Hormone replacement therapy and mid-term implant survival following knee or hip arthroplasty for osteoarthritis: a population-based cohort study.

OBJECTIVES: Osteolysis and subsequent prosthesis loosening is the most common cause for revision following total knee arthroplasty (TKA) or total hip arthroplasty (THA). Hormone replacement therapy (HRT) could reduce osteolysis through its antiresorptive effects. We studied whether HRT use is associated with reduced revision rates in a community-based cohort of women undergoing TKA or THA for osteoarthritis. METHODS: Female participants in the General Practice Research Database undergoing a primary TKA or THA from 1986 to 2006 were included. We excluded patients aged <40 years at the date of primary, and those with a history of previous hip fracture or rheumatoid arthritis. Women with at least 6 months of HRT were identified as HRT users. We further explored the associations among HRT use of ≥12 months, adherence (medication possession ratio) and cumulative use and revision risk. Cox models were fitted to model implant survival in years. Propensity score matching was used to control for confounding. RESULTS: We matched 2700 HRT users to 8100 non-users, observed for a median (IQR) of 3.3 (1.5-6.1) years after TKA/THA. HR for HRT ≥6 months was 0.62 (95% CI 0.41 to 0.94), whereas HR for ≥12 months was 0.48 (0.29 to 0.78). Higher adherence and therapy duration were associated with further reductions in revision rates. Preoperative HRT appeared unrelated to implant survival. CONCLUSIONS: HRT use is associated with an almost 40% reduction in revision rates after a TKA/THA. These findings require replication in external cohorts and experimental studies.

Future projections of total hip and knee arthroplasty in the UK: results from the UK Clinical Practice Research Datalink.

OBJECTIVE: To estimate the future rate of primary total hip (THR) or knee (TKR) replacement in the UK to 2035 allowing for changes in population demographics and obesity. DESIGN: Using age/gender/body mass index (BMI)-specific incidence rates from a population-based cohort study of 50,000 THR and 45,609 TKR patients from the UK Clinical Practice Research Datalink (CPRD) between 1991 and 2010, we projected future numbers of THR and TKR using two models: a static, estimated rate from 2010 applied to population growth forecasts to 2035, and a log-linear rate extrapolation over the same period. Both scenarios used population forecast data from the UK Office for National Statistics (ONS). RESULTS: Assuming rates of THR and TKR for 2010, and given projected population changes in age, gender and BMI, the number of THRs and TKRs performed in the UK in 2035 is estimated to be, respectively: 95,877 and 118,666. By comparison, an exponential extrapolation of historical rates using a log-linear model produces much higher estimates of THR and TKR counts in 2035 at 439,097 and 1,219,362 respectively. Projected counts were higher for women than men. Assuming a changing (rather than fixed) future BMI distribution increases TKRs by 2035 but not THRs. CONCLUSIONS: Using historical rates and population forecasts we have projected the number of THR/TKR operations in the UK up to 2035. This study will inform policymakers requiring estimates of future demand for surgery. Incorporating future forecasts for BMI into projections of joint replacement may be more relevant for TKR rather than THR.

The lifetime risk of total hip and knee arthroplasty: results from the UK general practice research database.

OBJECTIVE: To estimate the lifetime risk of undergoing primary total hip (THR) or knee (TKR) replacement in the UK. METHOD: A Population-based cohort study of 25,845 patients who had undergone a THR and 23,260 patients who had undergone a TKR between 1991 and 2006, using data from the UK General Practice Research Database. RESULTS: The estimated mortality-adjusted lifetime risk of THR at age 50 for the year 2005 was 11.6% (95% CI: 11.1, 12.1) for women and 7.1% (95% CI: 6.7, 7.5) for men. For TKR the risks were 10.8% (95% CI: 10.3, 11.3) for women and 8.1% (95% CI: 7.6, 8.5) for men. Between 1991 and 2006, the lifetime risk of THR at age 50 rose from 4.0% (95% CI: 3.5, 4.4) to 11.1% (95% CI: 10.6, 11.6) for women and for men from 2.2% (95% CI: 1.8, 2.5) to 6.6% (95% CI: 6.2, 7.0). Over the same period, for TKR the risk for women increased from 2.9% (95% CI: 2.6, 3.3) to 10.6% (95% CI: 10.1, 11.1) and for men from 1.8% (95% CI: 1.5, 2.2) to 7.7% (95% CI: 7.3, 8.2). CONCLUSION: The lifetime risk of undergoing THR or TKR is estimated to be substantially less than the risk of developing symptomatic hip or knee osteoarthritis. For the knee, the difference between these risk estimates is particularly wide. The reasons for the size of these differences are not clear, and further work is needed to quantify the extent of latent demand for these cost-effective and established interventions among the population with symptomatic osteoarthritis of the hip or knee.

The effect of hip and knee arthroplasty on oral anti-inflammatory use and the relationship to body mass index: results from the UK general practice research database.

OBJECTIVE: To determine the use of oral anti-inflammatory drugs in the year before and the 2 years after primary total hip (THR) or knee (TKR) replacement, and whether this varies according to Body mass Index (BMI). DESIGN: 28,068 THR's and 24,364 TKR's, with five matched controls per case were identified from the General Practitioner Research Database. Anti-inflammatory usage was categorized into "zero coverage" - no prescribed anti-inflammatory medication and ">80% coverage" - prescribed anti-inflammatory medication for greater than 80% of the days in the year. Secondary subset analysis was performed according to BMI. RESULTS: 1 year post-surgery the proportion of cases on >80% coverage reduced from 21% (95%confidence interval (CI): 20-22%) to 8% (95%CI: 7-10%) for THR and 21% (95%CI: 20-22%) to 13% (95%CI: 11-14%) for TKR, with no ongoing reduction at 2 years. Zero coverage increased at one and both time points. The proportion of THR's on >80% coverage increased with BMI pre-op. The magnitude in reduction post-op was similar across all BMI groups. The proportion of TKR's on >80% coverage pre-op was greatest in extreme BMI categories. The magnitude in reduction post-op was similar across all BMI groups. CONCLUSION: THR/TKR's reduce the need for anti-inflammatory medication with most benefit observed in the first post-operative year. Increasing BMI affects anti-inflammatory use both in the general population and those undergoing THR/TKR surgery but without strong evidence of a detrimental effect on the benefits of pain relief.

Bisphosphonate use and risk of post-operative fracture among patients undergoing a total knee replacement for knee osteoarthritis: a propensity score analysis.

SUMMARY: We have shown that patients with osteoarthritis are at increased risk of fracture after total knee replacement (TKR). We conducted a population-based cohort study to assess the effect of bisphosphonate use on their post-surgery fracture risk. Cox regression adjusted by propensity score suggested a 50-55% reduction in risk of fracture post-surgery. INTRODUCTION: Patients with osteoarthritis have a higher bone mass but similar or higher risk of fracture. We recently demonstrated that patients have an elevated fracture risk after TKR, but it is unknown if bisphosphonate therapy in this patient group would reduce fracture risk. We aimed to assess the effect of bisphosphonate prescription to patients undergoing a TKR, on their risk of fracture after surgery. METHODS: From the General Practice Research Database, all patients ≥ 40 years old, who received a TKR from 1986 to 2006 for knee osteoarthritis were eligible. We identified bisphosphonate use (BPU) as the main exposure. Propensity scores (equivalent to the estimated conditional probability of being treated given the individual's covariates) were calculated using logistic regression and used to reduce observed confounding. We fitted Cox models to study the effect of BPU on post-surgery fracture occurrence. Analyses were stratified by history of previous fracture: no fracture, osteoporotic fracture (hip, wrist, humerus, spine), and other fractures. RESULTS: The hazard ratio (HR) associated with BPU in non-previously fractured patients was 0.50 (95% confidence interval, 0.37-0.68; propensity-adjusted model), and 0.48 (0.35-0.65; matched analysis). In subjects with osteoporotic and with other previous fracture, BPU was associated with a propensity-adjusted HR of 0.46 (0.30 to 0.71) and 0.47 (0.26-0.85), respectively, and with a propensity-matched HR of 0.45 (0.29 to 0.70) and 0.45 (0.25-0.82). CONCLUSION: Our results suggest that BPU in primary prevention could reduce post-operative risk of fracture by 50% and by 55% in secondary prevention.

The resolution of bacteroides lipopolysaccharides by polyacrylamide gel electrophoresis.

The lipopolysaccharides (LPS) of the 10 species of the genus Bacteroides (sensu stricto) were extracted by the proteinase K method and their resolution compared by several methods of polyacrylamide gel electrophoresis (PAGE). These included sodium dodecyl sulphate (SDS)-PAGE with and without urea, polyacrylamide gradient gels and Tricine [N-Tris (hydroxymethyl) methyl glycine]-SDS-PAGE. The original discontinuous system showed good resolution of LPS from B. thetaiotaomicron, B. caccae and B. ovatus and this was enhanced by urea; B. vulgatus showed a typical ladder pattern associated with repeating polysaccharide units of the O side chains. The LPS profiles of the other species, including B. fragilis, were poorly resolved; the majority of components migrated with the leading edge of the wave front. The resolution of the LPS of these species was marginally improved with gradient gels but the majority of components were separated only within the regions of high polyacrylamide concentration. The Tricine-SDS system was consistently superior to the other methods, with excellent resolution of the LPS profiles of all Bacteroides species.

The pathogenicity of Bacteroides fragilis and related species estimated by intracutaneous infection in the guinea-pig.

The pathogenicity of 42 strains of Bacteroides of human origins was estimated by intracutaneous injection of bacterial suspensions into guinea-pig skin. Comparisons of living and heat-killed suspensions revealed that B. fragilis strains maintained themselves and possibly multiplied in the skin, whereas the lesions induced by non-fragilis strains appeared to be due mainly to toxicity. Measurement of skin pathogenicity in terms of the number of viable organisms in the inoculum that produced a lesion 10 mm in diameter showed that B. fragilis was, on average, 17 times as pathogenic as non-fragilis strains. Skin tests of pathogens may be of value in the analysis of virulence factors of Bacteroides and possibly of other anaerobic organisms.

The antagonism of tetracycline and ferric iron in vivo.

To test the hypothesis that the in-vivo antibiotic action of tetracycline might be affected by ferric iron and the enhancement of infection by ferric iron by tetracycline, the actions of intraperitoneal antibiotic and local ferric ammonium citrate, given separately and together, were measured in the dorsal skin of guinea-pigs bearing lesions due to staphylococci, streptococci, a Proteus sp., an Erysipelothrix sp., Clostridium perfringens, Pseudomonas aeruginosa, Aeromonas hydrophila and Klebsiella pneumoniae. Tetracycline, given in two intraperitoneal doses of 25 mg/kg at 0 and 2 h after intracutaneous challenge, maintained plasma concentrations of 4-6 micrograms/ml for more than the first 4 h of infection, after which the local lesions had become largely insusceptible to the antibiotic. The intracutaneous injection of Fe 10 micrograms in a volume of 0.1 ml containing the bacteria was sufficient to enhance infection by those strains susceptible to this effect. The in-vivo efficacy of tetracycline was not always related to low MIC; a low MIC was sometimes associated with little action and a high MIC with moderate action. Sixteen organisms were tested. The iron diminished the tetracycline effect only feebly with one staphylococcal strain and the strain of E. rhusiopathiae. In only one case, with a strain of Proteus sp., was the tetracycline action grossly diminished. On the other hand, tetracycline diminished the enhancement effect of iron moderately with three strains of staphylococci and one strain each of K. pneumoniae, P. aeruginosa and C. perfringens, and strongly with two strains of staphylococci, a group-C streptococcus and one strain each of K. pneumoniae, E. rhusiopathiae and A. hydrophila. It is evident that the diminution of tetracycline action by moderate excess of readily available Fe , whether endogenous or administered, is an unlikely event (three instances among the 16 tested) whereas the diminution of the infection-enhancing effect of iron by tetracycline is much more likely (12 instances among the 16). Insofar as a decrease in iron available for enhancement of infection is valid evidence of a diminution of the iron available for necessary physiological processes of the subject treated, our results suggest that these processes might be affected by tetracycline.

The variable response of bacteria to free haemoglobin in the tissues.

The local enhancement of infection by exogenous ferric iron, as ferric ammonium citrate, and by ferrous iron as guinea-pig haemoglobin, was assessed in studies with 55 strains of bacteria injected into the skin of guinea-pigs. The test organisms included Staphylococcus aureus, Streptococcus spp., Klebsiella spp., Escherichia coli and Pseudomonas aeruginosa. Four strains of Bacteroides spp. were tested with haemoglobin only. As previously reported with other strains, enhancement of infection by members of a given species by ferric iron was variable; in this study infection with only 11 of 59 strains was enhanced. Haemoglobin either of equal or lesser iron content was a more potent enhancer, affecting 27 of the 59 strains. The enhancement ranged from two-fold to 80-fold, the higher figures on the whole being characteristic of haemoglobin enhancement. Some few instances of depression by both haemoglobin and ferric ammonium citrate were noted. A few tests were made with systemic haemoglobin but the concentrations attainable were largely ineffective. Enhancement of infection did not appear to be related to the capacity of a strain to lyse or digest host red blood cells. In so far as guinea-pigs, whose antibacterial defences are lowered by ferric or ferrous iron, represent human subjects at risk of infection because of clinical circumstances characterised by excess of available iron--either exogenous or as a result of haemolysis--our results with organisms of a kind commonly associated with infection in hospitals suggest that only a small proportion of environmental bacteria can take advantage of any decreased resistance associated with iron excess.

The variable response of bacteria to excess ferric iron in host tissues.

The enhancement by exogenous ferric iron, both systemic and local, of the infectivity of 120 strains of bacteria, representing 17 genera, was measured in the skin of guinea-pigs. Systemic iron enhanced only 23% of 115 strains, and local iron 49% of 71 strains. Systemic iron, by an apparently anti-inflammatory action, depressed the size of lesions produced by 27 of the non-enhanced strains from nine of the genera tested. For most strains, the degree of enhancement was small, ranging from 2- to 8-fold, and often evident only with the more effective local iron; among these were some near-saprophytes like Mycobacterium phlei, M. smegmatis, Bacillus cereus and Clostridium bifermentans. Substantial enhancement, from 14- to 50-fold, was observed with the more pathogenic among the strains tested: namely BCG, Corynebacterium ovis, C. murium, Listeria monocytogenes, Erysipelothrix rhusiopathiae, Cl. perfringens, Cl. septicum, Cl. oedematiens, and some strains of Klebsiella spp., Proteus spp. and Aeromonas hydrophila. The enhancement of BCG by a single dose of iron given locally with the inoculum was only feebly manifest after 7 days, but substantial after 14--19 days, indicating the decisive effect of interference with an early humoral defence on the establishment of chronic infection some time later. Insofar as guinea-pigs whose antibacterial defences are lowered by substantial amounts of exogenous iron in the circulation represent human subjects at risk of infection because of clinical states characterised by excess of available iron, the results of the survey suggest that only a minority among the environmental bacteria can take advantage of the decreased resistance associated with such states; but that this minority is likely to include the more virulent strains in the environment.

Comparative in-vitro activity of penicillin alone and combined with gentamicin against clinical isolates of Streptococcus pneumoniae with decreased susceptibility to penicillin.

The worldwide emergence of Streptococcus pneumoniae with decreased susceptibility to penicillin has led to the suggestion that drug combinations might be used. The aim of this study was to determine possible synergy using a combination of penicillin with sub-inhibitory doses of gentamicin against 26 clinical isolates of S. pneumoniae with decreased susceptibility to penicillin, using half-chequerboards and killing curves. Synergy was demonstrated for ten of the 26 isolates with the combination of penicillin with gentamicin at 1 mg/l and for 22 isolates with penicillin and gentamicin at 2 mg/l. Killing curves on three isolates showed synergy and confirmed the chequerboard results. Further synergy studies using penicillin or cefotaxime/ceftriaxone, plus low dose gentamicin against penicillin-resistant pneumococci are indicated.

Selection of resistant variants of respiratory pathogens by quinolones.

Quinolones are widely used in the treatment of respiratory tract infections. However, some disquiet has been expressed over using quinolones for community-acquired pneumonia since their activity is generally rather poor against Streptococcus pneumoniae. In addition, it is known that resistant variants emerge at a fairly high frequency during exposure of Enterobacteriaceae to quinolones; if this also occurred during quinolone treatment of community-acquired pneumonia it could lead to an increased risk of clinical failure. We therefore determined the selection rate of quinolone-resistant variants for six strains of S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis with nalidixic acid (except for S. pneumoniae), ciprofloxacin, ofloxacin and levofloxacin. We were only able to select resistant variants at low frequency from two of the six strains of S. pneumoniae with ciprofloxacin: no resistant variants were selected by either ofloxacin or levofloxacin. Variants of H. influenzae and M. catarrhalis with decreased susceptibility to quinolones were produced both with more strains and with a greater frequency; however, these variants still remained susceptible according to the NCCLS guidelines. Our study suggests that resistant variants of S. pneumoniae are relatively unlikely to occur in individuals treated with fluoroquinolones especially if they are given quinolones with enhanced anti-gram-positive activity compared to ciprofloxacin.

Failure of two macrolide antibiotics to prevent post-extraction bacteraemia.

Two macrolide antibiotics, erythromycin and josamycin, were compared in a double-blind trial to examine their efficacy in the prevention of post-dental extraction bacteraemia in a group of healthy patients. An in vitro blood culture system was used. Isolates of streptococci were identified to species level. Minimum inhibitory concentrations (MICs) of erythromycin and of josamycin for each isolate were estimated by an agar dilution technique, with controls. Levels of drug in the serum of volunteers and of patients were assayed after oral doses of the macrolide antibiotics. Levels found achieved early peaks and satisfactory concentrations for activity against streptococci. Within the specified parameters, the results demonstrated that the antibiotics failed to prevent survival in blood culture of various strains of streptococci for up to 24 hours following collection of the blood. It is recommended that an alternative antibiotic to either erythromycin or to josamycin be used to achieve prophylaxis against streptococci in infective endocarditis risk patients who are allergic to penicillin.

Temporal trends in hip and knee replacement in the United Kingdom: 1991 to 2006.

Using the General Practice Research Database, we examined the temporal changes in the rates of primary total hip (THR) and total knee (TKR) replacement, the age at operation and the female-to-male ratio between 1991 and 2006 in the United Kingdom. We identified 27 113 patients with THR and 23 843 with TKR. The rate of performance of THR and TKR had increased significantly (p < 0.0001 for both) during the 16-year period and was greater for TKR, especially in the last five years. The mean age at operation was greater for women than for men and had remained stable throughout the period of study. The female-to-male ratio was higher for THR and TKR and had remained stable. The data support the notion that the rate of joint replacement is increasing in the United Kingdom with the rate of TKR rising at the highest rate. The perception that the mean age for TKR has decreased over time is not supported.

Electrophoretic analysis of the lipopolysaccharides of Bacteroides spp.

Lipopolysaccharide (LPS) extracts of reference strains and isolates of Bacteroides spp. prepared by the proteinase K method were resolved by tricine-sodium-dodecyl-sulphate-polyacrylamide gel electrophoresis and located by silver staining. A considerable diversity of LPS profiles was evident within the Bacteroides genus although profiles were essentially species-specific, with some minor interstrain variations apparent among isolates of B. uniformis, B. ovatus, B. eggerthii and B. thetaiotaomicron. The LPS of most species consisted of a major rough LPS component of 2-5 kDa and a series of higher molecular weight bands which varied with species. B. vulgatus LPS was distinctive in showing an extensive ladder of multiple repeating oligosaccharide units with molecular weights ranging from 4 to > 17 kDa B. stercoris LPS included a high molecular weight (> 17 kDa) ladder of repeating oligosaccharide units. B. fragilis and B. thetaiotaomicron differed from most other species in producing a short ladder of repeating oligosaccharide units interspersing the rough LPS and a 5.6 kDa (B. fragilis) or 9 kDa (B. thetaiotaomicron) yellow-staining component. The heterogeneity of LPS profiles within the Bacteroides genus may reflect the differences in pathogenicity among the species and prove useful for typing.

The functional interchangeability of enterobacterial and staphylococcal iron chelators.

The functional interchangeability of staphylococcal and enterobacterial iron chelators was investigated with an indicator system in which minimally effective concentrations of ethylene diamine di-ortho-hydroxyphenyl acetic acid (EDDA) were used to inhibit the growth of indicator strains in the depth of simple agar media by making the iron unavailable. Test colonies were then applied to the surface of the media to determine whether the indicator organisms, by utilising chelators from the test colony could obtain the required iron for growth, in its vicinity. Approximately 50% of staphylococcal strains, both S. aureus and S. epidermidis, reversed the inhibition of enterobacterial indicators, whereas almost all enterobacterial test strains, representing five genera, reversed the inhibition of the staphylococcal indicators. A purified preparation of the enterobacterial iron chelator enterochelin also reversed the inhibition of four out of the five staphylococcal indicator strains.

The neutralization of antibiotic action by metallic cations and iron chelators.

The neutralization of the action of a variety of antibiotics on klebsiellae by moderate doses of di- and tri-valent metallic cations, was measured in vitro. Some beta-lactams tested were affected by Mg++ and by Cu++. Of six tetracyclines one was moderately neutralized by Ca++, two by Mg++, three by Cu++, and all, strongly, by Fe+++. Erythromycin was affected by Ca++, lincomycin by Ca++, Mg++ and Cu++. Aminoglycosides were affected by Ca++ and Mg++ and strongly by Fe+++. Five antibiotics (three beta-lactams and two macrolides) with high MICs for klebsiellae were tested against staphylococci: most of the reversing agents were ineffective. The microbial iron chelators, desferrioxamine and enterochelin were largely inactive, affecting only two aminoglycosides.

In-vitro susceptibility of oral streptococci to pristinamycin.

The inhibitory activity of pristinamycin against oral streptococci was compared with that of amoxycillin, erythromycin and vancomycin. Minimum inhibitory concentrations (MICs) of pristinamycin ranged from 0.03-1 mg/l (mode 0.25 mg/l), similar to those for amoxycillin. Erythromycin had a mode MIC of 0.06 mg/l and vancomycin, the least active, 1 mg/l. However, in killing curve experiments to compare the bactericidal activities of pristinamycin and erythromycin against several strains of oral streptococci, pristinamycin was substantially more active, consistently producing a rapid decrease in viable count during the first few hours of incubation. Pristinamycin may prove to be of value for the prophylaxis of post-dental extraction bacteraemia.

Comparative in-vitro activity of azithromycin and erythromycin against Gram-positive cocci, Haemophilus influenzae and anaerobes.

The in-vitro activities of azithromycin and erythromycin were compared against 689 clinical isolates, including Gram-positive cocci, Haemophilus influenzae, and anaerobes. Of the 100 methicillin-susceptible isolates of Staphylococcus aureus tested, 77% were susceptible to 1 mg/l azithromycin and 0.5 mg/l erythromycin, whereas 22% were resistant to 32 mg/l of both compounds. All methicillin-resistant S. aureus isolates were highly resistant to both macrolides (MIC greater than 64 mg/l). Coagulase-negative staphylococci showed a wide range of susceptibilities to both compounds; MIC50 values for azithromycin and erythromycin for all isolates were 0.5 and 0.25 mg/l, respectively. With the exception of enterococci, both macrolides showed similar activity against streptococci; MIC90 values for both group A and group B streptococci were 0.03 and 0.06 mg/l for erythromycin and azithromycin, respectively. Azithromycin was less active than erythromycin against enterococci, with mode MICs of 4.0 and 1.0 mg/l, respectively; about 20% of isolates were highly resistant to both compounds. Azithromycin was substantially more active than erythromycin against H. influenzae; 41% of isolates were inhibited by 0.5 mg/l azithromycin and all isolates were inhibited by 2 mg/l. The MIC90 for erythromycin was 8 mg/l; 36% of isolates required concentrations of greater than or equal to 4 mg/l for inhibition. The anaerobic bacteria tested showed similar susceptibility to both azithromycin and erythromycin.

The quantification of the neutralization of the action of antibiotics by cationic iron.

This paper describes the reversal of antibiotic action by iron. Crude measurements of the molar ratio of iron to various antibiotics at reversal indicated that ampicillin, carbenicillin and lincomycin had low ratios of 0.2 to 2.4. With the remainder the ratios lay between 13 and 105; they averaged 46 for the tetracyclines, and 70 for the aminoglycosides. Precise measurement with Fe+++ and tetracycline revealed that the molar ratio for neutralization increased with increasing concentrations of tetracycline; from 1 to 625 mg/l the ratio increased over three-fold from 35 to 118. At the tetracycline concentration of 5 mg/l--usually achieved in plasma during effective therapy--the ratio is of the order of 45.