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Third-generation cephalosporin and carbapenem resistance in Streptococcus

mitis/oralis. Results from a nationwide registry in the Netherlands

Article  in  Clinical Microbiology and Infection · December 2018

DOI: 10.1016/j.cmi.2018.11.021

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 Clinical Microbiology and Infection 25 (2019) 518e520

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Clinical Microbiology and Infection

journal homepage: www.clinicalmicrobiologyandinfection.com

Letter to the Editor

Third-generation cephalosporin and carbapenem resistance in

Streptococcus mitis/oralis. Results from a nationwide registry in the
Netherlands
J. van Prehn 1, *, M.I. van Triest 2, W. Altorf-van der Kuil 2, K. van Dijk 1on behalf of the
Dutch National AMR Surveillance Study Group
1)
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Microbiology and Infection Control, Amsterdam, The Netherlands
2)
Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

a r t i c l e i n f o

Article history:
Received 28 August 2018
Received in revised form
13 November 2018
Accepted 14 November 2018
Available online 4 December 2018
Editor: L. Leibovici
To the editor,
Knowledge of beta-lactam resistance rates in Streptococcus mitis
group bacteria is especially important in neutropenic haemato-
logical patients as adequate empirical antibiotic treatment (often
including agents like meropenem [1]) is paramount. EUCAST
guidelines allow one to infer viridans group streptococci (VGS)
beta-lactam susceptibility from benzylpenicillin susceptibility;
penicillin-resistant isolates should be tested for individual agents.
Few studies reported the association between penicillin resistance
and broad-spectrum beta-lactam resistance in VGS [2,3], and data
from Northern European countries is lacking. Here, we first
describe the prevalence of beta-lactam resistance in S. mitis/oralis in
The Netherlands. Second, we describe the association between
penicillin MIC and broad-spectrum beta-lactam resistance.
The Dutch national surveillance system for antimicrobial resis-
tance (ISIS-AR) [4], covering 44 out of 56 Dutch clinical microbi-
ology laboratories in 2017, was searched for susceptibility results of
S. mitis/oralis isolates for (benzyl)penicillin, amoxicillin/ampicillin,
cefotaxime/ceftriaxone, and meropenem from 2013 through 2017.
* Corresponding author. Joffrey van Prehn, Department of Medical Microbiology
and Infection Control, Amsterdam University Medical Centres, Location VUmc, PK 1
X 124, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
E-mail address: j.vanprehn@vumc.nl (J. van Prehn).
ISIS-AR collects susceptibility test results of all bacterial isolates of
collaborating laboratories. The analysis was limited to the first
isolate of each patient. Patients whose first isolate was not tested
for penicillin susceptibility were excluded.
To avoid bias due to selective testing, for each antibiotic only
laboratories testing
50% of isolates were included. Forty-one
laboratories were included for analyses on penicillin susceptibil-
ity, 24 laboratories for amoxicillin/ampicillin, and 23 for cefotax-
ime/ceftriaxone. Meropenem was tested in 15 laboratories; here
the inclusion rule was not applied, as this resulted in a significant
impact on the number of isolates for analysis. All selected labora-
tories used EUCAST guidelines, except one laboratory in 2013. MIC
breakpoint for susceptibility is  0.25 mg/L for penicillin, 0.5 mg/L
for amoxicillin/ampicillin and cefotaxime/ceftriaxone, and 2 mg/L
for meropenem.
Of 4164 S. mitis/oralis isolates tested for penicillin, 3634 were
reported susceptible (87.2%), 281 intermediate (6.7%), and 249
resistant (6.0%). Of 2019 isolates with amoxicillin/ampicillin sus-
ceptibility reported, 117 isolates were reported resistant (5.8%) to
either agent. Of 2079 isolates with cefotaxime/ceftriaxone suscep-
tibility reported, 159 were resistant (7.6%). Of 306 isolates with
meropenem susceptibility reported, four were resistant (1.3%).
Percentages of broad-spectrum beta-lactam resistance by penicillin
susceptibility category is shown in the Table S1.
For amoxicillin/ampicillin susceptible isolates, the median
penicillin MIC with automated testing was 0.06 mg/L (IQR
0.06e0.12; n ¼ 875), for intermediate isolates 1.0 mg/L (IQR
0.5e2.0; n ¼ 55), and for resistant isolates 2.0 mg/L (IQR 2.0e4.0;
n ¼ 51). Results with gradient testing were similar: for susceptible
isolates median penicillin MIC was 0.047 mg/L (IQR 0.023e0.094;
n ¼ 327), for intermediate isolates 0.75 mg/L (IQR 0.38e1.0; n ¼ 34),
and for resistant isolates 2.0 mg/L (IQR 1.0e4.0; n ¼ 29) (Fig. 1a).
For cefotaxime/ceftriaxone susceptible isolates, the median
penicillin MIC with automated testing was 0.06 mg/L (IQR
0.06e0.063; n ¼ 698), for resistant isolates 1.5 mg/L (IQR 1.0e4.0;
n ¼ 68). With gradient testing median penicillin MIC for susceptible
isolates was 0.064 mg/L (IQR 0.032e0.19; n ¼ 463), for resistant

https://doi.org/10.1016/j.cmi.2018.11.021
1198-743X/© 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
 Letter to the Editor / Clinical Microbiology and Infection 25 (2019) 518e520
isolates 2.0 mg/L (IQR 1.0e4.0; n ¼ 57) (Fig. 1b). All four
meropenem-resistant isolates were penicillin resistant; all tested
for cefotaxime/ceftriaxone were resistant (n ¼ 3). Penicillin MIC
was available for three meropenem-resistant isolates: 8 and 32 mg/
L (gradient test; n ¼ 2), and >4 mg/L (automated testing; n ¼ 1).
We found third-generation cephalosporin resistance in <8% of
isolates and meropenem resistance in 1.3% or less. A similar mer-
openem resistance percentage for S. mitis and S. oralis (4/254, 1.6%)
was found in the EUCAST database (6 November 2018). Elevated
penicillin MICs were associated with broad-spectrum beta-lactam
resistance.
Observations based on national registries have inherent
strengths and weaknesses. Bias due to inferred beta-lactam sus-
ceptibility from benzylpenicillin may slightly amplify the positive
association between penicillin MIC and beta-lactam resistance.
Furthermore, different automated testing systems were used in the
participating laboratories (89% bioMe
rieux VITEK2, 11% Siemens
MicroScan or BD Phoenix), although all laboratories use validated
methods according to (inter)national standards. Also, 0.7% amoxi-
cillin/ampicillin and 1.5% cefotaxime/ceftriaxone resistance in
penicillin susceptible isolates (Table S1) may be due to technical
errors in participating laboratories as this cannot be explained by
altered penicillin-binding proteins [5]. Not all laboratories routinely
tested mitis group streptococci for amoxicillin/ampicillin, cefotax-
ime/ceftriaxone, and meropenem. However, it has been calculated
that in the ISIS-AR database, data from
15 laboratories adequately
reflects the situation in The Netherlands (data not published).
Therefore, we expect that the results for amoxicillin/ampicillin and
cefotaxime/ceftriaxon can be generalized to the whole country. For
meropenem we did not apply the inclusion criterion that at least
50% of isolates should have been tested. Owing to selective mer-
openem testing, our results may be biased towards a higher resis-
tance and may not be generalizable. A 1.3% meropenem resistance
percentage (4/306 isolates tested) therefore probably is an over-
estimation of the prevalence of resistance, whereas 0.1% mer-
openem resistance (4/4164 isolates) based on all isolates included
in the study might be an underestimation.
Strengths are that ISIS-AR is a centrally curated national registry
with high coverage. Data are submitted in a standardized format
and are double-checked for deviating results. All Dutch medical
microbiology laboratories test and report susceptibility according
to EUCAST guidelines. In a sensitivity analysis in which the period of
Fig. 1. Penicillin MICs as determined by automated and gradient susceptibility testing, stratified by reported amoxicillin/ampicillin (a) and cefotaxime/ceftriaxone (b) susceptibility.
Median (benzyl)penicillin MICs with interquartile ratio and range are shown. The grey horizontal lines represent EUCAST (benzyl)penicillin cut-off values for susceptible (MIC 0.25
mg/L) and resistant isolates (MIC >2 mg/L).
519
CLSI guidelines for one laboratory was excluded, no difference was
found in the overall results.
In conclusion, for mitis group streptococci in The Netherlands,
broad-spectrum beta-lactam resistance should be taken into ac-
count. Not all laboratories routinely test VGS for broad-spectrum
beta-lactam agents. Elevated penicillin MICs should prompt addi-
tional cephalosporin and carbapenem susceptibility testing.
Members of the Dutch National AMR Surveillance Study
Group
J.W.T. Cohen Stuart, Department of Medical Microbiology,
Noordwest Ziekenhuisgroep, Alkmaar; A.J.L. Weersink, Department
of Medical Microbiology, Meander Medical Centre, Amersfoort; K.
van Dijk, Department of Medical Microbiology and Infection Con-
trol, Amsterdam University Medical Centres, location VUmc,
Amsterdam; D. Notermans, Department of Medical Microbiology,
Amsterdam University Medical Centres, location AMC, Amsterdam;
M.L. van Ogtrop, Department of Medical Microbiology, Onze Lieve
Vrouwe Gasthuis, Amsterdam; M.M. Jager, Department of Medical
Microbiology, Slotervaart Hospital/Netherlands Cancer Institute,
Amsterdam; B.F.M. Werdmuller, Public Health Laboratory, Public
Health Service, Amsterdam; B.C. van Hees, Department of Medical
Microbiology and Infection prevention, Gelre Hospitals, Apeldoorn;
P.H.J. van Keulen, Department of Medical Microbiology, Bravis
Hospital, Bergen op Zoom; J. Alblas, W. Altorf-van der Kuil, L. Blij-
boom, S.C. de Greeff, S. Groenendijk, J. van Heereveld, R. Hertroys,
J.C. Monen, D.W. Notermans, E.A. Reuland, A.F. Schoffelen, M.I. van
Triest, C.C.H. Wielders, S.H.S. Woudt, Centre for Infectious Diseases,
epidemiology and Surveillance. National Institute for Public Health
and the Environment (RIVM), Bilthoven.; P.H.J. van Keulen, J.A.J.W.
Kluytmans, Laboratory for Microbiology and Infection Control,
Amphia Hospital, Breda; E.M. Kraan, Department of Medical
Microbiology, IJsselland hospital, Capelle a/d IJssel; E.E. Mattsson,
Department of Medical Microbiology, Reinier de Graaf Groep, Delft;
F.W. Sebens, Department of Medical Microbiology, Deventer Hos-
pital, Deventer; E. de Jong, Department of Medical Microbiology,
Slingeland Hospital, Doetinchem; H.M.E. Fre
nay, B. Maraha,
Department of Medical Microbiology, Albert Schweitzer Hospital,
Dordrecht; A.J. van Griethuysen, Department of Medical Microbi-
ology, Gelderse Vallei Hospital, Ede; A. Demeulemeester, SHL-
Groep, Etten-Leur; B.B. Wintermans, Department of Medical
520 Letter to the Editor / Clinical Microbiology and Infection 25 (2019) 518e520
Microbiology, Admiraal De Ruyter Hospital, Goes; M. van Trijp,
Department of Medical Microbiology and Infection Prevention,
Groene Hart Hospital, Gouda; A. Ott, Department of Medical
Microbiology, Certe, Groningen; E. Bathoorn, M. Lokate, University
of Groningen, University Medical Centre Groningen, Department of
Medical Microbiology, Groningen; J. Sinnige, Regional Laboratory of
Public Health, Haarlem; A.J.L. Weersink, Department of Medical
Microbiology, St Jansdal Hospital, Harderwijk; E.I.G.B. de Brauwer,
F.S. Stals, Department of Medical Microbiology and Infection Con-
trol, Zuyderland Medical Centre, Heerlen; W. Silvis, Laboratory of
Medical Microbiology and Public Health, Hengelo; L.J. Bakker, J.W.
Dorigo-Zetsma, Department of Medical Microbiology, CBSL, Tergooi
Hospital, Hilversum; B. Ridwan, Department of Medical Microbi-
ology, Westfriesgasthuis, Hoorn; K. Waar, Izore Centre for Infectious
Diseases Friesland, Leeuwarden; A.T. Bernards, Department of
Medical Microbiology, Leiden University Medical Centre, Leiden;
S.P. van Mens, Department of Medical Microbiology, Maastricht
University Medical Centre, Maastricht; N. Roescher, Department of
Medical Microbiology and Immunology, St Antonius Hospital,
Nieuwegein; M.H. Nabuurs-Franssen, Department of Medical
Microbiology and Infectious Diseases, Canisius Wilhelmina Hospi-
tal, Nijmegen; H. Wertheim, Department of Medical Microbiology,
Radboud University Medical Centre, Nijmegen; B.M.W. Diederen,
Department of Medical Microbiology, Bravis Hospital, Roosendaal;
L. Bode, Department of Medical Microbiology, Erasmus University
Medical Centre, Rotterdam; M. van Rijn, Department of Medical
Microbiology, Ikazia Hospital, Rotterdam; S. Dinant, O. Pontesilli,
Department of Medical Microbiology, Maasstad Hospital, Rotter-
dam; P. de Man, Department of Medical Microbiology, Sint Fran-
ciscus Gasthuis, Rotterdam; M.A. Leversteijn-van Hall, Department
of Medical Microbiology and Infection Control, Alrijne Zorggroep/
Bronovo Hospital, 's-Gravenhage; E.P.M. van Elzakker, Department
of Medical Microbiology, Haga Hospital, 's-Gravenhage; A.E. Muller,
Department of Medical Microbiology, MCH Westeinde Hospital, 's-
Gravenhage; N.H. Renders, Department of Medical Microbiology
and Infection Control, Jeroen Bosch Hospital, 's-Hertogenbosch;
D.W. van Dam, Department of Medical Microbiology and Infection
Control, Zuyderland Medical Centre, Sittard-Geleen; B.M.W. Die-
deren, Department of Medical Microbiology, ZorgSaam Hospital
Zeeuws-Vlaanderen, Terneuzen; A.G.M. Buiting, Department of
Medical Microbiology, St. Elisabeth Hospital, Tilburg; A.L.M. Vlek,
Department of Medical Microbiology and Immunology, Dia-
konessenhuis, Utrecht; A. Reuland, Department of Medical Micro-
biology, Saltro Diagnostic Centre, Utrecht; F.N.J. Frakking,
Department of Medical Microbiology, University Medical Centre
Utrecht, Utrecht; I.T.M.A. Overdevest, Department of Medical
Microbiology, PAMM, Veldhoven; R.W. Bosboom, Laboratory for
View publication stats
Medical Microbiology and Immunology, Rijnstate Hospital, Velp; T.
Trienekens, Department of Medical Microbiology, VieCuri Medical
Center, Venlo; G.J.H.M. Ruijs, M.J.H.M. Wolfhagen, Laboratory of
Medical Microbiology and Infectious Diseases, Isala Hospital,
Zwolle.
Transparency declaration
The authors report no conflict of interest. No specific funding
was obtained for this study. The national AMR surveillance system
(ISIS-AR) is a combined initiative of the Dutch Ministry of Health,
Welfare and Sport and the Netherlands Society for Medical
Microbiology and is financed by the Dutch Ministry of Health,
Welfare and Sport.
Acknowledgements
Part of this work has been presented at the ECCMID 2018 in
Madrid. We would like to thank the people involved in the national
AMR surveillance system (ISIS-AR) at the Netherlands National
Institute for Public Health and the Environment (RIVM) and the
members of the Dutch National AMR Surveillance Study Group.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.cmi.2018.11.021.
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