Influence of step length on 6-minute walk test performance in patients with chronic heart failure.

OBJECTIVE: To investigate the influence of gait parameters including step length and walking speed during performance of the 6-minute walking test (6MWT) in patients with chronic heart failure (CHF). DESIGN: Observational study. SETTING: Specialist heart failure clinic. PARTICIPANTS: Patients with CHF and aged-matched, apparently healthy controls. INTERVENTIONS: Each patient and control performed a 6MWT following a standardised protocol in a 15m corridor. The number of steps (defined as step from left foot to right foot) taken every 15m was counted, and reported as minute-by-minute changes in 6MWT performance. In addition, minute-by-minute changes in time taken to complete 15m and mean walking speed throughout the test were calculated. MAIN OUTCOME MEASURES: Walking speed and step length. RESULTS: Thirty patients with CHF {87% males; mean age 75 [standard deviation (SD) 8] years} and 10 healthy controls [80% males; mean age 77 (SD 11) years] undertook the 6MWT. For the CHF group, the mean distance walked was 309 (SD 48)m and the peak Borg score was 12 (SD 1). For the controls, the mean distance walked was 334 (SD 138)m and the peak Borg score was 12 (SD 1). Patients with CHF showed no significant minute-by-minute changes in step length or walking speed over the course of the 6MWT. In the first 5minutes, healthy controls had a longer step length and faster walking speed than patients with CHF [step length: mean difference in the first minute was 0.03m, 95% confidence interval (CI) of the difference 0.01 to 0.05m; P=0.02; walking speed: mean difference in the first minute 0.04m/second, 95% CI of the difference 0.02 to 0.07m/second; P=0.01]. A multiple linear regression analysis demonstrated that body mass index (P=0.02) was the most important predictor of 6MWT performance. CONCLUSION: Patients with CHF have a shorter step length and walk more slowly than controls during the 6MWT. Altered gait mechanics may contribute to limited exercise capacity in patients with CHF.

Emergence of drug resistance mutations in a group of HIV-infected children taking nelfinavir-containing regimens.

HIV-1-infected children are often treated with therapy regimens including protease inhibitors (PIs). We monitored the virologic response in a small group of pediatric patients undergoing therapy with regimens including the PI nelfinavir and determined whether new drug resistance mutations were present immediately after virologic failure. Seventeen reverse transcriptase inhibitor (RTI)-experienced children starting nelfinavir-containing therapy regimens were studied. After virologic failure, HIV-1 protease (PR) and RT sequences were examined for drug resistance mutations. Viral load levels decreased to <400 HIV RNA copies/ml in six patients and remained at <400 HIV RNA copies/ml in four patients. Three patients did not respond virologically; all three had mutations specific for one or more of their regimen drugs either before or soon after nelfinavir initiation. The virologic response was transient in eight patients whose viral loads did not decrease to <400 HIV RNA copies/ml. Genotypic data from seven of the eight patients revealed mutations specific for one or more of their regimen drugs after virologic rebound. PI resistance mutations occurred in eight patients: D30N in six, and L90M in three. In three patients, the only new mutation after failure was the RT mutation M184V. Despite virologic failure, sustained increases in CD4+ lymphocyte counts were noted in eight patients. We conclude that in this small group of pediatric patients, virologic failure occurred in all patients whose viral loads did not become undetectable after the switch to a nelfinavir-containing regimen. After failure, new drug resistance mutations were found in either PR or RT. Studies of larger cohorts are warranted to determine whether HIV-1 genotypic data can help in the formulation of effective salvage therapies in children.

Sequence analysis of dru regions from methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococcal isolates.

Methicillin-resistance in staphylococci results from expression of mecA, which occurs in a larger region of DNA (the mec region) lacking counterpart in susceptible cells. The mec region harbors in addition a highly polymorphic element, the dru (direct repeat unit) segment, which in an early S. aureus strain, BB270, was found to contain 10 imperfect 40 base-pair repeats. We have explored the utility of direct sequencing of dru segments for discriminating among strains of methicillin-resistant S. aureus (MRSA) and coagulase-negative staphylococci (MRCNS). We sequenced dru segments of 24 clinical isolates of MRSA, and 15 of MRCNS, and reexamined strain BB270. Six S. aureus and 2 S. epidermidis isolates were found to have deletions which removed all drus. The other strains were found to have multiple contiguous dru repeats of precisely 40 bp. Analysis of these strains plus dru segment sequence from 4 recent reports yielded 18 unique dru segment sequences (designated "dru types") differing in numbers of repeats and/or sequences of particular repeats. Dru typing was more discriminating than sequencing of non-mec region genes, including a repeat-containing segment (spa Xr) of the S. aureus protein A gene. Yet dru type was sufficiently stable to register epidemiological clusters. Dru sequencing is a useful tool for tracking methicillin-resistant lineages of S. aureus and CNS.

A sequence variant of Staphylococcus hominis with a high prevalence of oxacillin and fluoroquinolone resistance.

A newly identified subspecies of Staphylococcus hominis, S. hominis subsp. novobiosepticus, was found to be the cause of several invasive infections at a hospital in New Jersey. This subspecies differs from classical S. hominis, now S. hominis subsp. hominis, by the phenotypic characteristics of novobiocin resistance and the inability to ferment trehalose. DNA sequences of segments of 16S rRNA, DNA gyrase (gyrA), and DNA topoisomerase IV (grlA) genes were determined for the type strains of the 2 subspecies, and for 34 S. hominis clinical isolates. The 16S rRNA sequences of the type strains differed at 3 positions over 410 bp; the grlA sequences differed at 6 positions over 119 bp. These sequence differences define S. hominis subsp. novobiosepticus and S. hominis subsp. hominis "sequevars." Of 34 S. hominis clinical isolates, 31 were S. hominis subsp. novobiosepticus sequevars, 28 of which were resistant to both oxacillin and ciprofloxacin. The clinical microbiology laboratory, using a MicroScan system, identified 7 of the 31S. hominis subsp. novobiosepticus sequevars as S. hominis subsp. hominis on the basis of phenotypic characteristics. Three S. hominis subsp. hominis sequevars were all identified phenotypically as S. hominis subsp. hominis and were oxacillin- and ciprofloxacin-susceptible. Although the precise relationship between the S. hominis sequevars and their phenotypic subspecies remains to be determined, our results indicate that antibiotic-resistant clinical isolates of S. hominis belong almost exclusively to the S. hominis subsp. novobiosepticus sequevar.

HIV-1 reverse transcriptase mutations found in a drug-experienced patient confer reduced susceptibility to multiple nucleoside reverse transcriptase inhibitors.

HIV-1 reverse transcriptase (RT) genotypes were obtained from 13 patients treated with stavudine. No previously-reported mutations indicative of stavudine resistance were found in these patients and no novel mutations occurred in more than two patients. One patient, treated with stavudine for 1 month and treated previously with zidovudine, zalcitabine and lamivudine, carried a mutation at codon 75 of the RT (V75M). A chimeric virus, including the patient's RT sequence from codon 25 to codon 220, which carried the resistance mutations M41 L, D67N, T69D, K70R, L210W and T215Y in addition to V75M, displayed reduced susceptibility to multiple nucleoside RT inhibitors (NRTIs). Removal of V75M from this RT background resulted in a return of susceptibility to didanosine and lamivudine. Our data are in agreement with previous studies demonstrating the rarity of stavudine resistance mutations in stavudine-treated patients. However, we describe a new set of mutations, found in the RT of a heavily-treated patient, that can confer reduced susceptibility to multiple NRTIs. These results underscore the importance of increased vigilance for possible multiple-drug resistance in patients who have been heavily treated with NRTIs.

The microbial genetics of antibiotic cycling.

Cycling of currently available antibiotics to reduce resistance is an attractive concept. For cycling strategies to be successful, their implementation must have a demonstrable impact on the prevalence of resistance determinants already dispersed throughout the hospital and associated healthcare facilities. While antibiotic use in hospitals clearly constitutes a stimulus for the emergence of resistance, it is by no means the only important factor. The incorporation of resistance determinants into potentially stable genetic structures, including bacteriophages, plasmids, transposons, and the more newly discovered movable elements termed integrons and gene cassettes, forces some degree of skepticism about the potential for such strategies in institutions where resistance determinants are already prevalent. In particular, the expanding role of integrons may pose an ultimate threat to formulary manipulations such as cycling. Despite these concerns, the crisis posed by antimicrobial resistance warrants investigation of any strategy with the potential for reducing the prevalence of resistance. Over the next decade, new studies with carefully designed outcomes should determine the utility of antibiotic cycling as one control measure for nosocomial resistance.

Distribution of methicillin-resistant Staphylococcus aureus clones among health care facilities in Connecticut, New Jersey, and Pennsylvania. .

A previous surveillance study conducted in 12 hospitals in New York City in 1996 identified a unique multidrug-resistant genetic lineage of methicillin-resistant Staphylococcus aureus (MRSA) that was widespread and accounted for as much as 42% of all the MRSA isolates. The purpose of the study described here was to determine possible geographic spread of this New York clone of MRSA to neighboring states. Single-patient MRSA isolates (258) from 29 health care facilities in Connecticut (CT), New Jersey (NJ), and Pennsylvania (PA) were collected during the calendar year 1998. DNA typing, consisting of fingerprinting of chromosomal macrorestriction patterns generated by SmaI digestion followed by pulsed-field gel electrophoresis (PFGE), identified 22 patterns. PFGE type A, closely related to the PFGE type of the previously identified New York clone, accounted for 154 (60%) of 258 isolates. The clone was detected in all facilities, was predominant in 19 of the 29 health care centers, and accounted for 92% of the MRSA isolates collected in PA. The overwhelming majority of MRSA with PFGE type A was also resistant to erythromycin, ciprofloxacin, and clindamycin. One of the two most common PFGE subtypes detected in the three states sampled (PFGE subtype A1) had an identical PFGE pattern to that of the previously described vancomycin-resistant strain of S. aureus (VISA) recently detected in a hospital in Westchester, NY. The second most frequent MRSA clone with PFGE type E and accounting for 26% (68/258 isolates), also described earlier in the 12 New York City hospitals, was resistant not only to erythromycin, ciprofloxacin, and clindamycin, but also to gentamicin and sulfamethoxazole-trimethoprim as well. The unique multidrug resistance pattern of this second clone and its geographic distribution accounted for the differences observed in the frequency of multidrug resistance among MRSA isolates recovered in the three states. The pandemic Iberian clone recently detected in New York City was not detected among the 258 MRSA isolates recovered in CT, NJ, and PA.

Topoisomerase sequences of coagulase-negative staphylococcal isolates resistant to ciprofloxacin or trovafloxacin.

Coagulase-negative staphylococcal isolates (n = 188) were screened for susceptibility to oxacillin, ciprofloxacin, and trovafloxacin, a new fluoroquinolone. At an oxacillin concentration of >/=4 microg/ml, 43% were methicillin resistant; of these, 70% were ciprofloxacin resistant (MIC, >/=4 microg/ml). Of the methicillin-resistant, ciprofloxacin-resistant isolates, 46% were susceptible to /=8 microg/ml) and increased trovafloxacin MICs (0.25 to 2 microg/ml) could be conferred by the combined presence of single mutations in each gyrA and grlA gene. Trovafloxacin MICs of >/=8 microg/ml also occurred, but these required an additional mutation in grlA.

Topoisomerase mutations in trovafloxacin-resistant Staphylococcus aureus.

A total of 201 Staphylococcus aureus isolates were surveyed for susceptibility to ciprofloxacin and trovafloxacin. Of 66 methicillin-resistant isolates, 89% were ciprofloxacin resistant and 6% were also trovafloxacin resistant. Trovafloxacin-resistant strains had unusual patterns of quinoline resistance mutations in DNA topoisomerase genes, including two mutations in the A subunit (encoded by grlA) of topoisomerase IV.

Effect of the HIV-1 syncytium-inducing phenotype on disease stage in vertically-infected children.

The syncytium-inducing (SI) capability of HIV-1 isolates from 48 HIV-infected children was determined in order to examine the association of the SI phenotype with an AIDS diagnosis and/or with other clinical parameters in HIV-infected children. In a retrospective cross-sectional analysis, phenotypic data were linked to clinical and immunologic data from each patient. Multiple longitudinal samples were analyzed from 14 patients. Children with SI viruses were older than children with nonsyncytium-inducing (NSI) strains. Twelve of 13 children less than 2 years old carried NSI viruses, seven of the 12 already had a diagnosis of AIDS. Two children under 2 years of age died within 1 month of NSI virus isolation. Although plasma p24 antigen levels tended to be higher in the NSI group, the difference appeared to reflect high p24 levels in children under 2 years old with AIDS. When children under 2 were omitted, differences in age, CD4+ cell counts, p24 antigenemia, and clinical parameters were not significant. The SI phenotype of HIV-1 did not occur more frequently in children with an AIDS diagnosis. Four children remained stable with SI isolates overtime periods of 16 to 31 months. Three children's isolates converted from NSI to SI and 2 converted from SI to NSI. These data indicate that SI viruses do not play a significant role in progression to AIDS during the first 2 years of life. Furthermore, for children above the age of 2, the association between advanced disease stage and the SI phenotype in adults may not apply.

Risk factors associated with the acquisition of amikacin-resistant gram-negative bacilli in central New Jersey hospitals.

A case-control study was performed in central New Jersey hospitals to evaluate the potential patient factors associated with the acquisition of amikacin-resistant gram-negative bacilli (ARGNB). Univariate analysis revealed an association between numerous patient factors, and multivariate analysis revealed four factors to be associated independently with ARGNB: the number of hospital admissions during the prior year, previous aminoglycoside exposure, intubation, and intensive-care-unit admission.

Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals.

Antimicrobial resistance results in increased morbidity, mortality, and costs of health care. Prevention of the emergence of resistance and the dissemination of resistant microorganisms will reduce these adverse effects and their attendant costs. Appropriate antimicrobial stewardship that includes optimal selection, dose, and duration of treatment, as well as control of antibiotic use, will prevent or slow the emergence of resistance among microorganisms. A comprehensively applied infection control program will interdict the dissemination of resistant strains.

Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals.

Antimicrobial resistance results in increased morbidity, mortality, and costs of health care. Prevention of the emergence of resistance and the dissemination of resistant microorganisms will reduce these adverse effects and their attendant costs. Appropriate antimicrobial stewardship that includes optimal selection, dose, and duration of treatment, as well as control of antibiotic use, will prevent or slow the emergence of resistance among microorganisms. A comprehensively applied infection control program will interdict the dissemination of resistant strains.

Programmatic role of the infectious diseases physician in controlling antimicrobial costs in the hospital.

Controlling antimicrobial costs has preoccupied infectious diseases physicians (IDPs). IDPs have controlled antimicrobial costs by the use of eight strategies: education, formulary restriction, pharmacy justification, formulary substitution, computer surveillance, laboratory item cost listing, purchase plans, and multidisciplinary approaches. Most strategies had input from IDPs and resulted in cost savings (up to $500,000 annually), particularly during the initiation periods. Educational efforts were successful in reducing costs but needed continual intervention. Formulary restriction was the most straightforward cost-control mechanism. Restriction of "target antimicrobials" has given way to "switch" therapy between expensive and less costly agents or between parenteral and oral regimens. Switch therapy is facilitated through the use of innovative order forms and on-line computer interaction. Computer surveillance has a capacity for interactive controls. Purchase plans may give way to centralized pharmacy monitoring, a strategy that is attractive to managed care organizations. Multidisciplinary antimicrobial management programs (AMPs) offer the best potential for sustaining savings in antimicrobial costs. Ten recommendations lay a groundwork for IDPs to translate their expertise into leadership of AMPs.

Immunoprophylaxis against klebsiella and pseudomonas aeruginosa infections. The Federal Hyperimmune Immunoglobulin Trial Study Group.

To determine if passive immunization could decrease the incidence or severity of Klebsiella and Pseudomonas aeruginosa infections, patients admitted to intensive care units of 16 Department of Veterans Affairs and Department of Defense hospitals were randomized to receive either 100 mg/kg intravenous hyperimmune globulin (IVIG), derived from donors immunized with a 24-valent Klebsiella capsular polysaccharide plus an 8-valent P. aeruginosa O-polysaccharide-toxin A conjugate vaccine, or an albumin placebo. The overall incidence and severity of vaccine-specific Klebsiella plus Pseudomonas infections were not significantly different between the groups receiving albumin and IVIG. There was some evidence that IVIG may decrease the incidence (2.7% albumin vs. 1.2% IVIG) and severity (1.0% vs. 0.3%) of vaccine-specific Klebsiella infections, but these reductions were not statistically significant. The trial was stopped because it was statistically unlikely that IVIG would be protective against Pseudomonas infections at the dosage being used. Patients receiving IVIG had more adverse reactions (14.4% vs. 9.2%).

Use of acetabular models in planning complex acetabular reconstructions.

The number of patients requiring revision total hip arthroplasty continues to increase each year. Accurate preoperative planning is a key factor in obtaining a good result. Radiographs provide little information concerning the actual extent of the acetabular defects. Computed tomography-generated models of the acetabulum can provide the surgeon with accurate information concerning the size and location of the defects. Evaluation of radiographs and models in 24 cases showed that radiographs alone failed to detect all 13 anterior wall defects (P < .001), 8 of 18 posterior wall defects (44.4%, P < .001), and 8 of 19 segmental central defects (42%, P < .001), all of which were easily identified with the models. This study showed that preoperative planning based on the foam models accurately predicted the actual implant used in 22 of 24 cases (92%).