This article appears in the following Journal of Antimicrobial Chemotherapy issue: The British Society for Antimicrobial Chemotherapy Resistance Surveillance Project 1999/2000-2006/7 [View the issue table of contents]
Articles |
Non-susceptibility trends among Pseudomonas aeruginosa and other non-fermentative Gram-negative bacteria from bacteraemias in the UK and Ireland, 2001–06
1 Health Protection Agency Centre for Infections, 61 C olindale Avenue, London NW9 5EQ, UK 2 Department of Medical Microbiology, Southmead Hospital, Bristol BS10 5NB, UK
* Correspondence address. Antibiotic Resistance Monitoring and Reference Laboratory, HPA Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK. Tel: +44-20-8327-7223; Fax: +44-20-8327-6264; E-mail: david.livermore{at}hpa.org.uk
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Abstract |
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Background: Pseudomonas and Acinetobacter spp. are important opportunists, notorious for resistance. Pseudomonas spp. are collected in the British Society for Antimicrobial Chemotherapy (BSAC) bacteraemia surveillance, with Acinetobacter spp. and Stenotrophomonas maltophilia well represented in the ‘other Gram-negatives’ group.
Methods: Data for collected isolates were reviewed together with LabBase bacteraemia reports to the Health Protection Agency (HPA). Isolates with unusual resistances were subjected to molecular investigation.
Results: From 2001 to 2006, the BSAC surveillance collected 1226 Pseudomonas aeruginosa, 240 Acinetobacter spp.—125 of them Acinetobacter calcoaceticus/baumannii (Acb) complex—and 165 S. maltophilia. Among P. aeruginosa, non-susceptibility rates to β-lactams and gentamicin fluctuated, without trend, below 10%; those to ciprofloxacin ranged from 16% to 22%. One P. aeruginosa isolate from 2001 had VIM-2 metallo-β-lactamase. For Acb, the BSAC data indicated frequent non-susceptibility, except to imipenem, where only five non-susceptible isolates were collected, all after 2003, four of them belonging to the OXA-23 clone 1 lineage which is prevalent in Southeast England. Reports to the HPA indicated rising imipenem non-susceptibility in Acb (P < 0.0001). Co-trimoxazole retained near-universal activity against S. maltophilia. Among new antibiotics, doripenem MICs were 
4 mg/L for most imipenem-resistant P. aeruginosa but 
16 mg/L for Acb OXA-23 clone 1. Ceftobiprole had higher MICs than ceftazidime for P. aeruginosa, but 81% of the isolates were inhibited at 4 mg/L. Tigecycline had activity against most Acb, including OXA-23 clone 1, and also against S. maltophilia.
Conclusions: Most P. aeruginosa from bacteraemias in the UK and Ireland remain relatively susceptible by international standards; in contrast, multiresistance is widespread in Acb, with imipenem non-susceptibility emerging.
Keywords: bacteraemia , Pseudomonas aeruginosa , Acinetobacter spp. antibiotic resistance
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Introduction |
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Non-fermentative Gram-negative bacteria cause
5% of bacteraemias in England, Wales and Northern Ireland, based on voluntary reports by Hospital Trusts to the Health Protection Agency (HPA), with Pseudomonas aeruginosa alone causing 2.5% to 4% of cases.1,2 Besides P. aeruginosa, the main pathogens among non-fermenters are Acinetobacter calcoaceticus/baumannii (Acb) and Stenotrophomonas maltophilia, though each causes <1% of all bacteraemias.1,2 Non-Acb acinetobacters too are frequently isolated from blood, but often are only contaminants, introduced as the blood is collected and are not true pathogens. The difficulty of treating severe infections caused by non-fermentative bacteria is exacerbated by multiresistance and there is particular concern about the emergence of Acinetobacter clones pan-resistant to ‘good’ antibiotics, including carbapenems.3 These have OXA or, less often, metallo-carbapenemases.4 OXA-51-like carbapenemases are ubiquitous and chromosomal in A. baumannii, but confer resistance only if up-regulated by ISABA-1;5 other OXA β-lactamases, e.g. OXA-23, -40 or -58, are acquired types, and sometimes are plasmid-mediated.3,4 Two carbapenem-resistant Acb lineages, the SE clone with up-regulated OXA-51 enzyme and OXA-23 clone 1 with OXA-23 enzyme, now occur in many hospitals in London and Southeast England.6,7 P. aeruginosa, too, can develop pan-resistance, most often by successive mutations that: (i) up-regulate efflux and AmpC β-lactamases; (ii) alter quinolone targets; and (iii) down-regulate permeability, but occasionally by acquisition of plasmids encoding metallo-β-lactamases and multiple aminoglycoside-modifying enzymes.8
The British Society for Antimicrobial Chemotherapy (BSAC) bacteraemia surveillance of non-fermenters is reviewed here, along with data reported to the HPA via its LabBase/CoSurv system.9 The analysis aimed to identify trends and to characterize mechanisms in the more multiresistant isolates.
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Materials and methods |
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The collection strategy, identification methods and MIC determination methods for the BSAC Bacteraemia Resistance Surveillance Programme are described elsewhere in this Supplement.10 The HPA's bacteraemia surveillance is based on capturing routine data for bacteraemia isolates from the great majority of hospital trusts in England, Wales and Northern Ireland (not Scotland or the Republic of Ireland) and was outlined previously.9 The molecular methods used to seek and sequence genes for metallo- and OXA-carbapenemases have been published,5,6,11,12 as has the PFGE technique, with ApaI-digested genomic DNA, used to recognize the major Acb clones.7
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Pathogens and patients
In its 6 years of operation to date, the BSAC Bacteraemia Resistance Surveillance Programme collected 1291 Pseudomonas spp. isolates, comprising 1226 P. aeruginosa, 23 P. fluorescens, 20 P. putida and 16 P. stutzeri and 6 pseudomonads belonging to other species with one or two representatives each. Within the ‘other Gram-negative bacteria’ group, the BSAC surveillance collected 240 Acinetobacter spp. isolates, 125 of them Acb, along with 165 S. maltophilia, 22 Alcaligenes spp., 19 Burkholderia spp., 16 Chryseomonas spp., 12 Flavimonas spp. 11 Agrobacterium spp. 10 Comamonas spp. and 20 belonging to non-fastidious species with five or fewer representatives. Haemophilus spp. were well-represented, too, with 77 isolates but, as fastidious non-fermenters, are beyond the scope of this review.
Over 60% of the P. aeruginosa, Acinetobacter and S. maltophilia isolates were from patients hospitalized for longer than 48 h (Table 1), with <10% from non-hospitalized or community patients. Over 40% of the S. maltophilia isolates were from haematology and oncology patients and nearly 60% were from line-associated bacteraemias. Source patients for the Acinetobacter and P. aeruginosa isolates were more diverse, mostly scattered among intensive care, surgery, general medicine and haematology/oncology units. Sites of origin of the Pseudomonas and Acinetobacter bacteraemias were more diverse too, though remaining unknown in many cases (Table 1).
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Non-susceptibility rates and trends
Table 2 shows the proportions of non-susceptible (intermediate or resistant) isolates in each surveillance year, based on both the BSAC and HPA surveillances.
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There were no significant trends in non-susceptibility over time for the P. aeruginosa isolates collected under the BSAC surveillance; likewise, year-to-year fluctuation in non-susceptibility was insignificant, except that the MIC distribution for piperacillin/tazobactam in 2004 was more scattered than in other years. Bacteraemia reporting to the HPA confirmed the lack of non-susceptibility trends among P. aeruginosa from bacteraemias, except for suggesting a weak uptrend in imipenem non-susceptibility (P = 0.048). An uptrend in meropenem non-susceptibility was apparent too, but analysis was tenuous because most laboratories test either meropenem or imipenem, with the proportion testing meropenem rising over time.
For Acb, analysis was complicated by the fact that just six centres contributed over half the isolates in the BSAC surveillance, risking distortion by local outbreak clones. Within this caveat, the data showed high but fluctuating rates of non-susceptibility to ciprofloxacin, gentamicin, tigecycline and piperacillin/tazobactam, without significant temporal trends. There were too few imipenem-non-susceptible isolates for trend analysis, though it was notable that all five such isolates dated from 2004 or later and that they represented an increasing proportion of isolates in each subsequent year. Trend analysis of the HPA data for all Acinetobacter spp., or specifically for those reported as A. baumannii, indicated high and stable non-susceptibility rates to most antibiotics, but a significant uptrend (P < 0.0001) for imipenem non-susceptibility. By 2006, 20% of the isolates reported as A. baumannii, and 10% of all Acinetobacter spp., were reported imipenem non-susceptible. It should be added that species data are included for 63% of Acinetobacter bacteraemias reported to the HPA, but that there are concerns about accuracy, as the limits of non-molecular identification for this genus must be allowed for.
For S. maltophilia, the BSAC recommends testing only co-trimoxazole, a drug for which we found no non-susceptibility and, therefore, no resistance trend, based on a 2 mg/L trimethoprim breakpoint (Table 2). Co-trimoxazole results for S. maltophilia reported to the HPA indicated very little non-susceptibility, with no trend, though it should be added that the combination was under-reported in the earlier years, with results for just 17/522 reported isolates in 2001, though rising to 188/552 in 2005 and 218/773 in 2006.
In view of the general lack of temporal trends, except maybe for imipenem against Acb, MIC data for all years were pooled for further analysis and are presented in Table 3.
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P. aeruginosa
Most MIC distributions for P. aeruginosa were unimodal, with slight positive skew, exceptions being those for ciprofloxacin, gentamicin and possibly ceftazidime, where there were small but discrete clusters of highly resistant isolates (Table 3). Non- susceptibility rates were <10%, except for ciprofloxacin, at up to 22%. Similar rates of non-susceptibility were seen in the data reported to the HPA for most drugs (Table 2); lower rates for ciprofloxacin are probably because the BSAC data were reviewed against the S 0.5 mg/L European Committee on Antimicrobial Susceptibility Testing (EUCAST) harmonized breakpoint, adopted by the BSAC in 2007, whereas reports to the HPA would be graded relative to the former BSAC susceptibility breakpoint of S 1 mg/L. Logistic regression analysis showed that P. aeruginosa isolates from intensive care unit (ICU) patients were significantly, and independently, more often non-susceptible than non-ICU isolates to imipenem (especially) and piperacillin/tazobactam but not to other antibiotics (Table 4). Isolates from patients aged 60 years, and those hospitalized for 48 h also appeared more often non-susceptible, but these differences were insignificant after allowing that more of these patients were in ICUs.
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Very few of the 1226 P. aeruginosa isolates had resistance profiles that warranted molecular investigation: among the 39 P. aeruginosa isolates with substantive imipenem resistance (MICs > 8 mg/L), all but one were inhibited at 16–32 mg/L and 23 were susceptible to both ceftazidime and piperacillin/tazobactam. Such narrow-spectrum resistance is almost always contingent on mutational loss of porin OprD. MICs of ceftazidime (8–32 mg/L) and piperacillin/tazobactam (32–64 mg/L) were only modestly raised for 14 of the remaining 16 imipenem-resistant isolates, implying that they had a degree of AmpC derepression and/or up-regulation of efflux along with loss of OprD while, of the final two, one had broad-multiresistance (MICs: ceftazidime 128 mg/L; ciprofloxacin 128 mg/L; gentamicin 8 mg/L; piperacillin/tazobactam 64 mg/L), without unusual β-lactamase activity, implying some more-extreme combination of impermeability and efflux. Just one isolate, collected in southern England in 2001, had broad multiresistance (MICs: ceftazidime >256 mg/L; gentamicin >256 mg/L; imipenem 128 mg/L; piperacillin/tazobactam 64 mg/L; ciprofloxacin 32 mg/L) associated with a metallo-β-lactamase, identified by PCR and sequencing as VIM-2. High-level ceftazidime resistance (MIC
128 mg/L), above that usually associated with efflux or derepressed AmpC, was seen in four imipenem-susceptible or -intermediate P. aeruginosa isolates. These varied in susceptibility and resistance to piperacillin/tazobactam (MIC 8–256 mg/L) but were not investigated further.
Of the two new agents tested, ceftobiprole had weaker antipseudomonal activity than ceftazidime, with a mode MIC of 2 mg/L and with MICs > 4 mg/L for 19% of isolates, whereas doripenem, with a mode MIC of 0.12 mg/L, was more active than imipenem (mode MIC, 1 mg/L) and meropenem (mode MIC 0.25 mg/L). Most isolates with raised ceftazidime MICs also had reduced susceptibility to ceftobiprole, and those with raised imipenem MICs had reduced susceptibility to doripenem. Nevertheless, doripenem MICs were 4 mg/L for 17/18 imipenem-resistant P. aeruginosa tested, and 1 mg/L for 9. A doripenem MIC of 8 mg/L was also recorded for one imipenem-intermediate (MIC 8 mg/L) isolate. The isolate with VIM-2 enzyme was not among those tested with doripenem but, in general, metallo-β-lactamase producers are resistant to all carbapenems, including doripenem.13
Among the 240 Acinetobacter spp. collected, 125 were identified as Acb, 41 as Acinetobacter lwoffii, 24 as Acinetobacter junii, 21 as Acinetobacter haemolyticus, with 29 not identified to species level. The Acb isolates were more often non-susceptible than non-Acb (P< 0.01) but caution is necessary because, as already noted, many Acb isolates were from just a few centres. Among the factors considered, the best candidate for a significant independent relationship to non-susceptibility in Acb was acquisition more than 48 h after hospitalization; ICU isolates also appeared more likely to be non-susceptible, but this association was attenuated when it was allowed that more ICU patients had been hospitalized for longer than 48 h. MIC distributions of relevant cephalosporins, carbapenems, ciprofloxacin, gentamicin, tetracycline and minocycline for Acb and, less so, non-Acb Acinetobacter showed some bimodal character (Table 3), with discrete susceptible and non-susceptible populations, though the proportions non-susceptible were tiny for the carbapenems. For piperacillin/tazobactam, many isolates, particularly of non-Acb species, were very susceptible, with MICs 0.5 mg/L, whereas the MICs for the remainder were scattered up to 512 mg/L. It is likely that these patterns partly reflected antibacterial activity by tazobactam itself. Tigecycline had skewed unimodal MIC distributions, with values for Acb slightly higher than those for non-Acb species: 17% of the Acb isolates required tigecycline MICs > 1 mg/L, counting as non-susceptible, though only 3% required MICs > 2 mg/L, indicating full resistance. MICs of doripenem were similar to those of imipenem for both Acb and non-Acb isolates or were slightly higher; MICs of ceftobiprole were lower than those of ceftazidime, but also more clearly stratified into a bimodal distribution.
Three imipenem-resistant (MIC > 8 mg/L) Acb isolates were collected, along with two showing intermediate resistance (MICs 8 mg/L), all of them in 2004 or later. Four of these belonged to the OXA-23 clone 1 lineage, which is widespread in southern England.6 Four were tested with doripenem, with MICs of 16–32 mg/L; two were tested with meropenem, with MICs of 16–32 mg/L again being found.
The agents with the best activity were co-trimoxazole (predictably), minocycline and tigecycline, which had positive-skewed MIC distributions with single modes at 0.12, 0.25 and 0.25 mg/L, respectively; MIC maxima were 2, 4 and 4 mg/L, respectively. All isolates were susceptible to co-trimoxazole, based on a breakpoint of 2 mg/L trimethoprim, and 119/121 were susceptible based on a 1 mg/L breakpoint (the BSAC breakpoint is 32 mg/L sulfamethoxazole, based on a 19+1 sulfamethoxazole/trimethoprim combination, corresponding to 1.68 mg/L trimethoprim); 89% were susceptible to tigecycline at the breakpoint of 1 mg/L used for Enterobacteriaceae and Acinetobacter spp. The huge majority (91%) had high-level resistance to imipenem, with MICs of 64 mg/L; ceftobiprole MICs were mostly high too, exceeding 4 mg/L for 89/93 isolates tested. MICs of other β-lactams were more scattered, with many low values; thus the mode for ceftazidime was only 0.5–1 mg/L, with 93% of values 4 mg/L, while that for piperacillin/tazobactam was 8 mg/L.
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P. aeruginosa presents a paradox. The organism is notorious for resistance and the Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL) receives a steady flow of referred UK isolates, mostly from cystic fibrosis patients, that are resistant to all antibiotics except polymyxins. In the case of bacteraemias, the European Antimicrobial Resistance Surveillance System database (http://www.earss.rivm.nl) for 2006 reveals that 25% to 50% of the P. aeruginosa isolates in Greece, the Czech Republic, Turkey and (based on small numbers) Poland were resistant to relevant aminoglycosides, quinolones and β-lactams. High general resistance rates are reported also for nosocomial P. aeruginosa in East Asia and Latin America.14–16 In short, P. aeruginosa infections can and do present major treatment challenges; nevertheless, both the BSAC and HPA surveillances indicated non-susceptibility rates below 10% for bacteraemia isolates in the UK and Ireland, except for ciprofloxacin. These rates are little higher than in national surveys in the UK in 1982 and 1993 (Table 5).17,18 The 1993 P. aeruginosa survey is readily comparable since it used what later became the BSAC MIC method, with Iso-Sensitest agar, and (by chance rather than design) excluded cystic fibrosis isolates. The 1982 survey used Diagnostic Sensitivity Test agar, included cystic fibrosis isolates and had less overlap with the drugs tested in the BSAC surveillance. These factors complicate comparison, but the lack of major shifts in a quarter century is striking.
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With only five core antibiotics, the BSAC Pseudomonas panel is not ideal for interpretive reading. In particular, it is difficult to assess whether isolates with raised MICs for both piperacillin/tazobactam and ceftazidime have up-regulated efflux or derepressed AmpC; these mechanisms might be distinguished by testing carbenicillin, which is little affected by derepressed AmpC,19,20 or by seeking cephalosporin/boronic acid synergy, which confirms derepressed AmpC.21 Nevertheless, it was apparent that most imipenem resistance was narrow-spectrum, implying loss of porin OprD as a mechanism.19 Only one isolate, collected in 2001, had a metallo-carbapenemase, VIM-2. In total, around 100 P. aeruginosa isolates with VIM or IMP carbapenemases have been referred to ARMRL from UK hospitals in the past 5 years, and a few sites—none participating in the BSAC surveillance—have persistent clones.
Analysis for Acb is more complicated than that for P. aeruginosa, because fewer isolates were collected and were within the ‘other Gram-negative bacteria’ group fluctuating in species, numbers and site distribution by year, with a heavy bias to just six centres. Although no resistance trends were statistically significant in the BSAC data set, it was notable that all five imipenem-non-susceptible isolates were collected in the last 3 years and that four of them belonged to a regionally disseminated clone, OXA-23 clone 1, which has now been found in over 58 hospitals in and around London. Typically, it is resistant to all antimicrobials except tigecycline (as found here) and polymyxins.6 Bacteraemia reports to the HPA gave statistical support to the view that there has been a rise in imipenem non-susceptibility among acinetobacters and, especially, in A. baumannii, where 20% of the isolates were reported non-susceptible in 2006. Non-susceptibility to most other established compounds besides carbapenems was frequent among the Acb isolates, based on both the BSAC and HPA surveillances, though it should be added that only 17/99 BSAC isolates tested were non-susceptible to tigecycline and only 3/99 had full resistance, with MICs > 2 mg/L. There was less non-susceptibility to antibiotics among the non-Acb Acinetobacters (Table 3), as found by others.1,22
In the case of S. maltophilia, the BSAC only advocates susceptibility testing with co-trimoxazole, to which we found near-universal susceptibility. Minocycline and tigecycline also had good activity, both with unimodal MIC distributions clustered around 0.25 mg/L, but there are no data published on their efficacy in S. maltophilia infections and, as an oral agent, minocycline would not ordinarily be considered in bacteraemia. The low MICs of ceftazidime (mode 0.5 mg/L; MIC90 4 mg/L) were striking too, but difficult to assess, since the in vitro activity of β-lactams versus S. maltophilia notoriously varies with the test medium, appearing better on Iso-Sensitest than Mueller–Hinton agar, and with no clarity on which better represents the patient.23 Co-trimoxazole data for S. maltophilia isolates are poorly, if increasingly, reported to the HPA, but support the view that there is little or no resistance; likewise, ARMRL has had very few co-trimoxazole-resistant S. maltophilia isolates referred. Consequently, there seems no reason to eschew this treatment combination, except if the patient is intolerant of the sulphonamide component. Tigecycline may be a future alternative but, as yet, there are no data on its efficacy in S. maltophilia infections and usage in bacteraemia should be cautious, allowing for the low serum levels.24
Ceftobiprole and doripenem were tested from 2004 and 2005, respectively. Both have now been submitted to the European Medicines Evaluation Agency for licensing. Doripenem was around 8-fold more active than imipenem against P. aeruginosa and around 2-fold more active than meropenem, confirming the findings of other studies.13 It retained activity at 4 mg/L against 17/18 imipenem-resistant P. aeruginosa isolates tested. These data are positive, as are two studies suggesting that doripenem may have a slightly lesser propensity than other carbapenems to select resistance in P. aeruginosa.13,25 On the other hand, doripenem (and meropenem) had no advantage over imipenem against Acinetobacter spp., with slightly higher MIC values for the generality of isolates and with high values (16–32 mg/L) for the OXA-23 clone 1 isolates. Ceftobiprole was less potent than ceftazidime against P. aeruginosa but inhibited 81% of the isolates at 4 mg/L.
In conclusion, the BSAC and HPA bacteraemia surveillances both show that, despite widespread concern, resistance remains rare in bloodstream isolates of P. aeruginosa in the UK and Ireland and that there is little evidence of increase, even over much longer time periods than those considered in the present surveillance. In contrast, non-susceptibility to all established agents except imipenem is frequent in Acb, and reports suggest a rising trend of imipenem resistance. S. maltophilia remains almost universally susceptible to co-trimoxazole and, potentially, tigecycline, while a question mark hangs over the activity of β-lactams, where susceptibility varies with the medium, but with ceftazidime in particular remaining active in some media. Among newer agents, doripenem may have some advantage against P. aeruginosa, including some imipenem-resistant isolates, while—contingent on clinical results—tigecycline is a potential option against infections due to Acb and perhaps represents a new alternative against S. maltophilia.
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The BSAC Bacteraemia Resistance Surveillance Programme 2001–06 has received financial support from AstraZeneca, Basilea, Cubist, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, Theravance and Wyeth or their predecessors. The BSAC funds the work of the Resistance Surveillance Coordinator (R. R.) and Resistance Surveillance Working Party.
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This article is part of a Supplement sponsored by the British Society for Antimicrobial Chemotherapy.
D. M. L. has shareholdings in AstraZeneca, Pfizer, Schering Plough and GlaxoSmithKline, held within a diversified portfolio, and also, as Enduring Attorney, manages family holdings, including in GlaxoSmithKine, Dechra and Eco-Animal Health. All are held in diversified portfolios. He has accepted grants, advisory invitations, speaking invitations and conference invitations from most major pharmaceutical companies and many biotechnology companies. He is also employed within the UK public sector and is subject to influence by the HPA's views of antibiotic prescribing, policy and usage. All other authors have none to declare.
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Acknowledgements |
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We are grateful to all who have contributed to the success of the BSAC Resistance Surveillance Project, in particular to the many laboratories that have collected isolates and all who have played a part in testing them [see page ii10 (Acknowledgements)]. Additional information on the isolates collected in the Project is available on the BSAC surveillance web site (www.bsacsurv.org or through a link on the BSAC homepage www.bsac.org.uk). See page ii12 (Publications) for a full list of previous publications from the Project, some of which may include parts of the information presented here. We are grateful also to all the laboratories that have contributed to the HPA's LabBase/CoSurv system.
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References |
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R. Reynolds, R. Hope, L. Williams, and on behalf of the BSAC Working Parties on Resistanc Survey, laboratory and statistical methods for the BSAC Resistance Surveillance Programmes J. Antimicrob. Chemother., November 1, 2008; 62(suppl_2): ii15 - ii28. [Abstract] [Full Text] [PDF]
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R. Reynolds, P. C. Lambert, P. R. Burton, and on behalf of the BSAC Extended Working Parties on Analysis, power and design of antimicrobial resistance surveillance studies, taking account of inter-centre variation and turnover J. Antimicrob. Chemother., November 1, 2008; 62(suppl_2): ii29 - ii39. [Abstract] [Full Text] [PDF]
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