tertiary hospitals between 2000 and 2004. We studied the incidence, microbiology, and risk factors of MPI (bloodstream or chest wound infections within 30 days after surgery), as well as 30-day mortality. We used multivariate regression analyses to evaluate the risk of MPI and mortality.
MPI was identified in 341 of 10,522 patients (3.2%). Staphylococci were found in 52.5% of these patients, gram-negative bacilli (GNB) in 24.3%, and other pathogens in 23.2%. High body mass index, previous coronary bypass surgery, emergency surgery, renal impairment, immunosuppression, cardiac failure, and peripheral/cerebrovascular disease were associated with the development of MPI. Median postoperative duration of hospitalization (15 days vs 6 days) and mortality (8.5% vs 2.2%) were higher in patients with MPIs. Compared with uninfected individuals, odds of mortality were higher in patients with S aureus MPIs (adjusted odds ratio, 3.7) and GNB MPIs (adjusted odds ratio, 3.0).
Staphylococci accounted for the majority of MPIs after cardiac surgery. Mortality was higher in patients with Staphylococcus aureus- and GNB-related MPIs than in patients with MPIs caused by other pathogens and uninfected patients. Preventive strategies should target likely pathogens and high-risk patients undergoing cardiac surgery.
PMCID: PMC3535474  PMID: 22609237
Wound infection; Sepsis; Cardiac surgical procedures; Morbidity; Mortality
2.  Chelating agents exert distinct effects on biofilm formation in Staphylococcus aureus depending on strain background: role for clumping factor B 
Journal of Medical Microbiology  2012;61(Pt 8):1062-1070.
Staphylococcus aureus is a leading cause of catheter infections, and biofilm formation plays a key role in the pathogenesis. Metal ion chelators inhibit bacterial biofilm formation and viability, making them attractive candidates as components in catheter lock solutions. The goal of this study was to characterize further the effect of chelators on biofilm formation. The effect of the calcium chelators ethylene glycol tetraacetic acid (EGTA) and trisodium citrate (TSC) on biofilm formation by 30 S. aureus strains was tested. The response to subinhibitory doses of EGTA and TSC varied dramatically depending on strain variation. In some strains, the chelators prevented biofilm formation, in others they had no effect, and they actually enhanced biofilm formation in others. The molecular basis for this phenotypic variability was investigated using two related strains: Newman, in which biofilm formation was inhibited by chelators, and 10833, which formed strong biofilms in the presence of chelators. It was found that deletion of the gene encoding the surface adhesin clumping factor B (clfB) completely eliminated chelator-induced biofilm formation in strain 10833. The role of ClfB in biofilm formation activity in chelators was confirmed in additional strains. It was concluded that biofilm-forming ability varies strikingly depending on strain background, and that ClfB is involved in biofilm formation in the presence EGTA and citrate. These results suggest that subinhibitory doses of chelating agents in catheter lock solutions may actually augment biofilm formation in certain strains of S. aureus, and emphasize the importance of using these agents appropriately so that inhibitory doses are achieved consistently.
PMCID: PMC3542134  PMID: 22516131
4.  Presence of Genes Encoding Panton-Valentine Leukocidin Is Not the Primary Determinant of Outcome in Patients with Hospital-Acquired Pneumonia Due to Staphylococcus aureus 
Journal of Clinical Microbiology  2012;50(3):848-856.
The impact of Panton-Valentine leukocidin (PVL) on the outcome in Staphylococcus aureus pneumonia is controversial. We genotyped S. aureus isolates from patients with hospital-acquired pneumonia (HAP) enrolled in two registrational multinational clinical trials for the genetic elements carrying pvl and 30 other virulence genes. A total of 287 isolates (173 methicillin-resistant S. aureus [MRSA] and 114 methicillin-susceptible S. aureus [MSSA] isolates) from patients from 127 centers in 34 countries for whom clinical outcomes of cure or failure were available underwent genotyping. Of these, pvl was detected by PCR and its product confirmed in 23 isolates (8.0%) (MRSA, 18/173 isolates [10.4%]; MSSA, 5/114 isolates [4.4%]). The presence of pvl was not associated with a higher risk for clinical failure (4/23 [17.4%] versus 48/264 [18.2%]; P = 1.00) or mortality. These findings persisted after adjustment for multiple potential confounding variables. No significant associations between clinical outcome and (i) presence of any of the 30 other virulence genes tested, (ii) presence of specific bacterial clone, (iii) levels of alpha-hemolysin, or (iv) delta-hemolysin production were identified. This study suggests that neither pvl presence nor in vitro level of alpha-hemolysin production is the primary determinant of outcome among patients with HAP caused by S. aureus.
PMCID: PMC3295120  PMID: 22205797
5.  Influence of Host Genetics and Environment on Nasal Carriage of Staphylococcus aureus in Danish Middle-Aged and Elderly Twins 
The Journal of Infectious Diseases  2012;206(8):1178-1184.
Background. Nasal carriage is a major risk factor for Staphylococcus aureus infection. Approximately, one-quarter of adults carry S. aureus. However, the role of host genetics on S. aureus nasal carriage is unknown.
Methods. Nasal swabs were obtained from a national cohort of middle-aged and elderly Danish twins. Subjects colonized with S. aureus were identified by growth on selective plates and spa typing. A second sample was obtained from twins initially concordant for carriage. Twins found to again be colonized with S. aureus were defined as persistent carriers.
Results. The prevalence of S. aureus carriage among 617 twin pairs (monozygotic/dizygotic pairs: 112/505) was 26.3% (95% confidence interval [CI], 24.0%–28.9%). The concordance rate for carriage did not differ significantly between pairs of monozygotic (37.5%; 95% CI, 22.3%–53.8%) twins and same sex (24.2%; 95% CI, 15.4%–34.5%), and opposite sex (21.4%; 95% CI, 12.0%–33.4%) dizygotic twins. Despite shared childhoods, only 1 of 617 pairs was concordant with respect to lineage. Although heritability increased for S. aureus and lineage persistency, no significant heritability was detected.
Conclusion. In this study, host genetic factors exhibited only a modest influence on the S. aureus carrier state of middle-aged and elderly individuals.
PMCID: PMC3448969  PMID: 22872733
6.  Haplotype Association Mapping Identifies a Candidate Gene Region in Mice Infected With Staphylococcus aureus 
G3: Genes|Genomes|Genetics  2012;2(6):693-700.
Exposure to Staphylococcus aureus has a variety of outcomes, from asymptomatic colonization to fatal infection. Strong evidence suggests that host genetics play an important role in susceptibility, but the specific host genetic factors involved are not known. The availability of genome-wide single nucleotide polymorphism (SNP) data for inbred Mus musculus strains means that haplotype association mapping can be used to identify candidate susceptibility genes. We applied haplotype association mapping to Perlegen SNP data and kidney bacterial counts from Staphylococcus aureus-infected mice from 13 inbred strains and detected an associated block on chromosome 7. Strong experimental evidence supports the result: a separate study demonstrated the presence of a susceptibility locus on chromosome 7 using consomic mice. The associated block contains no genes, but lies within the gene cluster of the 26-member extended kallikrein gene family, whose members have well-recognized roles in the generation of antimicrobial peptides and the regulation of inflammation. Efficient mixed-model association (EMMA) testing of all SNPs with two alleles and located within the gene cluster boundaries finds two significant associations: one of the three polymorphisms defining the associated block and one in the gene closest to the block, Klk1b11. In addition, we find that 7 of the 26 kallikrein genes are differentially expressed between susceptible and resistant mice, including the Klk1b11 gene. These genes represent a promising set of candidate genes influencing susceptibility to Staphylococcus aureus.
PMCID: PMC3362298  PMID: 22690378
host genetic susceptibility; infectious disease; kallikrein gene family
7.  Genetic Variability in Beta-Defensins Is Not Associated with Susceptibility to Staphylococcus aureus Bacteremia 
PLoS ONE  2012;7(2):e32315.
Human beta-defensins are key components of human innate immunity to a variety of pathogens, including Staphylococcus aureus. The aim of the present study was to investigate a potential association between gene variations in DEFB1 and DEFB103/DEFB4 and the development of S. aureus bacteremia (SAB) employing a case-control design.
Cases were unique patients with documented SAB, identified with the National S. aureus Bacteremia Register, a comprehensive dataset of all episodes of community associated-SABs (CA-SAB) occurring in children (≤20 yrs) in Denmark from 1990 to 2006. Controls were age-matched healthy individuals with no history of SAB. DNA obtained from cases and controls using the Danish Newborn Screening Biobank were genotyped for functional polymorphisms of DEFB1 by Sanger sequencing and copy number variation of the DEFB103 and DEFB4 genes using Pyrosequencing-based Paralogue Ratio Test (P-PRT).
193 ethnic Danish SAB cases with 382 age-matched controls were used for this study. S. aureus isolates represented a variety of bacterial (i.e., different spa types) types similar to SAB isolates in general. DEFB1 minor allele frequencies of rs11362 (cases vs. controls 0.47/0.44), rs1800972 (0.21/0.24), and rs1799946 (0.32/0.33) were not significantly different in cases compared with controls. Also, DEFB4/DEFB103 gene copy numbers (means 4.83/4.92) were not significantly different in cases compared with controls.
Using a large, unique cohort of pediatric CA-SAB, we found no significant association between DEFB1 genetic variation or DEFB4/DEFB103 gene copy number and susceptibility for SAB.
PMCID: PMC3285211  PMID: 22384213
8.  Patient Detection of a Drug Dispensing Error by Use of Physician-Provided Drug Samples 
Pharmacotherapy  2012;22(12):1642-1643.
PMCID: PMC3736219  PMID: 12495175
9.  Evaluation of Dynamic [18F]-FDG-PET Imaging for the Detection of Acute Post-Surgical Bone Infection 
PLoS ONE  2012;7(7):e41863.
Diagnosing bone infection in its acute early stage is of utmost clinical importance as the failure to do so results in a therapeutically recalcitrant chronic infection that can only be resolved with extensive surgical intervention, the end result often being a structurally unstable defect requiring reconstructive procedures. [18F]-FDG-PET has been extensively investigated for this purpose, but the results have been mixed in that, while highly sensitive, its specificity with respect to distinguishing between acute infection and sterile inflammatory processes, including normal recuperative post-surgical healing, is limited. This study investigated the possibility that alternative means of acquiring and analyzing FDG-PET data could be used to overcome this lack of specificity without an unacceptable loss of sensitivity. This was done in the context of an experimental rabbit model of post-surgical osteomyelitis with the objective of distinguishing between acute infection and sterile post-surgical inflammation. Imaging was done 7 and 14 days after surgery with continuous data acquisition for a 90-minute period after administration of tracer. Results were evaluated based on both single and dual time point data analysis. The results suggest that the diagnostic utility of FDG-PET is likely limited to well-defined clinical circumstances. We conclude that, in the complicated clinical context of acute post-surgical or post-traumatic infection, the diagnostic utility accuracy of FDG-PET is severely limited based on its focus on the increased glucose utilization that is generally characteristic of inflammatory processes.
PMCID: PMC3408436  PMID: 22860021
10.  Proton-Binding Capacity of Staphylococcus aureus Wall Teichoic Acid and Its Role in Controlling Autolysin Activity 
PLoS ONE  2012;7(7):e41415.
Wall teichoic acid (WTA) or related polyanionic cell wall glycopolymers are produced by most Gram-positive bacterial species and have been implicated in various cellular functions. WTA and the proton gradient across bacterial membranes are known to control the activity of autolysins but the molecular details of these interactions are poorly understood. We demonstrate that WTA contributes substantially to the proton-binding capacity of Staphylococcus aureus cell walls and controls autolysis largely via the major autolysin AtlA whose activity is known to decline at acidic pH values. Compounds that increase or decrease the activity of the respiratory chain, a main source of protons in the cell wall, modulated autolysis rates in WTA-producing cells but did not affect the augmented autolytic activity observed in a WTA-deficient mutant. We propose that WTA represents a cation-exchanger like mesh in the Gram-positive cell envelopes that is required for creating a locally acidified milieu to govern the pH-dependent activity of autolysins.
PMCID: PMC3402425  PMID: 22911791
11.  Panton-Valentine Leukocidin Is Not the Primary Determinant of Outcome for Staphylococcus aureus Skin Infections: Evaluation from the CANVAS Studies 
PLoS ONE  2012;7(5):e37212.
The impact of Panton-Valentine leukocidin (PVL) on the severity of complicated skin and skin structure infections (cSSSI) caused by Staphylococcus aureus is controversial. We evaluated potential associations between clinical outcome and PVL presence in both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) isolates from patients enrolled in two large, multinational phase three clinical trials assessing ceftaroline fosamil for the treatment of cSSSI (the CANVAS 1 and 2 programs). Isolates from all microbiologically evaluable patients with monomicrobial MRSA or MSSA infections (n = 473) were genotyped by PCR for pvl and underwent pulsed-field gel electrophoresis (PFGE). Genes encoding pvl were present in 266/473 (56.2%) isolates. Infections caused by pvl-positive S. aureus were associated with younger patient age, North American acquisition, and presence of major abscesses (P<0.001 for each). Cure rates of patients infected with pvl-positive and pvl-negative S. aureus were similar overall (93.6% versus 92.8%; P = 0.72), and within MRSA-infected (94.5% vs. 93.1%; P = 0.67) and MSSA-infected patients (92.2% vs. 92.7%; P = 1.00). This finding persisted after adjustment for multiple patient characteristics. Outcomes were also similar when USA300 PVL+ and non-USA300 PVL+ infections were compared. The results of this contemporary, international study suggest that pvl presence was not the primary determinant of outcome in patients with cSSSI due to either MRSA or MSSA.
PMCID: PMC3356380  PMID: 22623995
12.  Catheter Colonization and Abscess Formation Due to Staphylococcus epidermidis with Normal and Small-Colony-Variant Phenotype Is Mouse Strain Dependent 
PLoS ONE  2012;7(5):e36602.
Coagulase-negative staphylococci (CoNS) form a thick, multilayered biofilm on foreign bodies and are a major cause of nosocomial implant-associated infections. Although foreign body infection models are well-established, limited in vivo data are available for CoNS with small-colony-variant (SCV) phenotype described as causative agents in implant-associated infections. Therefore, we investigated the impact of the Staphylococcus epidermidis phenotype on colonization of implanted PVC catheters and abscess formation in three different mouse strains. Following introduction of a catheter subcutaneously in each flank of 8- to 12-week-old inbred C57BL/6JCrl (B6J), outbred Crl:CD1(ICR) (CD-1), and inbred BALB/cAnNCrl (BALB/c) male mice, doses of S. epidermidis O-47 wild type, its hemB mutant with stable SCV phenotype, or its complemented mutant at concentrations of 106 to 109 colony forming units (CFUs) were gently spread onto each catheter. On day 7, mice were sacrificed and the size of the abscesses as well as bacterial colonization was determined. A total of 11,500 CFUs of the complemented mutant adhered to the catheter in BALB/c followed by 9,960 CFUs and 9,900 CFUs from S. epidermidis wild type in BALB/c and CD-1, respectively. SCV colonization was highest in CD-1 with 9,500 CFUs, whereas SCVs were not detected in B6J. The minimum dose that led to colonization or abscess formation in all mouse strains was 107 or 108 CFUs of the normal phenotype, respectively. A minimum dose of 108 or 109 CFU of the hemB mutant with stable SCV phenotype led to colonization only or abscess formation, respectively. The largest abscesses were detected in BALB/c inoculated with wild type bacteria or SCV (64 mm2 vs. 28 mm2). Our results indicate that colonization and abscess formation by different phenotypes of S. epidermidis in a foreign body infection model is most effective in inbred BALB/c followed by outbred CD-1 and inbred B6J mice.
PMCID: PMC3346766  PMID: 22586482

Results 1-12 (12)