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Objective: Advances in pharmacological care for RA have in general reduced functional disability. However, subgroups of patients may need treatment by a multidisciplinary team. This study aimed to describe the levels of functional ability and outcomes of patients with RA admitted for multidisciplinary rehabilitation in the past 20 years., Methods: Data from three observational studies including four cohorts (1, 1992; 2a, 2001; 2b, 2003 and 3, 2008) on outcomes of multidisciplinary rehabilitation for RA patients conducted in one Dutch rheumatology clinic were used. Baseline and change scores of the HAQ were compared using a one-way analysis of variance with post hoc multiple comparisons (Bonferroni correction)., Results: The mean HAQ scores were 1.94 (s.d. 0.74) for cohort 1, 1.40 (0.74) and 1.39 (0.66) for cohorts 2a and 2b, respectively, and 1.49 (0.59) for cohort 3, with the difference between cohort 1 on the one side and cohorts 2a/2b and 3 on the other side being statistically significant (P < 0.01). The mean changes in HAQ score between admission and discharge were 0.24 (s.d. 0.50) for cohort 1, 0.17 (0.49) for cohort 2a, 0.15 (0.37) for cohort 2b and 0.25 (0.46) for cohort 3., Conclusion: The level of functional disability of RA patients admitted for multidisciplinary rehabilitation decreased between 1992 and 2001. The magnitude of improvement in functional ability during admission was in the same range in all three periods. These results suggest that in the era of MTX and biologics there are patients with RA who have considerable disability and benefit from multidisciplinary rehabilitation.

Objective: To compare the effectiveness of two educational courses aiming to improve adherence to recommendations in a Dutch physiotherapy practice guideline for hip and knee OA., Methods: Physiotherapists (PTs) from three regions in The Netherlands were invited to participate in a study comparing an interactive workshop (IW) with conventional education (CE). Participants were randomly assigned to one of the two courses. Satisfaction with the course (scale 0-10), knowledge (score range 0-76) and guideline adherence (score range 0-72) were measured at baseline, immediately after the educational course and 3 months after that. Data were analysed using a linear mixed model., Results: In total, 203 (10%) PTs participated in the IW (n = 108) and the CE (n = 95). There were no differences between groups at baseline. Satisfaction was significantly higher in the IW than in the CE group [mean scores (S.D.) 7.5 (1.1) and 6.7 (1.6), respectively (P < 0.001)]. A significantly greater improvement in adherence was seen over time in the IW group compared with the CE group (F = 3.763, P = 0.024), whereas the difference in improvement of knowledge was not significant (F = 1.283, P = 0.278)., Conclusion: An IW led to greater satisfaction and was more effective in improving adherence to recommendations in a PT guideline on hip and knee OA than CE, whereas the increase in knowledge did not differ significantly.

Background: Although the increasing complexity and expansion of the body of knowledge in physical therapy have led to specialized practice areas to provide better patient care, the impact of specialization on guideline implementation has been scarcely studied. Objectives The objective of this study was to identify the similarities and differences in barriers to the implementation of a Dutch rheumatoid arthritis (RA) guideline by generalist and specialist physical therapists. Design This observational study consisted of 4 focus group interviews in which 24 physical therapists (13 generalist and 11 specialist physical therapists) participated., Methods: Physical therapists were asked to discuss barriers to the implementation of the RA guideline. Data were analyzed qualitatively using a directed approach to content analysis. Both the interviews and the interview analysis were informed by a previously developed conceptual framework., Results: Besides a number of similarities (eg, lack of time), the present study showed important, although subtle, differences in barriers to the implementation of the RA guideline between generalist physical therapists and specialist physical therapists. Generalist physical therapists more frequently reported difficulties in interpreting the guideline (cognitive barriers) and had less favorable opinions about the guideline (affective barriers) than specialist physical therapists. Specialist physical therapists were hampered by external barriers that are outside the scope of generalist physical therapists, such as a lack of agreement about the roles and responsibilities of medical professionals involved in the care of the same patient., Conclusions: The identified differences in barriers to the implementation of the RA guideline indicated that the effectiveness of implementation strategies could be improved by tailoring them to the level of specialization of physical therapists. However, it is expected that tailoring implementation strategies to barriers that hamper both generalist and specialist physical therapists will have a larger effect on the implementation of the RA guideline.

Objective: To investigate the validity and responsiveness of the World Health Organization Disability Schedule II (WHODAS II) in patients with established RA., Methods: In 85 RA patients admitted for rehabilitation, the WHODAS II (0-100) was applied at admission and 6 weeks after discharge. Additional assessments included measures of physical and psychological functioning, disease activity and quality of life. The internal consistency of the WHODAS II was determined with Cronbach's-alpha. Associations between the WHODAS II and other outcome measures were determined by Pearson's rank correlation coefficients. Responsiveness measures included the standardized response mean (SRM), effect size (ES) and responsiveness ratio (RR)., Results: Cronbach's-alpha of the WHODAS II total score was 0.91. The baseline WHODAS II total score correlated significantly with all other outcome measures, except for the 50-feet walk test, the timed-stands test and the Escola Paulista de Medicina Range of Motion scale. The mean WHODAS II total score improved from 40.5 (s.d. 14.9) at baseline to 4.6 at 6 weeks after discharge (95% CI -8.1, -1.2). The WHODAS II responsiveness scores were -0.35 (SRM), -0.34 (ES) and -0.58 (RR) at 6 weeks after discharge. CONCLUSION; The WHODAS II appeared to be internally consistent, valid and responsive to assess disability in patients with established RA admitted for multidisciplinary team care in terms of International Classification of Functioning, Disability and Health. The WHODAS II showed significant floor effects regarding the subscales--'understanding communicating' and 'getting along with people'. In a multidisciplinary setting, the additional use of measures to evaluate personal and environmental factors seems warranted.

Aims: Although probiotic prophylaxis has been suggested to prevent small bowel bacterial overgrowth, bacterial translocation and infection of pancreatic necrosis in severe acute pancreatitis, limited data are available on their antimicrobial activity., Methods and Results: Using the well-diffusion method, we studied the antimicrobial properties of a multispecies probiotic product (Ecologic 641) against a collection of pathogens cultured from infected pancreatic necrosis. All individual probiotic strains included in the multispecies preparation were able to inhibit the growth of the pathogens to some extent. However, the combination of the individual strains (i.e. the multispecies preparation) was able to inhibit all pathogenic isolates. Probiotic-free supernatants adjusted to pH 7 were not able to inhibit pathogen growth., Conclusion: Ecologic 641 is capable of inhibiting growth of a wide variety of pathogens isolated from infected pancreatic necrosis. The antimicrobial properties are to a large extent explained by the production of organic acids., Significance and Impact of the Study: Ecologic 641 is currently being used in a Dutch nationwide double-blind, placebo-controlled, randomized multicentre trial in patients with predicted severe acute pancreatitis.

In this retrospective cohort study, patients who had Staphylococcus aureus bacteremia but who lacked signs and symptoms of urinary tract infection due to S. aureus and who did not have an indwelling urinary catheter had a likelihood of S. aureus bacteriuria of 2.5% (2 of 79 patients). Therefore, we strongly question the theory that S. aureus bacteremia causes S. aureus bacteriuria.

Objectives: We assessed the current resistance rates of Haemophilus influenzae against beta-lactams and other agents in Europe and compared the results with those of our previously performed surveillance study., Methods: MICs of the antibiotics were determined using broth microdilution. The penicillin-binding domain of PBP3 of beta-lactamase (BL)-negative, amoxicillin-resistant (BLNAR) isolates was sequenced., Results: The percentage of BL-positive and BLNAR strains ranged from 0% to 17.6% and 0% to 33.9%, respectively. Compared with 1997/98 and 2002/03, the overall percentage of strains non-susceptible to amoxicillin decreased from 19.8% and 23.3%, respectively, to 16.4% in 2004/05. The percentage of BL-producing strains decreased from 11.0% and 13.7%, respectively, to 7.6%, whereas the number of BLNAR strains remained stable (8.8% and 9.6%, respectively, versus 8.8% in 2004/05). Comparison of penicillin binding protein (PBP) 3B gene sequences between BLNAR and susceptible strains revealed novel amino acid mutations., Conclusions: In spite of large inter-regional differences, the overall resistance of H. influenzae to amoxicillin in Europe seems to decline due to a decreasing number of BL-producing strains, whereas the overall percentage of BLNAR strains seems relatively constant.

Background: Control of vancomycin-resistant Enterococcus faecium (VRE) in European hospitals is hampered because of widespread asymptomatic carriage of VRE by healthy Europeans. In 2000, our hospital (The University Medical Center Utrecht, Utrecht, The Netherlands) was confronted with a large outbreak of VRE., Intervention: On the basis of genotyping (by pulsed-field gel electrophoresis), epidemic and nonepidemic VRE strains were distinguished, and infection-control measures were exclusively targeted toward epidemic VRE. The outbreak was retrospectively divided into 3 periods of different infection-control measures. Compliance with use of alcohol-based hand rubs was enforced during all periods. Period I involved active surveillance, isolation of carriers, and cohorting (duration, 4 months); preemptive isolation of high-risk patients for VRE colonization was added in period II (7 months); and cohorting and preemptive isolation were abandoned in period III (18 months)., Methods: When the outbreak was identified, 27 patients in 6 wards were colonized; 93% were colonized with an epidemic VRE strain. Detection rates of nonepidemic VRE were 3.5%, 3.0%, and 2.9% among 683, 810, and 977 screened patients in periods I, II, and III, respectively, comparable to a prevalence of 2% (95% confidence interval [CI], 1%-3.5%) among 600 nonhospitalized persons. The relative risks of detecting epidemic VRE in periods II and III, compared with period I, were 0.67 (95% CI, 0.41-1.10) for period II and 0.02 (95% CI, 0.002-0.6) for period III. Infection-control measures were withheld for patients colonized with nonepidemic VRE (76 [54%] of 140 patients with a test result positive for VRE). Use of alcohol-based hand rubs increased by 31%-275% in outbreak wards., Conclusion: Genotyping-targeted infection control, isolation of VRE carriers, enhancement of hand-hygiene compliance, and preemptive isolation successfully controlled nosocomial spread of epidemic VRE infection.

Aims: To test prospectively the activity of cefixime and comparators against Haemophilus influenzae from Europe and to compare the susceptibilities of isolates from 1997/1998 with isolates from 2002/2003 paying special attention to the epidemiology of amoxicillin resistance., Methods: MICs of antibiotics were determined using broth microdilution. For beta-lactamase-negative isolates with reduced susceptibility to amoxicillin, the nucleotide sequence of the penicillin-binding domain of PBP3 was determined., Results: The prevalence of beta-lactamase-positive isolates in certain countries has reached 38%. During the period 1997/1998, 8.8% of the isolates were beta-lactamase-negative and non-susceptible to amoxicillin (BLNAR). During the period 2002/2003, 9.6% of the isolates were BLNAR. The emergence of the BLNAR phenotype of H. influenzae was demonstrated in all countries with a prevalence ranging from 2% to 20%. The penicillin-binding domain of PBP3 from 30 sequenced isolates showed known amino acid substitutions, although no amino acid changes were observed in two BLNAR isolates. Clonal spread of BLNAR strains was limited or absent in our study. Both beta-lactamase-producing and BLNAR strains of H. influenzae were fully susceptible to cefixime. However, neither beta-lactamase-producing nor BLNAR isolates were fully susceptible to the other cephalosporins tested. All isolates were also fully susceptible to levofloxacin, moxifloxacin, azithromycin and telithromycin., Conclusions: The prevalence of the BLNAR phenotype in Europe is increasing, but no new amino acid substitutions were detected in the penicillin-binding domain of PBP3. Cefixime remains a useful treatment option for respiratory tract infections, including in areas with increasing resistance problems.

Neutrophils can be primed by bacterial lipopolysaccharide (LPS) for an enhanced oxidative burst, which is a key element in the pathogenesis of Gram-negative sepsis. Some serum proteins (e.g. lipopolysaccharide-binding protein) avidly bind LPS and markedly enhance receptor binding and cellular activation while other serum factors (lipoproteins, bactericidal/permeability-increasing protein) neutralize LPS and prevent neutrophil activation. In this paper we examined the kinetics of this priming reaction in whole blood. To study the balance between neutrophil activation and LPS neutralization a sensitive chemiluminescence assay was used in a whole blood system. LPS was able to prime neutrophils for enhanced oxidative burst in whole blood with an optimum incubation time of 25 min. However, LPS was neutralized very rapidly with a t(1/2) of 10 min. After 20 min a second priming factor was already generated, which was shown to be monocyte-derived tumour necrosis factor (TNF).

Previous work had shown that the immunogenicity of conjugate vaccine against group C meningococci (CRM-MenC) is enhanced when it is delivered intranasally (inl) with mucosal adjuvants, such as mutants of the Escherichia coli enterotoxin (LT), and with delivery systems such as chitosan derivatives. We show, in mice, that the concomitant use of limiting doses of the fully nontoxic LTK63 mutant as a mucosal adjuvant and of the trimethyl derivative of chitosan as a delivery system allows the reduction of each of the components for the induction of antibody and bactericidal responses to CRM-MenC conjugate vaccine delivered inl at titers similar to or higher than those induced by parenteral immunization. These data could affect the design of efficacious mucosal vaccines and their safety.

Objectives: The use of multiple drug combinations in current anti-human immunodeficiency virus (HIV) therapy allows lower dosages of individual drugs and results in enhancement of the therapeutic effect due to synergic interactions between different drugs. We have shown that o-(acetoxyphenyl)hept-2-ynyl sulphide (APHS), a recently developed non-steroidal anti-inflammatory drug, shows anti-HIV activity in a dose-dependent manner. The first aim of this study was to investigate whether APHS can act synergically with the clinically available reverse transcriptase and protease inhibitors (RTIs and PIs, respectively) in vitro. Because of the increasing prevalence of RTI- and PI-resistant HIV-1 strains, the second aim of this study was to assess the antiviral activity of APHS against drug-resistant HIV-1 strains in vitro., Materials and Methods: HIV-infected peripheral blood mononuclear cells (PBMC) were treated for 7 days with different combinations of APHS and RTIs or PIs. The MT-2 cell line was infected with different HIV-1 strains and treated with APHS for 5 days., Results: APHS showed synergic interactions with the RTIs zidovudine, lamivudine and efavirenz and with the PIs indinavir and ritonavir. The 50% inhibitory concentration (IC50) of APHS in this assay dropped from 13 microM when used alone, to 5 micro M after combination with an RTI or PI. In combination with APHS the IC50 of the RTI and PI drugs tested also dropped. APHS inhibits the replication of HIV-1 strains resistant to zidovudine, lamivudine, stavudine, didanosine, zalcitabine and ritonavir., Conclusions: These results indicate that APHS can be combined with RTIs and PIs and can inhibit several NRTI and PI-resistant HIV-1 strains.

This study investigated the extent to which multidrug resistance (MDR) among Enterobacteriaceae is related to DNA elements called "integrons," whether the relationship is species dependent or origin dependent, and which resistance patterns are associated with integrons. Analysis of 867 nonrepeat isolates comprising 8 species and originating from the community and 23 European hospitals showed a significant relation between MDR and integrons, independent of species or origin. Although resistance to each tested antimicrobial agent was significantly associated with integrons, only resistance to sulfamethoxazole, cotrimoxazole, gentamicin, tobramycin, ampicillin, piperacillin, and cefuroxime predicted the presence of integrons. Combined resistance to both ampicillin and sulfamethoxazole-trimethoprim was the starting point for the development of resistance to additional beta-lactams, aminoglycosides, cephalosporins, and ciprofloxacin, a development paralleled by an increasing prevalence of integrons. The acquisition of resistance genes is not random, and the transfer of integron-carrying elements plays a dominant role in the development of MDR by Enterobacteriaceae.

AZD2563 is a new oxazolidinone that has targeted activity against Gram-positive bacteria. The in vitro activity of AZD2563 and nine comparators against 1543 European enterococcal, staphylococcal and streptococcal isolates was determined. The compound is a potent oxazolidinone, with no isolate tested displaying an MIC > 4 mg/L and 94.4% having an MIC < or =2 mg/L. Compared with linezolid, the distribution of MICs for all species of bacteria tested, with the exception of Enterococcus faecium, was shifted by one or two dilution steps to lower values for AZD2563. Thus, this oxazolidinone is a promising new antibiotic for the treatment of infections with Gram-positive cocci.

Multidrug resistance in gram-negative bacteria appears to be primarily the result of the acquisition of resistance genes by horizontal transfer. To what extent horizontal transfer may be responsible for the emergence of multidrug resistance in a clinical setting, however, has rarely been investigated. Therefore, the integron contents of isolates collected during a nosocomial outbreak of genotypically unrelated multidrug-resistant Enterobacteriaceae were characterized. The integron was chosen as a marker of transfer because of its association with multiresistance. Some genotypically identical isolates harbored different integrons. Grouping patients carrying the same integron yielded 6 epidemiologically linked clusters, with each cluster representing a different integron. Several patients carried multiple species harboring the same integron. Conjugation experiments with these strains resulted in the transfer of complete resistance patterns at high frequencies (10(-2) to 10(-4)). These findings provide strong evidence that the horizontal transfer of resistance genes contributed largely to the emergence of multidrug-resistant Enterobacteriaceae in this clinical setting.

Interpretive reading analyses the complete resistance profiles of bacteria to multiple antibiotics and infers the resistance mechanisms present; it aids therapeutic choice and enhances surveillance data. We evaluated the Advanced Expert System (AES), which interprets MICs generated by the VITEK 2. Ten European laboratories tested 42 reference strains and 76-106 of their own strains, representing important resistance genotypes. Interpretive reading by the VITEK 2 AES achieved full agreement with genotype data for 88-89% of strains, with the correct mechanism identified as one of two possibilities for a further 5-6%. Mechanisms inferred with 90% agreement with reference data included methicillin resistance in staphylococci, glycopeptide resistance in enterococci, quinolone resistance in staphylococci and Enterobacteriaceae, AAC(6')-APH(2")-mediated aminoglycoside resistance in Gram-positive cocci, erm-mediated macrolide resistance in pneumococci, extended-spectrum beta-lactamases (ESBLs) in Enterobacteriaceae and Pseudomonas aeruginosa, and acquired penicillinases in Enterobacteriaceae. VanA, VanB and VanC phenotypes of enterococci were distinguished reliably, and ESBL production was accurately inferred in AmpC-inducible species as well as Escherichia coli and Klebsiella spp. Mechanisms identified, but only as possibilities among several, included IRT-type beta-lactamases and individual aminoglycoside-modifying enzymes in Enterobacteriaceae. Most disagreements with reference data concerned pneumococci found to have high-level penicillin resistance by the VITEK 2 AES but previously determined, phenotypically, to have intermediate resistance. When ESBL production was inferred in E. coli and klebsiellae, the VITEK 2 AES edited susceptible results for cephalosporins (except cefoxitin) to resistant; when an acquired penicillinase was inferred in Enterobacteriaceae, piperacillin results were edited to resistant; and when staphylococci were found methicillin resistant, resistance was reported for all beta-lactams. Further editing may be desirable (e.g. of cephalosporin results for salmonellas inferred to have ESBLs).

The SENTRY Antimicrobial Surveillance Program has incorporated molecular strain typing and resistance genotyping as a means of providing additional information that may be useful for understanding pathogenic microorganisms worldwide. Resistance phenotypes of interest include multidrug-resistant pathogens, extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, and fluoroquinolone-resistant (FQR) strains of gram-negative bacilli and Streptococcus pneumoniae. Clusters of > or =2 isolates within a given resistance profile that are linked temporally and by hospital location are flagged for DNA fingerprinting. Further characterization of organisms with respect to resistance genotype is accomplished with use of polymerase chain reaction and DNA sequencing. This process has been highly successful in identifying clonal spread within clusters of multiresistant pathogens. Between 50% and 90% of MRSA clusters identified by phenotypic screening contained evidence of clonal spread. Among the Enterobacteriaceae, ESBL-producing strains of Escherichia coli and Klebsiella pneumoniae are the most common pathogens causing clusters of infection, and approximately 50% of recognized clusters demonstrate clonal spread. Clusters of Pseudomonas aeruginosa, Acinetobacter species, and Stenotrophomonas maltophilia have been noted with clonal spread among patients with urinary tract, respiratory, and bloodstream infections. Characterization of mutations in the FQR-determining region of phenotypically susceptible isolates of E. coli and S. pneumoniae has identified first-stage mutants among as many as 40% of isolates. The ability to characterize organisms phenotypically and genotypically is extremely powerful and provides unique information that is important in a global antimicrobial surveillance program.

As part of the SENTRY Antimicrobial Surveillance Program, a total of 1078 Acinetobacter species and 842 Stenotrophomonas maltophilia isolates were collected between January 1997 and December 1999 from 5 geographic regions (Canada, the United States, Latin America, Europe, and the Asia-Pacific). The frequency of infections (by geographic region and body site), including those due to imipenem-resistant Acinetobacter species and trimethoprim-sulfamethoxazole (TMP-SMZ)-resistant S. maltophilia, was evaluated. The possibility of seasonal variations in bloodstream infections caused by Acinetobacter species was studied, as was the activity of several therapeutic antimicrobials against all strains. Acinetobacter species and S. maltophilia were most frequently associated with pulmonary infections, independent of the region evaluated. In contrast, patterns of antimicrobial resistance markedly varied among distinct geographic regions, especially for nosocomial isolates. Although the carbapenems were the most active antimicrobials against Acinetobacter species, nearly 11.0% of the nosocomial isolates were resistant to this drug group in both regions. TMP-SMZ, ticarcillin-clavulanic acid, gatifloxacin, and trovafloxacin were the only agents with consistent therapeutic activity against S. maltophilia isolates. Rates of resistance to TMP-SMZ ranged from 2% in Canada and Latin America to 10% in Europe. The geographic differences in resistance patterns among Acinetobacter species and S. maltophilia isolates observed in this study emphasize the importance of local surveillance in determining the most adequate therapy for acinetobacter and S. maltophilia infections and the possible clonal, epidemic nature of occurrence.

To study clonal diversity of penicillin-resistant Streptococcus pneumoniae, 161 randomly selected isolates with reduced susceptibility to penicillin, collected from the nasopharynx of children under 5 years of age with community-acquired pneumonia and healthy controls from public day-care and immunization centres in Fortaleza, Brazil, were characterized by microbiological and serological techniques and automated ribotyping. Also included were 44 randomly selected penicillin-susceptible strains and three international reference strains. With automated ribotyping 75 ribopatterns were observed: 50 ribogroups were unique and 25 ribogroups were represented by two or more isolates. Genetic diversity was extensive but some degree of genetic homogeneity was found in strains from children with pneumonia, strains from children in day-care centres, isolates with reduced susceptibility to penicillin and isolates expressing 'paediatric' serogroups. Fourteen (56%) clusters contained both isolates with reduced penicillin susceptibility and penicillin-susceptible isolates, suggesting emergence of penicillin resistance. In general, there was a good correlation between ribogroups and serogroups, but 12 (48%) clusters contained isolates with alternative serogroups. Isolates with such alternative serogroups were more often encountered in penicillin-susceptible strains (41%) than in strains with reduced susceptibility to penicillin (7%). Thirty-eight (19%) isolates (including seven penicillin-susceptible strains) showed ribotypes indistinguishable from those of two international epidemic clones of S. pneumoniae: ribogroup 54-S-1 (15 isolates) with a ribopattern characteristic of the 23F multiresistant 'Spanish/USA' clone and ribogroup 74-S-3 (23 isolates) with a pattern similar to that of the 6B multiresistant 'Spanish' clone.

Selective digestive decontamination (SDD) is the most extensively studied method for the prevention of infection in patients in intensive care units (ICUs). Despite 27 prospective randomized studies and six meta-analyses, routine use of SDD is still controversial. In this review, we summarize the available scientific information on effectiveness of SDD in ICU patients. The effects of SDD have been studied in different combinations of the concept, using different antibiotics. Comparison of the individual studies, therefore, is difficult. In most studies, SDD resulted in significant reductions in the number of diagnoses of ventilator-associated pneumonia. However, incidences of ventilator-associated pneumonia in control groups ranged from 5% to 85%. Moreover, these reductions in incidences of ventilator-associated pneumonia in individual studies were not associated with improved patient survival, reductions of duration of ventilation or ICU stay, or reductions in antibiotic use. The numbers of patients studied are too small to determine effects on patient survival. Although two meta-analyses suggested a 20% mortality reduction when using the full concept of SDD (topical and systemic prophylaxis) these results should be interpreted with caution. Formal cost-benefit analyses of SDD have not been performed. SDD is associated with the selection of microorganisms that are intrinsically resistant to the antibiotics used. However, the studies are too small and too short to investigate whether SDD will lead to development of antibiotic resistance. As long as the benefits of SDD (better patient survival, reduction in antibiotic use or improved cost-effectiveness) have not been firmly established, the routine use of SDD for mechanically ventilated patients is not advised.

Human immunodeficiency virus type-1 (HIV-1)-associated dementia (HAD) is a neurodegenerative disease characterized by HIV infection and replication in brain tissue. HIV-1-infected monocytes overexpress inflammatory molecules that facilitate their entry into the brain. Prostanoids are lipid mediators of inflammation that result from cyclooxygenase-2 (COX-2) activity. Because COX-2 is normally induced during inflammatory processes, the aim of this study was to investigate whether COX-2 expression is up-regulated during monocyte-brain endothelium interactions. In vitro cocultures of HIV-infected macrophages and brain endothelium showed an up-regulation of COX-2 expression by both cell types. This up-regulation occurs via an interleukin-1beta (IL1beta)-dependent mechanism in macrophages and via an IL-1beta-independent mechanism in endothelial cells. Thus, interactions between HIV-infected monocytes and brain endothelium result in COX-2 expression and, as such, might contribute to the neuropathogenesis of HIV infection.

The in vitro potency of three newer fluoroquinolones, moxifloxacin, clinafloxacin and sitafloxacin was tested against 248 genetically defined Staphylococcus aureus isolates, comprising 116 unrelated S. aureus, seven heterogeneous intermediate vancomycin-resistant S. aureus strains as well as 125 clonally related methicillin-resistant S. aureus. All strains were susceptible to clinafloxacin and sitafloxacin based on an investigational breakpoint of 1 mg/L and were less influenced by mutations within the grl and gyr gene loci. In one-quarter to one-third of the strains tested, reserpine decreased slightly the MICs of moxifloxacin, clinafloxacin and sitafloxacin. Compared with moxifloxacin, clinafloxacin and sitafloxacin showed a significantly increased anti-staphylococcal potency.

The polymerase chain reaction (PCR) was used to study the prevalence of the macrolide resistance genes ermA, ermB, ermC, msrA/msrB, ereA and ereB, in 851 clinical isolates of Staphylococcus aureus and 75 clinical isolates of Enterococcus faecium that were erythromycin resistant. The isolates were from 24 European university hospitals. In S. aureus, the ermA gene was more common in methicillin-resistant S. aureus (MRSA) isolates (88%) than in methicillin-susceptible S. aureus (MSSA) isolates (38%), and occurred mainly in strains with constitutive MLS(B) expression. In contrast, ermC was more common in MSSA (47%) than in MRSA (5%), occurring mainly in strains with inducible expression. The ereB gene was only found in MRSA isolates expressing a constitutive MLS(B) phenotype (1%). The ereA gene was not detected. Macrolide resistance by efflux due to the msrA/msrB gene was only detected in MSSA isolates (13%). In contrast to S. aureus, erythromycin resistance in E. faecium was almost exclusively due to the presence of the ermB gene (93%).

Two unrelated strains of Staphylococcus aureus, one with a single mutation in grlA, the other with multiple mutations in gyrA, gyrB, grlA, grlB, norA and the norA promoter region, encoding low-level and high-level ciprofloxacin resistance, respectively, were studied. The characterized mutations in these genes were conserved when both strains were passaged for at least 500 generations in an antibiotic-free environment. New, rapidly stabilized mutations and higher MICs were detected for strains passaged in sub-MIC ciprofloxacin concentrations. The seeming irreversibility of quinolone resistance may affect the long-term success of this drug class.

As part of the European arm of the SENTRY Antimicrobial Surveillance Program, 25 European university hospitals referred 9613 blood isolates for in vitro testing against >20 antimicrobial agents. Escherichia coli, Staphylococcus aureus, coagulase-negative Staphylococcus, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the 5 most frequent isolates and accounted for two-thirds of all referrals, with minor regional variation. Of these, approximately 0.36% of E. coli and 16.7% of K. pneumoniae isolates proved to be potential extended-spectrum beta-lactamase producers, and their incidence clearly varied regionally. Quinolone resistance was detected among gram-negative species; in particular, P. aeruginosa and Acinetobacter species. Considerable regional variation was observed in the incidences of methicillin resistance in S. aureus and penicillin resistance in Streptococcus pneumoniae. The incidence of vancomycin resistance in enterococci was relatively low overall and primarily associated with Enterococcus faecium. However, extrapolation of these data to smaller and nonteaching hospitals should be undertaken with caution, since resistance rates may be lower in these facilities.

As part of a nationwide surveillance in The Netherlands during 1994-1997, 53 patients with invasive group A streptococcal (GAS) infections were evaluated for medical history, symptoms, and outcome. Patients' isolates were tested for the production of pyrogenic exotoxins A (SPE-A) and B (SPE-B). Acute-phase sera from all patients and convalescent sera from 12 patients were investigated for the presence of antibodies against SPE-A and SPE-B. Twenty-three patients developed toxic shock-like syndrome and 16 died. Absence of antibodies against SPE-A and/or SPE-B was a risk factor for developing invasive streptococcal disease. Toxic shock and mortality were associated with a lack of anti-SPE-A antibodies (P<.025). Anti-SPE-A antibodies were found in convalescent sera from all patients infected by speA-positive isolates. Virtually all invasive speA-positive streptococci expressed SPE-A protein in vitro. Thus antibodies against SPE-A appeared vital for mediating the outcome of invasive GAS disease in this population.

Macrolide, lincosamide and streptogramin (MLS) antibiotics are chemically distinct inhibitors of bacterial protein synthesis. Resistance to MLS antibiotics may be constitutive or inducible. The purpose of this study is to update our understanding of the prevalence of different forms of MLS resistance in Europe. The analysis of 3653 clinical pneumococcal, staphylococcal and enterococcal isolates exhibited an average percentage of 21.3% and 6.2% intermediate and high-level penicillin-resistant Streptococcus pneumoniae, 21.8% methicillin-resistant Staphylococcus aureus and 11% vancomycin-resistant Enterococcus faecium. Geographical differences in erythromycin and clindamycin resistance in isolates of S. pneumoniae and S. aureus strongly reflect geographical variations in susceptibility to penicillin and methicillin, respectively. A very narrow range of MICs was obtained with quinupristin/dalfopristin, with no S. pneumoniae, S. aureus and E. faecium isolate having an MIC of > 4 mg/L, indicating a possible role of quinupristin/dalfopristin in the treatment of infections by multi-resistant Gram-positive bacteria.

The population structure of Bordetella pertussis in The Netherlands in 5 successive periods, encompassing 1949-1996, was analyzed by DNA typing ("fingerprinting"). In 10 years following the introduction of wide-scale vaccination in 1953, a decrease in genotypic diversity (GD) was observed, suggesting clonal expansion of strains that were adapted to vaccine-induced immunity. In subsequent periods, GD increased to prevaccination levels, probably reflecting a gradual adaptation of the B. pertussis population involving many lineages. In the 1990s, GD decreased again. This decrease coincided with an antigenic shift in the surface protein pertactin. No evidence was found for changes in DNA types or GD in 1996, when a large pertussis epidemic occurred. Thus, gradual changes in the bacterial population previous to 1996 were probably the cause of the 1996 epidemic. The results herein suggest that vaccination has selected for strains that are adapted to a highly vaccinated population. Similar changes may have occurred in other countries, explaining the reemergence of pertussis in vaccinated populations.

Aminoglycosides still play an important role in antistaphylococcal therapies, although emerging resistance amongst staphylococci is widespread. To further our understanding of the prevalence of aminoglycoside resistance in Europe, we tested 699 and 249 consecutive unrelated clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci (CNS), respectively, from the SENTRY Antimicrobial Surveillance Program, for susceptibility to gentamicin, tobramycin, kanamycin and streptomycin, and examined the relationship between susceptibility to these antimicrobials and susceptibility to methicillin. Three hundred and sixty-three staphylococcal isolates demonstrated resistance to at least one of the aminoglycosides tested; all of these isolates were screened for the presence of aac(6')-Ie + aph(2"), ant(4')-Ia and aph(3')-IIIa, the genes encoding the most clinically relevant aminoglycoside-modifying enzymes. S. aureus isolates derived from hospital-acquired pneumonia tended to be more resistant to aminoglycosides and methicillin than isolates from blood or wound infections. In S. aureus, resistance to aminoglycosides was closely associated with methicillin resistance. Susceptibility of S. aureus to gentamicin has decreased by 9% from previous European studies to a current level of 77%, while susceptibility of CNS, currently at 67%, has increased by 21%. Geographical variation occurred, correlating with methicillin resistance, although intra-country variation was considerable. aac(6')-Ie + aph(2"), ant(4')-Ia and aph(3')-IIIa were found throughout Europe in 68%, 48% and 14% respectively of staphylococci resistant to at least one aminoglycoside. aph(3')-IIIa was considerably more common in methicillin-susceptible S. aureus and CNS isolates; the reverse was true for the other two resistance genes. The prevalence of ant(4')-Ia and aph(3')-IIIa genes in aminoglycoside-resistant staphylococci was significantly greater than that reported in previous European studies.

Class I integrons are associated with carriage of genes encoding resistance to antibiotics. Expression of inserted resistance genes within these structures can be poor and, as such, the clinical relevance in terms of the effect of integron carriage on susceptibility has not been investigated. Of 163 unrelated Gram-negative isolates randomly selected from the intensive care and surgical units of 14 different hospitals in nine European countries, 43.0% (70/163) of isolates were shown to be integron-positive, with inserted gene cassettes of various sizes. Integrons were detected in isolates from all hospitals with no particular geographical variations. Integron-positive isolates were statistically more likely to be resistant to aminoglycoside, quinolone and beta8-lactam compounds, including third-generation cephalosporins and monobactams, than integron-negative isolates. Integron-positive isolates were also more likely to be multi-resistant than integron-negative isolates. This association implicates integrons in multi-drug resistance either directly through carriage of specific resistance genes, or indirectly by virtue of linkage to other resistance determinants such as extended-spectrum beta-lactamase genes. As such their widespread presence is a cause for concern. There was no association between the presence of integrons and susceptibility to cefepime, amikacin and the carbapenems, to which at least 97% of isolates were fully susceptible.

In Staphylococcus aureus, in addition to mutations in the grl and gyr gene loci, multidrug efflux pumps like NorA contribute to decreased fluoroquinolone susceptibility. Efflux pumps can be inhibited by the plant alkaloid reserpine, which, at 20 mg/L, reduced sparfloxacin, moxifloxacin and ciprofloxacin IC50s and MICs by up to four-fold in 11, 21 and 48 of the 102 unrelated clinical isolates tested, respectively. The effect was less pronounced with the hydrophobic drugs sparfloxacin and moxifloxacin than with the hydrophilic drug ciprofloxacin and was stable in all 25 clonally related isolates tested.

The relationship between T cell activation and human immunodeficiency virus type 1 (HIV-1) replication was studied in HIV-infected subjects, 20 with and 10 without anti-HIV treatment. Expression of Ki-67 proliferation-associated antigen was increased in CD4+ and CD8+ T cells and correlated with HLA-DR. In subjects without anti-HIV treatment, the plasma HIV-1 RNA level correlated with HLA-DR in CD4+ T cells, with Ki-67 in CD8+ T cells, and with expression of CD38 in both T cell subsets. A proportion of treated subjects had increased T cell activation despite 4 months of highly active antiretroviral treatment (HAART). In subjects receiving HAART, a high percentage of HLA-DR+ CD4+ T cells was associated with signs of opportunistic infections. This work supports the concept that, in the natural course of HIV-1 infection, HIV replication itself leads to general T cell activation and that opportunistic infections generate additional CD4+ T cell activation and HIV replication.

The topical agent mupirocin plays a crucial role in strategies designed to control outbreaks of methicillin-resistant Staphylococcus aureus. The extent of high- or low-level mupirocin resistance amongst S. aureus from European hospitals is not known. Six hundred and ninety-nine S. aureus and 249 coagulase-negative staphylococci (CNS) derived from blood, hospital-acquired pneumonia or skin and soft tissue infections from 19 European hospitals were tested for susceptibility to mupirocin and oxacillin. Methicillin sensitivity was found in 72% and 32% of S. aureus and CNS, respectively. High-level mupirocin resistance was detected in 1.6% of S. aureus and 5.6% of CNS isolates, while low-level mupirocin resistance was detected in 2.3% of S. aureus and 7.2% of CNS isolates. Amongst S. aureus, methicillin-resistant isolates were twice as likely to have high- or low-level mupirocin resistance. This difference was less pronounced in CNS. No relationship was found between the site of infection and prevalence of mupirocin resistance. High- and low-level mupirocin resistance was detected amongst staphylococci from 10 and 16 of the hospitals studied, respectively. To maintain the relatively low prevalence of mupirocin resistance in Europe amongst both S. aureus and CNS, the prudent use of mupirocin restricted to defined infection control strategies should be emphasized.

The presence of sequences related to the agr of Staphylococcus aureus was demonstrated in Staphylococcus epidermidis by agr-specific PCR, and Southern blot. The agr-like locus of S. epidermidis A086 was cloned and sequenced. An overall homology of 68% was found between the agr locus from S. epidermidis and S. aureus. The agr locus from S. epidermidis was organized similar to those from S. aureus and S. lugdunensis. The putative RNAII molecule contains four open reading frames, agr A, B, C and D. AgrA was a response regulator. AgrB showed homology with transducer and translocase molecules. AgrC is expected to act as a histidine protein kinase in which a leucine zipper is present. AgrD is presumably processed into an autoinducer peptide. The putative RNAIII molecule contained an open reading frame encoding a putative 26 amino acid (aa) polypeptide, which differed in 3 aa from the RNAIII encoded delta-toxin of S. aureus. Kinetic studies showed that the production of this RNAIII was elevated during the post-exponential phase. delta-Toxin activity was demonstrated for 21 of 23 tested S. epidermidis strains. Kinetic studies of the production of delta-toxin showed that the toxin was produced during the post-exponential phase. Sequencing of S. epidermidis A097, which showed a delayed agr-response, revealed a truncated AgrC lacking the histidine kinase domain. These data indicate that an agr-like locus is active in S. epidermidis during the post-exponential phase.