Tigecycline activity: low resistance rates but problematic disc

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J Antimicrob Chemother 2010; 65: 2602 – 2609 doi:10.1093/jac/dkq370 Advance Access publication 7 October 2010

Tigecycline activity: low resistance rates but problematic disc breakpoints revealed by a multicentre sentinel survey in the UK R. Hope *, S. Mushtaq , D. James , T. Pllana , M. Warner and D. M. Livermore on behalf of The Tigecycline Susceptibility Testing Group† Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5HT, UK *Corresponding author. Tel: +44-20-8327-6493; Fax: +44-20-8327-6264; E-mail: [email protected] †Members are listed in the Acknowledgements section.

Received 24 June 2010; returned 4 August 2010; revised 3 September 2010; accepted 4 September 2010 Objectives: A multicentre surveillance of tigecycline activity against relevant pathogens in the UK. Methods: Forty-three representative UK hospitals were each asked to test 150 consecutive, clinically significant isolates from hospitalized patients, excluding those from urine or faeces. The sentinel laboratories tested all these isolates against a panel of antibiotics by the BSAC disc method and a selection of isolates were retested centrally by the BSAC agar dilution method. Results: The isolates collected comprised Staphylococcus aureus (39.9%), Escherichia coli (13.3%), streptococci (11.9%), enterococci (6.3%), Klebsiella (6.1%), coagulase-negative staphylococci (6.1%), Enterobacter spp. (3.9%), Proteus spp. (2.2%) and other Gram-negative species (10.3%). The laboratories’ disc susceptibility testing found that 4% of isolates were resistant to tigecycline, using the zone breakpoints in place at that time. However, centralized retesting by agar dilution showed that many of these ‘resistant’ isolates were susceptible, with resistance only confirmed in a range of Gram-negative isolates and one S. aureus. These findings reduced the estimated resistance rate to 2.4%, or to 0.8% if Proteus spp. were ignored as intrinsically resistant to tigecycline. Sixty-two percent of the isolates found resistant by the disc method but susceptible by agar dilution had zones of inhibition within experimental error (4 mm) of the published breakpoints. Conclusions: Tigecycline resistance was rare in isolates causing clinically significant infections in the UK and was overestimated 2-fold by the BSAC disc method. Adjustment of the breakpoints might overcome this problem but at the risk of increasing the false susceptibility rate. The best advice is to perform dilution tests, e.g. by gradient strip test on isolates with borderline results, especially in severe infection and when tigecycline use is intended. Keywords: BSAC, TEST, agar dilution

Introduction Tigecycline was registered in the European Union (EU) in April 2006, for parenteral use in complicated skin and soft tissue infections and complicated intra-abdominal infections caused by enterococci, staphylococci, streptococci and Enterobacteriaceae excluding Proteeae, which are intrinsically resistant. Its spectrum includes most Escherichia coli and Klebsiella spp. as well as methicillin-resistant staphylococci and other multiresistant Gram-positive bacteria. Acquired ribosomal protection [tet(M)]1 and efflux [tet(A–E)]2,3 mechanisms affect other tetracyclines but not tigecycline.

Tigecycline has also been used for infections due to multiresistant Acinetobacter baumannii, against which it commonly has in vitro activity. While there are positive case reports,4 it should be cautioned that tigecycline did demonstrate inferiority when compared with imipenem/cilastatin in a Phase 3 trial of nosocomial ventilator-associated pneumonia—a common site for Acinetobacter infections. Susceptibility data for tigecycline versus UK pathogens are largely limited to single-centre studies or those focused on bacteraemia, a setting where the drug may be limited by low serum levels.5 Other large-scale ongoing mandatory and voluntary UK surveillance programmes [Mandatory MRSA,6 Labbase7 and the

# The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]

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JAC

UK tigecycline survey

European Antimicrobial Resistance Surveillance System (EARSS)8] do not collect information on the activity of tigecycline. We conducted the first large-scale multicentre surveillance of tigecycline activity and resistance in the UK.

Methods Selection of sentinel laboratories and isolate collection Ninety-three UK hospitals/sites were contacted and, from among these, 43 representative sites were chosen, based on agreement and geographical location to collect and test 150 consecutive, clinically significant isolates from hospitalized patients. The species included comprised: (i) all staphylococci, streptococci and enterococci; (ii) oxidase-negative Gramnegative bacilli (i.e. Enterobacteriaceae and Acinetobacter spp. but excluding Salmonella spp. and Shigella spp.); and (iii) Haemophilus spp. and Moraxella catarrhalis. Species excluded were: (i) oxidase-positive Gram-negative bacilli; (ii) anaerobes; (iii) agents of atypical pneumonia including mycoplasmas and Chlamydophila; (iv) Neisseria spp.; and (v) any category III pathogen. Isolates from urine or faeces were excluded, as were duplicate isolates of the same species, from the same patient and isolated within 7 days of the first isolate. Isolate collection was between September 2006 and April 2007. Urinary isolates were excluded

because they would otherwise form a large part of the collection whilst the drug is inappropriate for the setting owing to biliary excretion.

Sentinel laboratory testing Gram-negative bacilli were screened with an oxidase test, and oxidasepositive isolates were discarded. The oxidase-negative isolates were identified with API20E or API20NE strips (bioMe´rieux, Marcy l’E´toile, France) as appropriate. Staphylococci were differentiated by coagulase reaction. Streptococci and enterococci were identified with Streptex kits (Pro-Lab Diagnostics, Neston, UK) or API-STREP test strip (bioMe´rieux). Haemophilus influenzae were identified by morphology and their requirement for X and V factors (Thermofisher, Basingstoke, UK). Laboratories tested all isolates by the BSAC disc method9 versus a panel of antibiotics (see Table 1) using discs (Thermofisher) from the same batches, supplied to all hospitals.

Centralized testing Participating laboratories sent the following isolates to the Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL, London, UK) for central retesting by the BSAC agar dilution method:10 (i) a random 10% sample comprising every 10th sample collected per laboratory; and (ii) those with unusual resistance profiles, as detailed in Table 2.

Table 1. Antibiotic test panels for disc testing Antibiotic panela

Organism group Gram-negative bacillib Haemophilus/Moraxella Staphylococci Streptococci Enterococci

AMC 20/10 mg, AMP 10 mg, CAZ 30 mg, CIP 1 mg, CTX 30 mg, CXM 30 mg, FOX 30 mg, GEN 10 mg, MEM 10 mg, TET 30 mg, TGC 15 mg, TZP 75/10 mg AMC 2/1 mg, AMP 2 mg, CIP 1 mg, CTX 5 mg, TET 10 mg, TGC 15 mg CIP 1 mg, ERY 5 mg, GEN 10 mg, LZD 10 mg, MXF 1 mg, OXAc 1 mg, PEN 1 mg, TEC 30 mg, TET 10 mg, TGC 15 mg, VAN 5 mg AMC 2/1 mg, CIP 1 mg, CTX 5 mg, ERY 5 mg, LZD 10 mg, MEM 10 mg, MXF 1 mg, OXA 1 mg, PEN 1 mg, TET 10 mg, TGC 15 mg, TZP 75/10 mg AMP 10 mg, CIP 1 mg, ERY 5 mg, GEN 200 mg, LZD 10 mg, MEM 10 mg, Q/D 15 mg, TEC 30 mg, TET 10 mg, TGC 15 mg, TZP 75/ 10 mg, VAN 5 mg

AMP, ampicillin; AMC, amoxicillin/clavulanate; PEN, penicillin; CAZ, ceftazidime; CTX, cefotaxime; CXM, cefuroxime; FOX, cefoxitin; TZP, piperacillin/ tazobactam; CIP, ciprofloxacin; MXF, moxifloxacin; ERY, erythromycin; GEN, gentamicin; LZD, linezolid; MEM, meropenem; OXA, oxacillin; Q/D, quinupristin/dalfopristin; TET, tetracycline; TGC, tigecycline; TEC, teicoplanin; VAN, vancomycin. a Antibiotic concentrations as per BSAC 2007 guidelines.21 b Excluding Haemophilus and Moraxella spp. c Columbia agar + 2% NaCl incubated at 308C.

Table 2. Resistance designated as requiring the isolate to be submitted for central testing Enterobacteria and Acinetobacter spp. Tigecyclinea Meropenem Cefotaximeb Ceftazidimeb

Haemophilus/Moraxella tigecycline ciprofloxacin cefotaxime

Staphylococci tigecycline linezolid vancomycin teicoplaninc

Streptococci

Enterococci

tigecycline linezolid

tigecycline linezolid quinupristin/dalfopristin and ampicillin vancomycin teicoplanin

a

Any isolates with apparently borderline susceptibility to tigecycline based on inhibition zones of ,26 mm for staphylococci/Haemophilus and ,25 mm for Acinetobacter, streptococci, enterococci and Enterobacteriaceae, as compared with then BSAC resistance breakpoints of ,20 mm for Enterobacteriaceae and Acinetobacter, ,21 mm for enterococci, ,25 mm for streptococci and ,26 mm for staphylococci.11 b Enterobacteriaceae only, not Acinetobacter spp. c S. aureus only, not coagulase-negative staphylococci.

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Hope et al.

The latter group included any isolates with apparently borderline susceptibility to tigecycline based on inhibition zones of ,26 mm for staphylococci/Haemophilus and ,25 mm for Acinetobacter, streptococci, enterococci and Enterobacteriaceae, as compared with then BSAC resistance breakpoints of ,20 mm for Enterobacteriaceae and Acinetobacter, ,21 mm for enterococci, ,25 mm for streptococci and ,26 mm for staphylococci.11

Quality control Before any of the sentinel laboratories was allowed to test survey isolates they were asked to complete a quality control exercise. This involved disc testing of 10 distributed reference strains by the BSAC method. These comprised: three Klebsiella for which tigecycline MICs were 0.25, 1 and 4 mg/L, respectively; two E. coli for both of which the tigecycline MIC was 0.25 mg/L; two Acinetobacter spp. for which tigecycline MICs were 0.25 and 1 mg/L; one b-haemolytic Lancefield group G Streptococcus spp. for which the tigecycline MIC was 0.25 mg/L and one Staphylococcus aureus for which the tigecycline MIC was 0.125 mg/L. Laboratories were only allowed to proceed with the testing of the survey isolates once 80% of their zone determinations were within 4 mm of the mean zones determined centrally. Also, any quality control isolate where the sentinel laboratory’s zone diameter was ≥9 mm different from that centrally determined had to be retested, regardless of the number of zones obtained within 4 mm for the other quality control isolates.

Results Table 3 summarizes the collection: 6151 isolates were obtained from the 43 UK hospitals. Of these, 2460 (39.9%) were S. aureus, of which 40% were methicillin-resistant S. aureus (MRSA); 820 (13.3%) were E. coli, of which 19% were oxyiminocephalosporin resistant and 24% ciprofloxacin resistant; 720 (11.7%) were streptococci; 391 (6.3%) were enterococci, 17% of them vancomycin resistant; 375 (6.1%) were Klebsiella, of which 30% were oxyimino-cephalosporin resistant and 18%

ciprofloxacin resistant; 374 (6.0%) were coagulase-negative staphylococci, of which 66% were oxacillin resistant; 244 (4.0%) were Enterobacter, 46% of them oxyimino-cephalosporin resistant; 138 (2.2%) were Proteeae; and 629 (10.2%) belonged to various other Gram-negative species of which 31% were Enterobacteriaceae. Fifty-four percent of isolates were from men, 45% from women, with 1% unknown; the mean patient age was 56 years. Most isolates were from soft tissue/wound infections (33.1%) or blood (29.5%); 64% were from patients who had been in hospital for .48 h. The sentinel laboratories’ disc testing found 12.8% of isolates were apparently non-susceptible to tigecycline by the BSAC disc breakpoints in place at that time (Table 4) with rates of 25% –35% for Acinetobacter spp., b-haemolytic streptococci, Enterobacter and Klebsiella. The disc results also indicated that 0.2% of the S. aureus and 2% of the coagulasenegative staphylococci were non-susceptible to vancomycin, and that 0.3% – 3% of Gram-positive cocci were non-susceptible to linezolid, with the highest rate in the a-haemolytic streptococci. Apparent rates of non-susceptibility to oxyiminocephalosporins among Enterobacteriaceae ranged from 13% to 46%, with non-susceptibility to meropenem ranging from 1% to 8% depending on species. A total of 1603 isolates were received for central MIC testing, 605 as a random sample, 638 on the basis of reduced tigecycline zones and 360 with other unusual non-susceptibilities, as defined in Table 1. Among the 902 isolates received as tigecycline susceptible based on the laboratories’ disc tests, 881 (97.6%) (Table 5) were confirmed susceptible by agar dilution. Of the 21 isolates incorrectly identified as susceptible by the disc tests, one was an S. aureus with an MIC of 1 mg/L, three were tigecycline-resistant Enterobacter spp. for which the MIC was 4 mg/L, six were Klebsiella spp. for which the MIC was 2 mg/L, two were Proteus spp. for which the MIC was 16 mg/L, eight

Table 3. Summary of survey collection

Patient sex (%)

Patient age, years (%)

Inpatient status (%)

Organism (%)

Referring speciality (%)

Male

(54.5)

≤16

(10.2)

,48 h

(35.5)

S. aureus

(39.9)

Female NK

(44.8) (0.7)

17 –70 .70

(49.9) (35.9)

.48 h NK

(64.0) (0.6)

E. coli other Gram-negative bacteriaa b-haemolytic streptococci enterococci Klebsiella spp. CoNS Enterobacter spp. S. pneumoniae Proteeae a-haemolytic streptococci Acinetobacter spp.

(13.3) (10.2)

NK

(3.9)

(7.2) (6.3) (6.1) (6.0) (4.0) (2.8) (2.2) (1.6) (1.2)

general medicine other/NK surgery

(27.4)

ICU A&E paediatrics CoE

(11.0) (8.6) (8.6) (7.6)

(19.0) (17.8)

Isolation site (%) soft tissue/ wound blood other

(33.1)

sputum skin respiratory intra-abdominal NK

(12.1) (5.3) (4.6) (2.8) (0.2)

A&E, accident and emergency; CoE, care of the elderly; ICU, intensive care unit; NK, not known; CoNS, coagulase-negative staphylococci. Excludes species with specific entries in this table.

a

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(29.5) (12.3)

JAC AMP, ampicillin; AMC, amoxicillin/clavulanate; PEN, penicillin; CAZ, ceftazidime; CTX, cefotaxime; CXM, cefuroxime; FOX, cefoxitin; TZP, piperacillin/tazobactam; CIP, ciprofloxacin; MXF, moxifloxacin; ERY, erythromycin; GEN, gentamicin; LZD, linezolid; MEM, meropenem; OXA, oxacillin, Q/D, quinupristin/dalfopristin; TET, tetracycline; TGC, tigecycline; TEC, teicoplanin; VAN, vancomycin; NA, not applicable. a Excluding Proteus spp.

17 0.2 — — — — — 23 0.4 — — — — — 5 7 28 6 24 34 28 71 5 NA NA NA NA NA 71 — — — — — — — 40 — — — — — 65 — 23 1 8 5 2 0.8 0.3 — — — — — 41 2 16 10 11 12 4 NA 35 — — — — — — 4 — — — — — NA 42 30 24 15 18 26 NA — 20 12 18 18 20 — — NA 9 89 13 61 — — NA 18 46 25 70 — — NA 13 40 21 32 — — NA 19 46 30 27 — 89 — — — — — 33 — NA 63 83 94 86 391 2460 68 820 244 375 192

— — NA 35 88 27 74

— — 2 — — 2 27 NA 3 55 10 18 — — — NA NA 67 NA 5 — 2 0 1.3 — — 44 17 18 65 NA 4 44 NA 99 45 NA NA — — — — — — — 4 2 — — — — 1 5 90 — — — 446 173 374

NA NA —

— — 16 43 — NA NA 3 — 30 NA NA NA — — 4 — 24 NA — 101

a- & Non-haemolytic streptococci b-Haemolytic streptococci S. pneumoniae Coagulase-negative staphylococci Enterococci S. aureus Acinetobacter spp. E. coli Enterobacter spp. Klebsiella spp. Other Enterobacteriaceaea

TZP FOX CXM CTX CAZ PEN AMC AMP Number of isolates

Table 4. Non-susceptibility (%) determined by sentinel laboratories using the BSAC disc testing method

CIP

MXF

ERY

GEN

LZD

MEM

OXA

Q/D

TET

TGC

TEC

VAN

UK tigecycline survey

were Serratia spp. for which MICs were 2– 4 mg/L and one was a Citrobacter spp. for which the MIC was 2 mg/L. Ten of these 21 were resistant based on EUCAST/BSAC MIC breakpoint definitions and thus represented very major errors. The remaining 11 isolates, all of them Enterobacteriaceae, reported susceptible by disc were found to be intermediate by agar dilution; this equates to a 2.6% minor error rate. If only Enterobacteriaceae other than Proteeae were considered, the major error rate was 0.62%. Rates of false resistance were much higher than of false susceptibility. One hundred and thirty-six of the 3943 (3%) Gram-positive isolates collected had been found to be resistant in disc tests, but none of these was confirmed as intermediate or resistant; rather, the one MRSA isolate for which the tigecycline MIC was 1 mg/L was found among the isolates submitted as a random sample. The zone of inhibition for this isolate had been recorded by the sender as 26 mm; however, a zone of 24 mm was obtained at the central laboratory confirming the isolate as resistant by disc breakpoints as well as MIC. Tigecycline resistance (MIC .2 mg/L) was confirmed in 36 of the 49 Gram-negative isolates submitted as resistant (23 Klebsiella, 15 Proteus spp., 7 Enterobacter spp. and 4 E. coli). The majority of the cases (9/13), where tigecycline resistance was not confirmed proved to be Klebsiella spp. intermediate to tigecycline with MICs of 2 mg/L. Based on MIC results the overall tigecycline resistance rate in Enterobacteriaceae was only 7.5%, or 2.4% if Proteus were discounted as intrinsically resistant, versus the 3.1% found in the laboratories’ disc tests. Fully 62% of the isolates found to be tigecycline non-susceptible by the disc method but susceptible by agar dilution gave zones of inhibition within 4 mm of the published zone breakpoints and thus represent a population where a greater rate of categorization errors is to be expected, simply due to experimental variation.12 In the case of Haemophilus spp. neither the BSAC nor EUCAST has published tigecycline breakpoints. The highest MIC observed for the genus was 1 mg/L with a mode of 0.5 mg/L. Central testing by agar dilution did not confirm any disc results of non-susceptibility to vancomycin in staphylococci (n¼ 11) or for any Gram-positive species to linezolid (n¼ 19). By contrast, 82% of the Gram-negatives submitted as nonsusceptible to third-generation cephalosporins were confirmed as non-susceptible by agar dilution. It should be added here that the isolates collected for centralized MIC testing were not a representative sample but biased towards those resistant or borderline susceptible to tigecycline including, for example, those Enterobacteriaceae with zones of ≤24 mm, which was on the BSAC susceptible breakpoint in place at that time. Isolates with MICs or disc zones close to the breakpoints inevitably are more likely to be miscategorized than those with zones or MICs further from a breakpoint, simply due to the experimental error inherent to susceptibility testing methods.12 If only the isolates collected as the random 10% sample were considered the tigecycline disc breakpoints performed more adequately with 8.0% minor errors, 3.9% major and no very major errors (Table 6). This is within the acceptable limits specified by the BSAC or CLSI.12,13

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Table 5. Summary of tigecycline susceptibility, as determined with 15 mg tigecycline discs at sentinel laboratories and as based on agar dilution testing at the central laboratory Percentage tigecycline susceptibility as determined with 15 mg discsa

Percentage susceptibility corrected by agar dilutiona

Number of isolates referreda

S

I

R

S

I

R

101 446 173 374 391 2460 68 820 244 375 197 5649

84.2 73.4 83.8 98.1 94.9 96.4 72.5 94.1 75.8 65.4 72.5 89.5

12.9 24.6 11.5 0 0 0 21.7 5.4 21.3 28.5 23.5 7.2

3 2 4.6 1.9 5.1 3.6 5.8 0.5 2.9 6.1 3.9 3.2

97 99.7 100 100 100 99.6 89.3 100 93.2 82.3 84.1 97.6

3 0.3 0 0 0 0 6.1 0 1.8 12.6 11.7 1.4

0 0 0 0 0 0.4 4.6 0 5 5.1 4.2 0.8

a- & Non-haemolytic streptococci b-Haemolytic streptococci S. pneumoniae b Coagulase-negative staphylococci Enterococci S. aureus Acinetobacter spp. E. coli Enterobacter spp. Klebsiella spp. Other Enterobacteriaceaec Allc

S, susceptible; I, intermediate; R, resistant. Comprises isolates received as a random sample and those meeting any of the criteria in Table 2. b Species non-specific breakpoint. c Excluding Proteus spp. a

Table 6. Performance of the disc testing at the sentinel laboratories, based only on the random 10% sample of isolates excluding Proteeae Antibiotics Ampicillin Amoxicillin/clavulanate Ciprofloxacin Cefotaxime Ceftazidime Cefuroxime Cefoxitin Erythromycin Gentamicin Linezolid Meropenem Moxifloxacin Oxacillin Penicillin Piperacillin/tazobactam Quinupristin/dalfopristin Teicoplanin Tetracycline Tigecycline Vancomycin

Minor error (%)

Major error (%)

Very major error (%)

11 18 6.2 0.5 22.0 NA 2.0 NA 0.2 0.0 3 0 NA NA NA 61.9 NA NA 8.0 NA

1.1 5.7 0.9 3.3 1.3 1 1 0.6 0.9 0.3 5 45.8 2.3 0.3 3.1 0 0 0.8 3.9 0.7

3.9 2.5 1.4 1.4 1.3 12.6 1.9 11 2 0 0.0 0.4 0.4 1 3 0 0 6 0.0 0

NA, not applicable.

Discussion This study aimed to survey the prevalence of tigecycline nonsusceptibility among clinical isolates from relevant infections in

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the UK. Those from respiratory infections were included because these indications were then being sought. Subsequently, in a number of countries, including the USA but not Europe, the licence for tigecycline has been extended to include

JAC

UK tigecycline survey

community-acquired pneumonia. The study sought also to test the ability of the BSAC zone breakpoints in place at that time to categorize isolates in routine use. It was clear that sentinel laboratory disc results significantly overestimated tigecycline non-susceptibility compared with agar dilution tests. Three main factors most likely conspired to cause this discrepancy: (i) disc zone breakpoints are deliberately biased towards recording false non-susceptibility rather than false susceptibility, as the latter has more serious clinical consequences; (ii) the BSAC disc breakpoints were defined using results from a single centre study14 potentially underestimating the magnitude of inter-centre variation; and (iii) the 15 mg tigecycline disc, released as a global standard, has poor resolution (1 –2 mm) between disc modal zones for adjacent MICs when used with the BSAC disc testing method.15 Based on the central MIC testing the present surveillance showed low rates of non-susceptibility to tigecycline: ,1% in Gram-positive organisms and E. coli, though with 17.7%– 6.8% in Klebsiella and Enterobacter spp. The overall resistance rate was 2.4%. It should moreover be restated that these rates are probably overestimates, since the isolates collected for the centralized testing were biased to include those with zones around, or smaller than, the breakpoint. If only the isolates in the random 10% sample were considered, the overall percentage resistance rate fell to 1.02%. The only long-term ongoing surveillance programme in the UK monitoring tigecycline MICs for diverse pathogenic bacteria is the BSAC Bacteraemia Programme,5 which therefore provides the best comparator for the present study albeit with the caveats that: (i) the collection periods are different, with the BSAC based on a calendar year; (ii) the BSAC study only has 23 UK sentinel laboratories compared with 43 sites in this study; and (iii) this study included isolates from sites other than blood. The BSAC data from 2001–06 showed that tigecycline was almost universally active against common Gram-positive pathogens and E. coli, with greater (17.7% –6.8%) non-susceptibility

among Klebsiella spp. and Enterobacter spp. Additional UK tigecycline MIC data are available from the Tigecycline Evaluation and Surveillance Trial (TEST) programme for the period 2006 – 07,16 although this included only four UK hospitals and collected isolates from urine, a site not appropriate for tigecycline therapy owing to the drug’s largely (59%) biliary excretion. Table 7 compares the percentage tigecycline nonsusceptibilities for the different organism groups as determined here (disc based upon susceptibility corrected with agar dilution), BSAC and TEST in the UK. All three studies found similar rates of tigecycline non-susceptibility, except that the BSAC bacteraemia surveillance found 9.4% non-susceptibility in coagulase-negative staphylococci and 1%–5% in other Gram-positive species, whereas rates were lower here and in TEST. Irrespective of the study, most non-susceptibility was low level, with far more isolates intermediate rather than fully resistant. Comparison with non-European studies is complicated by the latter using the US FDA tigecycline breakpoints, which are higher than the EUCAST/BSAC values for the Enterobacteriaceae, with values of ≤2 mg/L counting as susceptible and only ≥8 mg/L as resistant. Such breakpoints result in significantly fewer Klebsiella spp. and Enterobacter spp. isolates being categorized as non-susceptible, and published outputs from TEST for global or non-European data17 – 19 then found that only 6% Klebsiella spp. and Enterobacter spp. species were non-susceptible, although MIC90 values of 2 mg/L indicated that at least 10% would have counted as non-susceptible based on EUCAST criteria. The present study is the largest UK point prevalence sentinel survey of tigecycline susceptibility to date, with more UK centres than BSAC and TEST combined and including isolates only from infection sites appropriate for tigecycline therapy. The positive finding is that the drug showed good activity: only 2.4% (0.8% excluding Proteus) of isolates were confirmed to be tigecycline resistant, whilst another 1.4% had intermediate resistance. The negative finding is that BSAC tigecycline disc

Table 7. Susceptibility by BSAC breakpoints21 to tigecycline as found by different surveillance programmes in 2007 Percentage of isolates non-susceptible to tigecycline

a- & Non-haemolytic streptococci b-Haemolytic streptococci S. pneumoniae Coagulase-negative staphylococci Enterococci S. aureus Acinetobacter spp. E. coli Enterobacter spp. Klebsiella spp. Other Enterobacteriaceae

UK tigecycline surveya

BSAC5

TEST22

2.9 0.3 0 0 0 0.4 10.7 0 6.8 17.7 15.9

5.3 3.1 0 9.4 3.1 1.2 12.1 0 10.3 12.7 15.7

NA 0.22 0.36 NA 0.1 0 10.2 0.79 10.3 11.2 18.4

NA, not applicable. a Based on agar dilution results.

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Hope et al.

breakpoints had poor specificity for identifying intermediate or resistant isolates. Because of this poor discrimination the BSAC has now withdrawn its Enterobacteriaceae disc breakpoints for tigecycline until further notice, except for E. coli.20 As with all antibiotics, MIC determination (e.g. by gradient strip test) should be performed on isolates with zones close to the susceptible breakpoint if the drug is intended for clinical use.

Acknowledgements Members of The Tigecycline Susceptibility Testing Group: Dr Derek Brown, Addenbrooke’s Hospital; Dr Paul Rooney, Belfast City Hospital; Dr Ruth Palmer/Dr Guleri, Blackpool Victoria Hospital; Dr John Croal, Countess of Chester Hospital, NHS Foundation Trust; Dr Michael Weinbren, University Hospitals Coventry and Warwickshire; Dr Selina Hogue, Royal Derby Hospital; Prof. Kate Gould, Freeman Hospital, Newcastle Upon Tyne; Dr N. Cumberland, Frimley Park Hospital, NHS Foundation Trust; Dr Margaret Logan, Gloucestershire Royal Hospital; Dr Devadas G. Pillay, Good Hope Hospital, Heart of England NHS Foundation Trust; Dr Claire Thomas/Dr Sue Want, Hammersmith Hospital, Imperial College Healthcare NHS Trust; Dr Beryl Oppenheim, Heartlands Hospital, NHS Trust; Dr Richard Kent, Ipswich Hospital, NHS Trust; Dr Manjula/ Dr Rizkalla, Kettering General Hospital; Dr J. Wade, Kings College Hospital, NHS Trust; Prof. Mark Wilcox, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust; Dr Andrew Swann, Leicester Royal Infirmary, University Hospitals of Leicester; Dr Alastair Leonard, Monklands Hospitals, NHS Lanarkshire; Dr Galloway, Victoria Hospital, NHS Greater Glasgow and Clyde; Dr W. Al-Wali, Rotherham District General Hospital, NHS Trent; Dr Susan Jane Hudson, Queen Elizabeth Hospital, Gateshead Health NHS Foundation Trust; Dr Julian Rogers, Royal Cornwall Hospital, NHS Trust; Dr Trevor Winstanley, Royal Hallamshire Hospital, Sheffield NHS Foundation Trust; Dr Unell B. G. Riley, The Royal Marsden Hospital, NHS Foundation Trust; Dr D. J. Johnstone, Scarborough Hospital, East Yorkshire NHS Trust; Dr Khalid El-Bouri, Singleton Hospital; Dr Graeme Jones, Southampton General Hospital, University Hospitals NHS Trust; Prof. Alasdair MacGowan, Southmead Hospital, North Bristol NHS Trust; Dr Annette Jepson, St Mary’s Hospital, Imperial College Healthcare NHS Trust; Dr Unsworth, Tameside Hospital, NHS Foundation Trust; Dr Edward James, Royal Free Hampstead NHS Trust; Dr Nandini Shetty/Michael Shemko, University College, London Hospitals NHS Trust; Dr Mark Hastings, University Hospital of South Wales; Dr Cyril Lafong, Victoria Hospital, NHS Fife; Dr Sarah Richards, West Cumberland Hospital, North Cumbria University Hospitals NHS Trust; Dr James Nash, William Harvey Ashford; Dr D. Waghorn, Wycombe Hospital, Buckinghamshire Hospitals NHS Trust; Dr Mairi Cullen, Wythenshaw Hospital. University of South Manchester NHS Foundation Trust; Dr N. Todd/Dr A. N. Anderson, York Hospitals NHS Foundation Trust; Dr Stuart D’Arcy, Ysbyty Gwynedd, North West Wales NHS Trust; Dr Colin Goodburn, Southend Hospital; and Dr Guiseppe Bignardi, Sunderland Royal Hospital, NHS Foundation Trust. We wish to express our thanks to all at these hospitals involved in the collection and testing of the isolates.

Funding This work was supported by Wyeth, who are now a part of Pfizer Inc.

Transparency declarations All authors work in the field of antibiotic resistance and could be considered to have vested interests in investment in this area, whether by governments or charities or industry. D. M. L. has accepted grants,

2608 Downloaded from https://academic.oup.com/jac/article-abstract/65/12/2602/755413 by guest on 31 January 2018

conference and speaking invitations from most major pharmaceutical companies with interests in new anti-Gram-positive agents including Novartis, Pfizer and Janssen-Cilag. He holds shares in AstraZeneca, Pfizer, GlaxoSmithKline and Merck, within a diversified portfolio.

References 1 Petersen PJ, Jacobus NV, Weiss WJ et al. In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Antimicrob Agents Chemother 1999; 43: 738–44. 2 Fluit AC, Florijn A, Verhoef J et al. Presence of tetracycline resistance determinants and susceptibility to tigecycline and minocycline. Antimicrob Agents Chemother 2005; 49: 1636–8. 3 Hirata T, Saito A, Nishino K et al. Effects of efflux transporter genes on susceptibility of Escherichia coli to tigecycline (GAR-936). Antimicrob Agents Chemother 2004; 48: 2179 –84. 4 Woodford N, Ellington MJ, Coelho JM et al. Multiplex PCR for genes encoding prevalent OXA carbapenemases in Acinetobacter spp. Int J Antimicrob Agents 2006; 27: 351–3. 5 BSAC Resistance Surveillance Project. http://www.bsacsurv.org (21 July 2009, date last accessed). 6 Department of Health’s mandatory MRSA reporting scheme, Health Protection Agency. http://www.hpa.org.uk/infections/topics_az/staphylo/ staphylo_mandatory_surveillance.htm (8 August 2010, date last accessed). 7 Reacher MH, Shah A, Livermore DM et al. Bacteraemia and antibiotic resistance of its pathogens reported in England and Wales between 1990 and 1998: trend analysis. BMJ 2000; 320: 213– 6. 8 European Antimicrobial Resistance Surveillance System (EARSS). http:// www.earss.rivm.nl (8 August 2010, date last accessed). 9 Andrews JM for the BSAC Working Party on Susceptibility Testing. BSAC standardized disc susceptibility testing method (version 6). J Antimicrob Chemother 2007; 60: 20 –41. 10 Andrews JM. Determination of minimum inhibitory concentrations. J Antimicrob Chemother 2001; 48 Suppl 1: 5– 16. 11 Andrews JM for the BSAC Working Party on Susceptibility Testing. BSAC standardized disc susceptibility testing method (version 8). J Antimicrob Chemother 2009; 64: 454– 89. 12 Clinical and Laboratory Standards Institute. Development of in Vitro Susceptibility Testing Criteria and Quality Control Parameters—Third Edition: Approved Guideline M23-A3. CLSI, Wayne, PA, USA, 2008. 13 MacGowan AP, Wise R. Establishing MIC breakpoints and the interpretation of in vitro susceptibility tests. J Antimicrob Chemother 2001; 48 Suppl 1: 17– 28. 14 Hope R, Parsons T, Mushtaq S et al. Determination of disc breakpoints and evaluation of Etests for tigecycline susceptibility testing by the BSAC method. J Antimicrob Chemother 2007; 60: 770–4. 15 Andrews JM for the BSAC Working Party on Susceptibility Testing. BSAC standardized disc susceptibility testing method (version 7). J Antimicrob Chemother 2008; 62: 256– 78. 16 Nørskov-Lauritsen N, Marchandin H, Dowzicky MJ. Antimicrobial susceptibility of tigecycline and comparators against bacterial isolates collected as part of the TEST study in Europe (2004– 2007). Int J Antimicrob Agents 2009; 34: 121–30. 17 Dowzicky MJ, Park CH. Update on antimicrobial susceptibility rates among Gram-negative and Gram-positive organisms in the United States: results from the Tigecycline Evaluation and Surveillance Trial (TEST) 2005 to 2007. Clin Ther 2008; 30: 2040 –50. 18 Garrison MW, Mutters R, Dowzicky MJ. In vitro activity of tigecycline and comparator agents against a global collection of Gram-negative and Gram-positive organisms: Tigecycline Evaluation

UK tigecycline survey

and Surveillance Trial 2004 to 2007. Diagn Microbiol Infect Dis 2009; 65: 288 – 99. 19 Bouchillon SK, Iredell JR, Barkham T et al. Comparative in vitro activity of tigecycline and other antimicrobials against Gram-negative and Gram-positive organisms collected from the Asia-Pacific Rim as part of the Tigecycline Evaluation and Surveillance Trial (TEST). Int J Antimicrob Agents 2009; 33: 130–6.

JAC 20 BSACwebsite. http://www.bsac.org.uk (8 August 2010, date last accessed). 21 BSAC standardized disc susceptibility testing method (version 6.1). http://www.bsac.org.uk/_db/_documents/version_6.1.pdf (15 December 2007, date last accessed). 22 Tigecycline Evaluation and Surveillance Trial (TEST). http://www. testsurveillance.com (8 August 2010, date last accessed).

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Tigecycline activity: low resistance rates but problematic disc

J Antimicrob Chemother 2010; 65: 2602 – 2609 doi:10.1093/jac/dkq370 Advance Access publication 7 October 2010 Tigecycline activity: low resistance ra...

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