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In vitro activity of flumequine in comparison with several other antimicrobial agents against five pathogens isolated in calves in the Netherlands a
a
D.J. Mevius , H.J. Breukink & A. S. J. P. A. M. van Miert
b
a
Department of Large Animal Medicine and Nutrition, Veterinary Faculty , Utrecht University , Yalelaan 16, Utrecht, 3508 TD, The Netherlands b
Department of Veterinary Basic Sciences, Division of Pharmacology, Pharmacy, Toxicology and Therapy, Veterinary Faculty , Utrecht University , P.O. Box 80176, Utrecht, 3508 TD, The Netherlands Published online: 01 Nov 2011.
To cite this article: D.J. Mevius , H.J. Breukink & A. S. J. P. A. M. van Miert (1990) In vitro activity of flumequine in comparison with several other antimicrobial agents against five pathogens isolated in calves in the Netherlands, Veterinary Quarterly, 12:4, 212-220, DOI: 10.1080/01652176.1990.9694268 To link to this article: http://dx.doi.org/10.1080/01652176.1990.9694268
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In vitro activity of flumequine in comparison with several other antimicrobial agents against five pathogens isolated in calves in the Netherlands D. J. Mevius', H. J. Breukinkl, and A. S. J. P. A. M. van
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Miert2
SUMMARY The in vitro activity of flumequine in comparison with several other drugs was tested against 17 P. multocida, 16 P. haemolytica, 21 S. dublin, 21 S. typhimurium and 21 E. coli strains, isolated in (veal) calves in the Netherlands. The MIC50 of flumequine for the respective pasteurellas was 0.25 and 1 pg/ml, for the salmonellas and E. coli 0.5 pg/ml. In comparison with flumequine, enrofloxacin and ciprofloxacin showed higher in vitro activity, with MICso 0.008 pg/m1 for ciprofloxacin. Decreased susceptibility of the pasteurellas was found for kanamycin, neomycin, streptomycin, gentamicin, oxytetracycline and doxycycline. The MIC50 of minocycline for P. multocida was 0.5 pg/m1 and there was no cross resistance with the other tetracyclines. P. multocida was very susceptible to ampicillin (MIC50 < 0.03 Ag/ml), P. haemolytica, however, was 100% resistant to this drug. Both pasteurellas were susceptible to cephalothin and approximately 50% of the strains of both bacteria were resistant to chloramphenicol. The MIC50 of either spiramycin or tylosin was their respective breakpoint-MIC values. Both pasteurellas were susceptible to the combination of trimethoprim and sulphamethoxazole. However, for P. multocida, the addition of sulphamethoxazole to trimethoprim had no synergistic effect on its MIC. In comparison with trimethorpim, aditoprim was less potent. Therefore only P. multocida was susceptible to aditoprim.
INTRODUCTION
The most important bacteria causing infectious diseases in calves are Salmonella dublin, Salmonella typhimurium, Escherichia coli, Pasteurella multocida and
Pasteurella haemolytica (1, 6, 9, 18, 19, 22). In the Netherlands, decreasing
susceptibility of these bacteria has been reported to P-lactam antibiotics, aminoglycosides, tetracyclines, chloramphenicol and trimethoprim-sulphonamide combinations (6). The main cause for this decreased susceptibility is the widespread profilactic and therapeutic use of antibiotics in these animals. To prevent severe economic losses in both dairy and veal calf husbandry, it is essential that
an adequate antimicrobial therapy should be established, based on clinical diagnostic measurements and laboratory information (19, 22). Since the middle
of the 70's, flumequine has been used in the Dutch veal calf industry for the treatment of salmonellosis and pasteurellosis (9, 10, 14). Veterinary literature contains little information on quantitative data about MIC values of flumequine against Salmonella spp., E. coli and Pasteurella spp. isolated in calves (14, 21, 22).
I
2
Department of Large Animal Medicine and Nutrition, Veterinary Faculty, Utrecht University, Yalelaan 16, 3508 TD Utrecht, The Netherlands. Department of Veterinary Basic Sciences, Division of Pharmacology, Pharmacy, Toxicology and
Therapy, Veterinary Faculty, Utrecht University, P.O. Box 80176, 3508 TD Utrecht, The Netherlands. Corresponding author: D. J. Mevius.
212
THE VETERINARY QUARTERLY, VOL. 12,
No. 4,
OCTOBER 1990
The purpose of this study was to investigate the in vitro activity of flumequine for clinical isolates of S. dublin, S. typhimurium, P. multocida and P haemolytica from veal calves and isolates of E. coli from dairy calves in comparison with several
other antimicrobial agents. MATERIAL AND METHODS
Bacterial strains Twenty-one isolates of Salmonella typhimurium, 21 of Salmonella dublin, 11 of Escherichia coli, 17 of Pasteurella multocida and 16 of Pasteurella haemolytica from clinically affected
calves were obtained from the Regional Animal Health centres in Zuid-Nederland, Downloaded by [Universitaetsbibliothek Dortmund] at 05:43 22 October 2014
Overijssel and Gelderland, the Netherlands. Ten isolates of E. coli were obtained from the
collection of the National Institute for Public Health and Environmental Hygiene, Bilthoven, the Netherlands. The E. coli strains were all K99+. No further biotyping was performed on the salmonella and pasteurella isolates. All isolates were inoculated into 2 ml vials containing trypton soja broth and 20% glycerine
and stored at 70°C. Subcultures of the clinical isolates were incubated overnight on Iso-Sensitest agar (Oxoid Ltd, Basingstoke, United Kingdom) containing 5% horse-blood under aerobic conditions at 35°C. Drugs
Drugs tested in the agar dilution method for S. typhimurium, S. dublin and E. coli were flumequine (UB; Rhone-Poulenc, Amstelveen, The Netherlands), ciprofloxacin (CIP) and enrofloxacin (ENF; Bayer AG, Leverkusen, West-Germany). Apart from these quinolones, streptomycin (S), kanamycin (K; Intervet By, Boxmeer, The Netherlands), neomycin (N; Lundbeck, Amsterdam, The Netherlands), gentamicin (GM; Schering, Weesp, The Netherlands), ampicillin (AM; Beecham, Amstelveen, The Netherlands), cephalothin (CF; Brunswich Chemie, Amsterdam, The Netherlands), oxytetracycline (OT), doxycycline (DC; Pfizer, Rotterdam, The Netherlands), trimethoprim-sulphamethoxazole 1 : 20 (SXT), aditoprim (ADP; Hoffman-la Roche, Mijdrecht, The Netherlands), chloramphenicol (C), spiramycin (SP) and tylosin (TY; Brunswich Chemie, Amsterdam, The Netherlands) were tested against P haemolytica. Against P. multocida thrimethoprim (TMP, Hoffman-La Roche, Mijdrecht, The Nether-
lands) and minocycline (MC; DG Lederle, Zoeterwoude, The Netherlands), were also tested.
Susceptibility test The MIC of the different antimicrobial agents was performed by means of the agar dilution
method, previously described by Pijpers et al. (16). Stock solutions of 10 mg/ml were prepared by dissolving most of the drugs in distilled water. UB and sulphamethoxazole (SMX) were dissolved in NaOH 0.1 mmo1/1, OT and DC in methanol, MC,'TMP, ADP and C in dimethylformamide, SP in ethanol and AM in a phosphate buffer according to Sorensen with pH = 8. These solutions were used to prepare serial dilutions (range 0.004 16 pg/m1) in Iso-Sensitest agar. For P haemolytica and P multocida, 5% sterile horse blood was added to the agar. Inoculae of the bacteria were prepared by suspending an overnight culture in 0.9% NaCI solution to a density corresponding with the McFarland nephelometer density standard No. 2. Subsequently each culture was diluted in 0.9% NaC1 solution to an approximate concentration of 106 CFU/ml, which was confirmed by counting CFU after serial dilutions.
These suspensions were used in the susceptibility tests by inoculating with a Steers' multipoint inoculator to the test plates, giving 103 CFU/spot. MIC values were read after overnight incubation under aerobic conditions at 35°C. Most of the breakpoint-MIC values used to determine whether a strain was susceptible or not were those recommended by the Dutch working party on guidelines for human susceptibility tests (12) and the Antibiotic
working party of the National Council for Agricultural Research (not an official publication). Strains with MIC values
breakpoint-MIC were considered resistant.
THE VETERINARY QUARTERLY, VOL. 12, No. 4, OCTOBER 1990
213
RESULTS
The distribution in MIC values of eighteen different drugs for P multocida, sixteen drugs for P. haemolytica and three drugs for S. dublin, S. typhimurium and E. coli are presented in Tables 1, 2 and 3 respectively. Tables 4 and 5 present the respective MIC50 and MIC90 values (the concentration at which 50% and 90% of the strains are inhibited) and the breakpoint-MIC values of the drugs for the tested bacterial species.
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The P multocida strains were resistant to K, N, S, GM, OT, DC, SP and TY, because the MIC50 values were higher than the respective breakpoint-MIC values and susceptible to UB, ENF, CIP, AM, CF, MC, SXT, TMP and ADP. The P haemolytica strains were resistant to K, S, AM, OT, DC, ADP, SP and TY and susceptible to UB, ENF, CIP, N, GM, CF, SXT and C. The S. dublin, S. typhimurium and E. coli strains were all well susceptible to the quinolones UB, ENF and CIP. Of these quinolones CIP was the most active drug. DISCUSSION
The purpose of the present study was to determine quantitatively the native susceptibility of the main bacterial pathogens of calves to flumequine in
comparison with several other antimicrobial drugs. In our view the MIC50 gives the best indication of the native susceptibility of the isolates tested. The value of the MIC90 is greatly influenced by one or two resistant isolates. Table 1. Distribution of minimal inhibitory concentrations (pg/m1) of 18 different antibiotics against 17 strains of Pasteurella multocida, isolated from veal calf lungs in the Netherlands. The recommended
breakpoint-MIC values of the respective antibiotics are underlined.
MIC:
5.004 .008 .015 .03
flumeguine
,
enrofloxacin
11
ciprofloxacin kanamycin
7
4
neomycin streptomycin gentamicin ampicillin
,
cephalothin
..
oxytetracycline doxycycline
..
minocycline
..
trim/sulfamethox. trimethoprim
.. ..
aditoprim
..
..
,
..
spiramycin tylosin
..
.
..
2
3
4
3
1
1
1
.,..
1
2
3
..
..
.
..
..
a.
Oe
oe
..
..
1
..
2
..
4
8
1
..
.. .. ..
..
_,_,_
..
1
..
..
..
1
5
3
.
12
..
2
1
2
9
4
..
..
..
2
2
..
1
2
1
1
2 2
..
..
2
2
4
9
...A.
1
2
6
3
1
..
..
1
2
4
2
3
1
2
..
2
8
1
J-11.
..
..
7
1
1
n6 2
..
.....
8
2 5
00
7
8
2
8
_,.,_
17
1
..
..
*
.
.5
2
..
..
chloramphenicol
.12 .25
..
.
3
.06
1
_,
1
1
J.J.
..
........°
.....:
..
..
..
..
1
..
..
..
1
.,.
..
10 2
6
1
..
1
2
1
..
3
..
1
3
1
.. ..
1
_2_a..
1
1
..
8
3
12
5
9
1
* . .
214
: for ampicillin 0.03 ug/m1 was the lowest concentration tested. : indicates those antibiotic concentrations where no inhibition was observed. THE VETERINARY QUARTERLY, VOL.
12, No. 4, OCTOBER 1990
Table 2.
Distribution of minimal inhibitory concentrations (pg/ml) of 16 different antibiotics against
16 strains of Pasteurella haemolytica, isolated from veal calf lungs in the Netherlands. The
recommended breakpoint-MIC values of the respective antibiotics are underlined. MIC:
.004
.008 .015
.03 .06
.12
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flumequine enrofloxacin
2
2
1
4
ciprofloxacin kanamycin
4
4
2
5
.25
.5
1
2
4
8
n6
3
3
3
1
2
2
1
6
..
1
..
..
..
..
1
..
..
..
..
..
2
1
7
6
neomycin
1
9
4
streptomycin
1
1
14
4
1
..
,.
.. ..
1
11
1
gentamicin ampicillin
cephalothin oxytetracycline
1
2
..
..
1
..
1
9
7
7
..
..
14
2
...
..
..
..
2
1
1
1
11 ...
..
chloramphenicol
..
spiramycin tylosin .
..
..
doxycycline trim/sulfamethox. aditoprim
.
2
2
2
1
1
3
4
2
3
..,_,
2
1
5
3
..
5
1
1
..
..
..
16.
..
..
....
16
..
1
2
1
1
3
6
.
..
: indicates those antibiotic concentrations where no inhibition was observed.
Distribution of minimal inhibitory concentrations (pg/ml) of flumequine, enrofloxacine and ciprofloxacine against Salmonella dublin, Salmonella typhimurium and Escherichia colt, isolated from calves in the Netherlands. The breakpoint-MIC values of the respective antibiotics are underlined. Table 3.
MIC (pg/ml):
.004 .008 .015 .03 .06 .12 .25
.5
5
13
1
2
8 ?16
4
Salmonella duhlin (n=21) flumequine
enrofloxacin ciprofloxacin
1 1
14
2
17
6
1
1
..
1
.
1
Salmonella typhimuriuni (n=21)
flumequine
.
enrofloxacin ciprofloxacin
21 7
19
2
..
es
.
.
..
14
Escherichia coli (n=21)
flumequine
enrofloxacin ciprofloxacin . .
9
.0
4
1
14
3
1
8
6
2
1
2
2
9
1
11{.
..
: indicates those antibiotic concentrations where no inhibition was observed.
THE VETERINARY QUARTERLY, VOL. 12, No. 4, OCTOBER 1990
215
Table 4. Minimal inhibitory concentrations (MIC) of antimicrobial agents against Pasteurella multocida and Pasteurella haemolytica strains, isolated from veal calves in the Netherlands. pasteurella multocida (n=17) MIC 50
flumequine enrofloxacin ciprofloxacin kanamycin neomycin streptomycin
0.25 50.004 0.008 8
8
216
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gentamicin,,7,
MIC 90
4
0.06 0.06 216 216 216
2
ampicillin cephalothin oxytetracycline doxycycline minocycline ** trim/sulfamethoxazole trimethoprim aditoprim chloramphenicol spiramycin tylosin
Breakpoint-MIC
4
1 1 4 4 4
2
50.03 0.06 216
1
0.25 0.12 216
2
4 4 1
4
0.5 0.015/0.3 0.06 0.25 2
216 216
1 1 1
0.5 8/160 4 8
1
1
216 ?16 216
16
4
4
4
4
pasteurella haemolytica (n=16) flumequine enrofloxacin ciprofloxacin kanamycin neomycin streptomycin getamicin ampicillin cephalothin oxytetracycline doxycycline ** trim/sulfamethoxazole aditoprim chloramphenicol spiramycin tylosin *
**
1
0.03 0.008
0.25 0.03 216
1
8
1 4 4
216
216
4
1 8 2
2
1
216
4
2
216
216
4 1
8
1
4/80 216
1
8 4
8
0.5/10 4
0.25 216 216
1
4
4
216 216
16 4
p/ml was the lowest ampicillin concentration tested. : The conentration ratio between trimethoprim and sulfamethoxazole is 1:20. 0.03
Table 5. Minimal inhibitory concentrations (MIC) of flumequine, enrofloxacin and cirpofloxacin against Salmonella dublin, Salmonella typhimurium and Escherichia coli isolated from calves in the Netherlands. Salmonella dublin (n=21) MIC 50
flumequine enrofloxacin ciprofloxacin
MIC 90
Breakpoint-MIC
0.5 0.03 50.004
0.5 0.03 0.008
4 1
0.5 0.03 0.008
0.5 0.03 0.008
4
0.5 0.015 0.008
4
4
0.12 0.06
1
1
Salmonella typhimurium (n=21) flumequine enrofloxacin ciprofloxacin
0
1 1
Escherichia colt (n=21) flumequine enrofloxacin ciprofloxacin
216
1
THE VETERINARY QUARTERLY, VOL. 12, No. 4, OCTOBER 1990
This present study is not meant to estimate the prevalence of antibiotic resistance in the Netherlands against the species involved, because it is doubtful whether the relatively small number of strains tested are representative of the entire Dutch
population. Comparisons to earlier publications on the susceptibility of calf's pathogens (1, 6, 14, 17, 18, 19, 21, 22) have to be done with caution. Quinolones
The in vitro activity of flumequine (UB) in veterinary literature has only been
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described by a few authors (3, 14, 21, 22). The MIC50 for S. dublin, S. typhimurium,
E. coli and P. multocida isolated in calves was published to be 0.4 pg/ml and the MIC90 0.8 pg/ml (14, 21, 22). For all bacterial species tested the MIC50 values found in the present study were similar. Virtually all strains were susceptible. The activity of UB found in the present study is similar to that described by Kremer and Overgoor in 1988 for the same bacterial species isolated in veal calves at the Regional Animal Health centre in Gelderland, the Netherlands (6). In their study all except a few E. coli strains were susceptible. Determination of breakpoint-MIC values is usually not based on clinical efficacy studies, but on both the in vitro activity of the drug and its achievable plasma concentrations (12). For UB, previous publications have shown that Cmax varies 5 pg/m1 after oral administration of 5 mg/kg twice daily mixed with from 3 milk replacer (9). This dosage regimen is often used in field conditions. Apart from the achievable plasma concentration, also protein binding and concentration of the drug at the site of infection should be taken into consideration (9, 10, 22). This suggests that 4 pg/ml as breakpoint-MIC for UB is rather high. Ziv et al. described 3 pg/m1 to be the desired plasma concentration based on MIC for UB of the target bacteria of 0.8 pg/ml and a safety factor (22). This indicates that in vivo bacteria with MIC > 1 pg/ml might be less susceptible to UB. The published median MIC values of enrofloxacin vary from 0.008 pg/ml for P. multocida to 0.06 pg/m1 for E. coli and Salmonella spp. (17), which are similar to those found in the present study. In vitro CIP is the most active quinolone at present (5, 11, 14, 20), with MIC90 values varying from 0.03 pg/m1 for Salmonella spp. and E. coli, and 0.06 pg/ml for P. multocida. This data from the literature is in correspondence with our results. Resistance of these species to ENF and CIP has not yet been described. Tables 1 and 2 show that in general P. haemolytica was less susceptible to UB than P. multocida. However, UB resistant strains were usually still susceptible to ENF and CIP, because of the difference in instrinsic activity, strains with increased MIC values of UB showed also increased MIC values for other quinolones. This implies that wide-spread use of UB for P. haemolytica infections might not only induce resistance for UB, but also to the newer quinolones. Other drugs The MIC50 values for both pasteurellas were higher than the breakpoint-MIC of
most of the aminoglycosides used in this experiment. Of neomycin (N) and gentamicin (G) this MIC is at the breakpoint. Kremer and Overgoor published resistance-patterns from 1966 to 1986 for these bacteria (6). They also observed an increasing resistance to S and N of both pasteurellas. In the study of Soback et al. (18), bovine Pasteurella spp. were susceptible to kanamycin (K) (MIC50 1.56
pg/ml) (18). The MIC50 published by Prescott and Baggot (16 pg/ml) (15), however, is similar to that found in the present study. For G the published MIC50 values are in the same range as those found in the present study (1.56 4 pg/ ml) (15, 18). THE VETERINARY QUARTERLY, VOL. 12, No. 4, OCTOBER 1990
217
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The low MIC50 of ampicillin (AM) for P. multocida (< 0.03 pg/m1) compared with the 100% resistance of P. haemolytica to AM in this study are in correspondence
with the resistance percentages published by Kremer and Overgoor in 1988 (P. multocida 3%, R haemolytica 82% resistant) (6). In the present study no resistance was observed of the pasteurellas to cephalothin (CF). This is in correspondence with data published before (2, 15). The activity of CF is much greater against P. multocida than against P haemolytica (MIC50 0.06 and 2 mg/ml, respectively), while in literature the activity is equal for both bacteria (15). Due to its lipophilicity, doxycycline (DC) has a higher oral bioavailability and better tissue distribution, than oxytetracycline (0T) (16). The activity found was higher than that of OT (table 4), but the MICR) was still above the breakpoint. Especially for P haemolytica, cross resistance with OT was almost complete. In the present study no cross resistance was observed between MC and OT or DC, all P. multocida strains were susceptible to MC (MIC50 0.5 pg/m1). Similar results have been described for P multocida strains isolated from pigs (16). In this study there was no evidence for a synergistic effect between trimethoprim-
sulphamethoxazole (SXT) against R multocida (tables 1 and 4). With this combination only the activity of trimethoprim (TMP) was apparently measured which could be due to resistance of the P multocida strains involved to sulfamethoxazole (SMX). The same phenomenon was described in pigs with Bordetella bronchiseptica and P multocida (8). In that study the MIC50 against P multocida for TMP was 0.06 pg/ml, for SMX 4 8 mg/ml and for the combination 0.03/0.5 0.06/1 pg/m1 (8). This is similar to the respective MIC50 values presented in the present study.
Four of the P. multocida strains were also resistant to TMP and to the closely
related aditoprim (ADP). In the susceptible strains, the overall activity of the latter was less than TMP plus SXT (tables 1 and 2). Similar results have been published for P multocida strains isolated from pigs (8). In vivo the lesser potency of ADP might be compensated by its better pharmacokinetical properties, including a prolonged elimination half-life (7, 8).
In the Netherlands the withdrawal time for chloramphenicol (C) has been
increased to .21 days because of its toxic residues. Since that time the use of C in large animal medicine has decreased substantially. In 1986 34% of the R multocida strains and 56% of the P haemolytica strains were resistant to C (6). In the present study both pasteurellas were susceptible to C. The obvious resistance of both pasteurellas to tylosin (TY) (tables 1 and 2), which has been published earlier (19), diminishes the therapeutic value of this macrolide antibiotic in pasteurellosis in veal calves. Of spiramycin (SP), clinical efficacy has been claimed at a dosage of 33.3 mg/ kg B.W., which produced sputum concentrations higher than the MIC of both pasteurellas (ranging from 2.1 17pg/m1) (1). Specht et al. found the MIC50 for SP against P. haemolytica to be 128 pg/ml, which is well above reachable sputum concentrations (19). In the present study the MIC50 of both pasteurellas was the breakpoint-MIC (16 pg/m1). Therefore the pasteurellas were resistant to SP. It is concluded that UB, in comparison with the other antimicrobial agents tested, has good in vitro activity against pasteurella, E. coli and salmonella bacteria. Only P haemolytica shows some decreased susceptibility. It was not the purpose of this study to present representative resistance patterns of (veal) calf pathogens, because the number of strains was too small. However, the demonstrated resistance is illustrative of the Dutch situation. It indicates that resistance development of calf pathogens as described before, is a permanent risk. 218
THE VETERINARY QUARTERLY. VOL. 12, No. 4, OCTOBER 1990
Even to UB some of the bacterial strains were resistant and the same can be expected to occur for the newer generation quinolones when their use increases (13).
Not the introduction of new, potentially active drugs controls multi-resistance development. Good Veterinary Practice is essential, which means selective use of antimicrobial agents based on accurate clinical and laboratory measurements and a balanced choice of a drug based on its pharmacokinetic behaviour, its in vitro activity, its potential toxic side effects and its residue profile in meat products. The pro- and metaphilactic treatment of entire herds should be restricted and individual treatment used instead.
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ACKNOWLEDGEMENTS
The authors thank Dr. B. van Klingeren, Mirjam Dessens-Kroon, Marga Verheuvel and
René Leeuw for technical assistance at the National Institute for Public Health and Environmental Hygiene, Bilthoven, the Netherlands and for critically reading the manu-
script. Dr. E. G. Hartman and Rob van de Pol, G. H. A. Borst and J. Bongers of the respective Regional Animal health Centres of Gelderland, Overijssel and Zuid-Nederland generously supplied the isolates. Johan Smit of the Veterinary Microbiological Diagnostic Centre and Hennie Beers-van Laar and Ina Bakker-de Kof of Intervet BV, Boxmeer, the Netherlands, are gratefully thanked for their technical support.
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