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.

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.

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.

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 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.

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.

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.

Multiple mutations modulate the function of dihydrofolate reductase in trimethoprim-resistant Streptococcus pneumoniae.

Trimethoprim resistance in Streptococcus pneumoniae can be conferred by a single amino acid substitution (I100-L) in dihydrofolate reductase (DHFR), but resistant clinical isolates usually carry multiple DHFR mutations. DHFR genes from five trimethoprim-resistant isolates from the United Kingdom were compared to susceptible isolates and used to transform a susceptible control strain (CP1015). All trimethoprim-resistant isolates and transformants contained the I100-L mutation. The properties of DHFRs from transformants with different combinations of mutations were compared. In a transformant with only the I100-L mutation (R12/T2) and a D92-A mutation also found in the DHFRs of susceptible isolates, the enzyme was much more resistant to trimethoprim inhibition (50% inhibitory concentration [IC50], 4.2 microM) than was the DHFR from strain CP1015 (IC50, 0.09 microM). However, Km values indicated a lower affinity for the enzyme's natural substrates (Km for dihydrofolate [DHF], 3.1 microM for CP1015 and 27.5 microM for R12/T2) and a twofold decrease in the specificity constant. In transformants with additional mutations in the C-terminal portion of the enzyme, Km values for DHF were reduced (9.2 to 15.2 microM), indicating compensation for the lower affinity generated by I100-L. Additional mutations in the N-terminal portion of the enzyme were associated with up to threefold-increased resistance to trimethoprim (IC50 of up to 13.7 microM). It is postulated that carriage of the mutation M53-I-which, like I100-L, corresponds to a trimethoprim binding site in the Escherichia coli DHFR-is responsible for this increase. This study demonstrates that although the I100-L mutation alone may give rise to trimethoprim resistance, additional mutations serve to enhance resistance and modulate the effects of existing mutations on the affinity of DHFR for its natural substrates.

Amino acid repetitions in the dihydropteroate synthase of Streptococcus pneumoniae lead to sulfonamide resistance with limited effects on substrate K(m).

Sulfonamide resistance in Streptococcus pneumoniae is due to changes in the chromosomal folP (sulA) gene coding for dihydropteroate synthase (DHPS). The first reported laboratory-selected sulfonamide-resistant S. pneumoniae isolate had a 6-bp repetition, the sul-d mutation, leading to a repetition of the amino acids Ile(66) and Glu(67) in the gene product DHPS. More recently, clinical isolates showing this and other repetitions have been reported. WA-5, a clinical isolate from Washington State, contains a 6-bp repetition in the folP gene, identical to the sul-d mutation. The repetition was deleted by site-directed mutagenesis. Enzyme kinetic measurements showed that the deletion was associated with a 35-fold difference in K(i) for sulfathiazole but changed the K(m) for p-aminobenzoic acid only 2.5-fold and did not significantly change the K(m) for 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine pyrophosphate. The enzyme characteristics of the deletion variant were identical to those of DHPS from a sulfonamide-susceptible strain. DHPS from clinical isolates with repetitions of Ser(61) had very similar enzyme characteristics to the DHPS from WA-5. The results confirm that the repetitions are sufficient for development of a resistant enzyme and suggest that the fitness cost to the organism of developing resistance may be very low.

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.

Mechanism of sulfonamide resistance in clinical isolates of Streptococcus pneumoniae.

The genetic basis of sulfonamide resistance in six clinical isolates of Streptococcus pneumoniae was demonstrated to be 3- or 6-bp duplications within sulA, the chromosomal gene encoding dihydropteroate synthase. The duplications all result in repetition of one or two amino acids in the region from Arg58 to Tyr63, close to but distinct from the sul-d mutation, a duplication previously reported in a resistant laboratory strain (P. Lopez, M. Espinosa, B. Greenberg, and S. A. Lacks, J. Bacteriol. 169:4320-4326, 1987). Six sulfonamide-susceptible clinical isolates lacked such duplications. The role of the duplications in conferring sulfonamide resistance was confirmed by transforming 319- or 322-bp PCR fragments into the chromosome of a susceptible recipient. Two members of a clone of serotype 9V, one susceptible and one resistant to sulfonamide, which are highly related by other criteria, were shown to have sulA sequences that differ in 7.2% of nucleotides in addition to the duplication responsible for resistance. It is postulated that horizontal gene exchange has been involved in the acquisition (or loss) of resistance within this clone. However, five of the six resistant isolates have distinct duplications and other sequence polymorphisms, suggesting that resistance has arisen independently on many occasions.

The in-vitro activity of trovafloxacin, a new fluoroquinolone, against Gram-positive bacteria.

The in-vitro activity of trovafloxacin, a new quinolone, was compared with that of ciprofloxacin, erythromycin, various beta-lactam antibiotics and, where appropriate, clindamycin and vancomycin against a range of Gram-positive bacteria including staphylococci (n = 201), Streptococcus pneumoniae (n = 83), beta-haemolytic streptococci (n = 46), viridans group streptococci (n = 100), Streptococcus milleri (n = 18) and enterococci (n = 161) by an agar dilution technique. In addition, time-kill studies were performed to estimate the bactericidal activity of trovafloxacin against S. milleri and viridans group streptococci. Trovafloxacin was the most active agent tested against staphylococci. It also showed good activity, at least four-fold and usually eight- to 16-fold that of ciprofloxacin, against all the streptococci. Trovafloxacin showed good activity against vancomycin-sensitive Enterococcus faecalis and Enterococcus faecium, but was less active against the 11 isolates of vancomycin-resistant enterococci. Trovafloxacin showed comparable or superior bactericidal activity to amoxycillin against the S. milleri and viridans group streptococci tested.

Comparative in-vitro activity of quinupristin/dalfopristin against Enterococcus spp.

The in-vitro activity of quinupristin/dalfopristin against Enterococcus spp. was compared with that of amoxycillin, vancomycin, telcoplanin and erythromycin. The susceptibility of 106 vancomycin-susceptible Enterococcus faecalis, 92 vancomycin-susceptible Enterococcus faecium and 14 vancomycin-resistant enterococci (VRE) was tested. Only one strain of vancomycin-susceptible E. faecium was not susceptible to < or = 0.5 mg/L quinupristin/dalfopristin; this strain required 4 mg/L. All strains of E. faecalis were inhibited by < or = 8 mg/L quinupristin/dalfopristin and all VRE strains were inhibited by < or = 2 mg/L. In contrast, teicoplanin and vancomycin showed inhibitory activity against E. faecalis and E. faecium but not against VRE. Amoxycillin was active against E. faecalis but not usually against E. faecium and showed variable activity against VRE; 38% of E. faecalis, 84% of E. faecium and 80% of VRE strains were resistant to erythromycin. The bactericidal activity of quinupristin/dalfopristin against E. faecium exceeded that of the comparator drugs as judged by MIC:MBC ratios and killing curves. The MBC99 of quinupristin/dalfopristin determined by a microdilution broth technique was < or = 1 mg/L for E. faecium. Four of the five strains of vancomycin-susceptible E. faecium and three of the five VRE strains tested with time-kill curves showed a > or = 2 log reduction in viable count after exposure to quinupristin/dalfopristin for 6 h.

Azithromycin in the treatment of periodontal disease. Effect on microbial flora.

Azithromycin is an azalide antibiotic with excellent in vitro activity against a wide variety of oral bacteria. It has a long half-life, good tissue penetration and is preferentially taken up by phagocytes. We investigated the microbiological efficacy of azithromycin as an adjunct to the non-surgical treatment of adult chronic periodontitis; its clinical efficacy is dealt with in a separate paper. 46 patients were treated in a double-blind placebo controlled trial. Microbiological assessment of the same periodontal pocket (initially > 6 mm) was made at weeks 0, 2, 3, 6, 10 and 22. Either azithromycin 500 mg 1 x daily for 3 days or placebo was given at week 2. Particular attention was paid to the numbers of black pigmented anaerobes and spirochaetes present since these are the most commonly implicated pathogens in periodontal disease. Pigmented anaerobes were significantly reduced at weeks 3 and 6 in patients who received azithromycin compared to placebo and remained lower, although not significantly so, throughout the study. Counts of spirochaetes were significantly reduced throughout the study in patients who received azithromycin compared to placebo. Our microbiological study suggests that azithromycin may be useful as an adjunct in the treatment of periodontal disease.

Comparative in-vitro activity of CP-99219, a new quinolone, against respiratory pathogens.

The comparative in-vitro activity of CP-99219, a new quinolone, against Haemophilus influenzae (150 isolates), Moraxella catarrhalis (100), Streptococcus pneumoniae (80) and Group A beta-haemolytic streptococci (40) was determined using an agar dilution technique. CP-99219 was the most active compound tested against M. catarrhalis (MIC50 = 0.015 mg/L, MIC90 = 0.03 mg/L). Ceftriaxone, CP-99219 and ciprofloxacin were the three most active agents tested against H.influenzae. CP-99219 showed good activity, 16-fold greater than that of ciprofloxacin, against S.pneumoniae (MIC50 = 0.12 mg/L; MIC90 = 0.25 mg/L) and was also active against Group A streptococci. Clinical studies regarding the use of CP-99219 in respiratory tract infections seem indicated.

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.

Comparative in-vitro activity of azithromycin, macrolides (erythromycin, clarithromycin and spiramycin) and streptogramin RP 59500 against oral organisms.

The in-vitro activities of azithromycin, clarithromycin, spiramycin and RP 59500 were compared with erythromycin against a wide range of oral organisms which have been implicated in oral infections and/or endocarditis (clindamycin was included for oral streptococci). All compounds tested showed good activity against many of these organisms, although some variation was observed with different species. Clarithromycin was the most active of the antibiotics tested against Gram-positive anaerobes, including Actinomyces spp., Propionibacterium spp., Lactobacillus spp. and Bifidobacterium dentium. Azithromycin was slightly less active than erythromycin against these species. In general, RP 59500 had higher MICs than the macrolides, other than spiramycin, against these organisms, but was superior in activity against Peptostreptococcus spp., inhibiting all isolates at 2 mg/L. Azithromycin was, in general, the most active antibiotic tested against the Gram-negative anaerobes: Fusobacterium spp., Bacteroides spp., Wolinella spp., Actinobacillus actinomycetemcomitans, Selenomonas spp. and Mitsuokella multiacida, including those isolates which were insusceptible to erythromycin. Clarithromycin showed similar activity to erythromycin against most Gram-negative species, but was superior against Capnocytophaga ochraceus and Eikenella corrodens. RP 59500 was less active than the macrolides against most Gram-negative anaerobes, but was superior to erythromycin and clarithromycin against Fusobacterium spp. and Leptotrichia buccalis, some strains of which were moderately resistant to erythromycin. The macrolides and clindamycin were about equally active against the oral streptococci, whereas RP 59500 showed lower inhibitory activity. The in-vitro results suggest that azithromycin and clarithromycin may be of value in the treatment of dental sepsis and the prophylaxis of endocarditis. RP 59500 showed useful activity against Gram-positive anaerobes and, because of its bactericidal activity against oral streptococci, may also prove to have a role in these areas.

Fine molecular specificity of linear and assembled antibody binding sites in HIV-1 p24.

A set of seven murine monoclonal antibodies were generated against a chemically synthesized 11-kDa 104-mer peptide covering the C-terminal residues 270-373 of the p24 gag protein (HIV-1BRU strain). All monoclonal antibodies recognized HIV-1IIIB infected MOLT3 cells by fluorescence and gave positive Western blot signals with viral gag peptides (p55 and/or p24). Oligopeptide binding regions were located with competitive enzyme-linked immunosorbent assays. Detailed epitope scanning analyses (the Geysen technique) were performed by serological testing of the monoclonal antibodies against 99 overlapping hexapeptides which corresponded to the entire 104-mer region. The antibodies bound to p24 peptide sequences located within the 275-293 and 351-368 regions. One antibody (LH104-B) which reacted with residues 357-362 bound to p55 alone. In contrast, another antibody (LH104-I), which recognized the residues 358-363, i.e. with five out of six residues in common with antibody LH104-B for its epitope region, reacted exclusively with p24. At least two of the antibodies (LH104-C and -A) which bound to p24 alone, apparently recognized conformational epitopes. They gave positive reactions with the regions 288-293/351-356 and 284-289/351-356, respectively. This work shows that chemical synthesis of large peptides is a viable alternative approach to immunochemical studies of viral proteins.