Implementation of short incubation MALDI-TOF MS identification from positive blood cultures in routine diagnostics and effects on empiric antimicrobial therapy
Köck et al. Antimicrobial Resistance and Infection Control
Implementation of short incubation MALDI- TOF MS identification from positive blood cultures in routine diagnostics and effects on empiric antimicrobial therapy
Robin Köck 0 1
Jörg Wüllenweber 1
Karsten Becker 1
Evgeny A. Idelevich 1
0 Present address: Institute of Hospital Hygiene, University of Oldenburg, European Medical School Oldenburg-Groningen , Rahel-Straus-Str. 10, 26133 Oldenburg , Germany
1 Institute of Medical Microbiology, University Hospital Münster , Domagkstr. 10, 48149 Münster , Germany
Background: Results of blood culture (BC) diagnostics should be swiftly available to guide treatment of critically ill patients. Conventional BC diagnostics usually performs species identification of microorganisms from mature solid medium colonies. Species identification might be speed up by using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) of biomass from shortly incubated solid media. Methods: This single-center analysis compared the applicability of MALDI-TOF-based species identification from shortly incubated cultures in laboratory routine vs. conventional diagnostics and assessed its effects of on empiric antibiotic therapy. Results: Median time between detection of BCs as “positive” by incubators and further processing (e.g. microscopy) was 6 h 21 min. Median time between microscopy and result reporting to the ward was 15 min. Including 193 BCs, MALDI-TOF from shortly incubated biomass resulted in significantly faster (p > 0.001) species identification. Species results became available for clinicians after a median of 188 min (231 min for Gram-positive bacteria, 151 min for Gram-negative bacteria) compared to 909 min (n = 192 BCs) when conventional diagnostics was used. For 152/179 bacteremia episodes (85%) empiric antibiotic therapy had already been started when the microscopy result was reported to the ward; microscopy led to changes of therapies in 14/179 (8%). In contrast, reporting the bacterial species (without antibiogram) resulted in therapeutic adjustments in 36/179 (20%). Evaluating these changes revealed improved therapies in 26/36 cases (72%). Conclusions: Species identification by MALDI-TOF MS from shortly incubated subcultures resulted in adjustments of empiric antibiotic therapies and might improve the clinical outcome of septic patients.
Antibiotic stewardship; MALDI-TOF MS; Sepsis; Diagnostics; Blood culture
Taking blood cultures (BC) is one of the most important
components of diagnostics performed for critically ill
patients. As the mortality of septic patients is highly
dependent on an accurate therapeutic approach during
the early phase of the infection, treatment follows the
general principle “frapper fort et frapper vite” (as
postulated by Paul Ehrlich in 1913) . This means that
empiric therapy is initiated immediately using adequate
doses of antibiotics covering the expected spectrum of
pathogens . Hence, the results of BC diagnostics will
usually not be used to start treatment, but rather to
reassess whether initial empiric therapy was accurate and
to adjust it, if necessary. This makes BC diagnostics a
key issue of antibiotic stewardship programs aiming to
de-escalate empiric broad-spectrum antibiotics and
improve the rational use of antimicrobials .
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However, a disadvantage associated with culture-based
BC diagnostics is that it follows the “biological” clock rate
of microbial growth but not the clock speed determined
by the clinical progress of a severe infection. This hampers
early adjustment of empiric antimicrobial therapies to
diagnostic findings and leads to, first, increased morbidity
or mortality of severely ill patients, and second, an
extended empiric use of broad-spectrum antibiotics .
As a result, many recent studies have assessed the
technical effectiveness of culture-independent BC diagnostic
methods with the aim of identifying DNA of the causative
species in the blood sample more rapidly [5–10]. However,
PCR approaches are still expensive and have drawbacks
regarding sensitivity and specificity [11, 12]. An alternative
is to conventionally incubate BC bottles in an automated
system and use matrix-assisted laser desorption ionization
time-of-flight mass-spectrometry (MALDI-TOF MS)
directly from BC bottles in which microbial growth was
indicated by the automated system . This approach is also
valuable, but requires more laborious and costly
processing of the BC in the microbiological laboratory.
Therefore, Idelevich et al. recently evaluated a simple
alternative method for species identification: it was
demonstrated that MALDI-TOF performed from “immature”
biomass growing on solid media shortly (2–4 h) after
inoculation with broth from a positive BC bottle,
successfully identified the growing microorganisms . This
can be done in all laboratories where MALDI-TOF MS
is available and does not increase consumable costs
compared with conventional BC diagnostics (as species
diagnostics has to be done anyway) .
While Idelevich et al. assessed the “technical” accuracy
of this method, its feasibility in clinical, microbiological
lab-routine has not been described. Moreover, it is
unclear to what extent clinicians use the faster species
information provided by MALDI-TOF MS from shortly
incubated cultures for adjustments of empiric antibiotic
therapy, because species information is initially provided
without antibiograms. Therefore, we assessed these two
issues in this retrospective study. The results shall allow
for conclusions whether implementing MALDI-TOF
based species identification from shortly incubated
biomass has effects on empiric antimicrobial therapy.
This analysis retrospectively assessed the effects of a change
in microbiological BC diagnostics. The study was
performed at the Institute of Medical Microbiology, University
Hospital Münster (UHM), Germany. The laboratory offers
microbiological service routinely from 7:30 a.m. to
6:30 p.m. (Monday through Friday), 7:30 a.m. through
1:00 p.m. (Saturday) and 9:00 a.m. through noon (Sunday).
The institute provides service almost exclusively for the
UHM, which is a maximum care university hospital with
about 1400 beds in Northwestern Germany. The facilities
of the institute are located on the UHM campus, i.e. the
distance of the microbiological laboratory to all clinics,
wards and other facilities of the hospital does not exceed
a.) BC bottles (BD BACTEC™ PLUS media) were
transported from the wards to the microbiological
laboratory. After arrival in the laboratory they were
placed in an automated BC incubation system (BD
BACTEC™ 9240). If growth in a BC bottle was
indicated by the automated system, the bottle was
immediately processed and streaked onto solid media
(Columbia and chocolate blood agar, Schaedler agar
additionally for anaerobic culture bottles). Solid media
were immediately placed in an incubator and a
Gram-stain was performed. The result of the Gram
stain was immediately communicated to a physician
on the respective ward (by phone call) and was
reported to the ward as a preliminary finding
b.) Further routine diagnostic procedures were as follows:
species identification was done via MALDI-TOF MS
and antibiotic susceptibility testing (mostly) via VITEK
2 automated system. Susceptibility testing was initiated
from “mature” colonies growing on solid media in the
afternoon (for BC bottles detected before 9 h in the
morning) or the next day (for all BC bottles detected
after 9 h); species identification was done from mature
colonies the next day for all BCs.
MALDI-TOF MS based species identification from
immature biomass growing on solid media was
implemented as follows: Step a.) described for conventional
diagnostics remained unchanged. In step b.) the solid
media inoculated with material from the positive BC
bottle were visually evaluated for the first time
approximately 2-3 h after start of incubation. As soon as growth
of biomass (rather mature “colonies”) was visible on the
agar plates, species identification was performed from
these “young” cultures using MALDI-TOF MS. As soon
as the species identification result was available (criteria
for reliability as mentioned in ), it was reported to
the ward. If no growth was visible, or no successful
identification was achieved, the next visual evaluation was
performed after further 2-3 h of incubation, followed by
MALDI-TOF MS in case of visible growth. Further
identification attempts after longer incubation were only
performed in individual cases at the discretion of
technologist or clinical microbiologist. In addition,
standardized susceptibility testing (using VITEK-2) was
We assessed all positive BCs from 01.01.2013–
30.06.2013 (before diagnostic change) and 01.01.2014–
30.06.2014 (after diagnostic change). We considered all
BC bottles (filled with blood, other body fluids were
excluded). BCs fulfilling the following criteria were then
removed from the dataset: i.) mixed cultures (i.e. >1
pathogen in one bottle, removed due to uncomplete or
unreliable MALDI-TOF results), ii.) detection of fungi
and anaerobic bacteria (removed due to slow growth),
iii.) detection of coagulase-negative staphylococci,
corynebacteria and propionibacteria (as we aimed to assess
and evaluate the effects of MALDI-TOF on empiric
therapy, the BCs were removed due to unclear clinical
relevance and unclear effects on empiric therapy), iv.)
consecutive cultures of the same patient (i.e. if the same
pathogen was detected in more than one BC of the same
patient, only the culture which was first indicated as
“positive” by the BC incubator remained in the dataset).
For all BCs remaining in the final dataset, the
following parameters were assessed from the laboratory
software (OpusL, OSM, Essen, Germany) and the electronic
patient record (Orbis, AGFA Healthcare, Bonn,
Germany), where they are routinely recorded:
1. Date and time of a documented Gram stain result (i.e. the time is recorded when the result is entered in the computer system),
2. Date and time of the first report of a microscopic result to the ward (i.e. the time of the phone call is actively recorded by the person communicating the result),
3. Date and time of successful species identification (i.e. the time is recorded when the species name is entered in the lab software),
4. Date and time of the species available on the ward
(i.e. the time when the finding appears in the
electronic patient record, which is after entering it
in the lab software (see point 3 and after electronic
5. For all cultures after implementation of MALDI-TOF
MS from shortly incubated cultures, we additionally
assessed antibiotic therapy of the patient for a time
period starting two days before the BC became
positive and ending after reporting the species result
to the ward. The quality of therapeutic adjustments
attributable to the intervention was evaluated within a
local antibiotic stewardship team, including an
intensive care clinician, microbiologists and a
pharmacist. An adjustment was considered rational
when the new therapy was more likely to target or
more efficient to treat the detected microorganism
than the previous therapy.
Statistical differences were assessed using Chi-Square or
t-test (Epi Info™, version 7.2, CDC Atlanta, USA); p < 0.05
was considered significant.
In the half-year period before the diagnostic change
1185 BC sets with microbial growth from 544 patients
were retrieved compared with 1132 BC sets from 540
patients after implementation of MALDI-TOF MS from
shortly incubated cultures. After clearing the dataset
(with respect to criteria i. to iv. see Methods), we
analyzed data for 192 BCs before and 193 BCs after the
diagnostic change, respectively (p = 0.62). Of all 385
BCs, 117 (30%) were indicated as “positive” by the BC
incubator during routine service times of the
microbiological laboratory and 268 (70%) outside service hours.
Overall, the median time between bacterial growth
reported by the BC incubation system and microscopy was
381 min (mean 410 min, range 6 min-1188 min). There
was a major difference depending on whether the BC
bottle was flagged “positive” during the service time of
the laboratory or not; during service time: median
48 min (mean 65 min, range 6 min-1123 min) vs.
outside service time: median 547 min (mean 561 min, range
18 min-1188 min), p < 0.001). The median time (mean,
range) between microscopy and report of the result to
the ward was 15 min (44 min, 0–1386 min).
Species identification time using conventional diagnostics
vs. MALDI-TOF MS from shortly incubated cultures in
clinical microbiological lab-routine
After implementation of the new concept for processing
BCs in the laboratory, the time needed to report a
species identification result (after initial microscopy) was
significantly reduced (Table 1), even though this study
partly included BCs for which MALDI-TOF MS was not
carried out the same day. This effect was more
prominent for Gram-negative (median 2.5 h) than for
Grampositive microorganisms (median about 4 h, Table 1).
Effects of species report on antimicrobial therapy
For the time after implementation of MALDI-TOF MS
from shortly incubated cultures we analyzed antibiotic
therapies for the patients with bacteremia (Fig. 1). The
species distribution for microorganisms detected in the
193 BCs included in the intervention phase is shown in
Fig. 2. The 193 BCs were derived from patients on
nephrology wards (n = 35, including patients in an emergency
department), hemato-oncology wards (n = 35), cardiology
Table 1 Time until species identification before and after implementation of MALDI-TOF MS from shortly incubated cultures
atime between microscopy and availability of species identification result before and after implementation of MALDI-TOF MS from shortly incubated cultures in
wards (n = 20), gastroenterology wards (n = 19), surgical
intensive care units (ICU) (n = 26), pediatric wards (n =
18), general-, heart- and trauma-surgical wards (n = 15),
neurology wards (n = 9), transplantation wards (n = 7),
urology wards (n = 4), orthopedic wards (n = 3), wards for
radiotherapy (n = 2), dermatology and ENT wards (each n
= 1). The 193 BCs were taken from 172 different patients.
If patients were included more than once, this was not
due to consecutive cultures (see methods), but due to
more than one bacteremia episode of this patient in which
different bacteria were identified. For 179 of the BCs (from
158 patients), we were able to analyze the antibiotic
prescriptions initiated for the respective patients (Fig. 1). The
remaining patients were discharged or had died when the
BC was detected positive. For 152 of the 179 bacteremia
episodes (85%) an empiric antibiotic therapy was already
initiated at the time of the initial contact with the ward
(i.e. report of microscopy result).
Overall, after reporting the microscopy results
antibiotic therapies were changed in 14/179 (8%) patients
(Fig. 1). For none of these 14 cases the antimicrobial
therapy was later adjusted again after the species
identification result became available (before results of
susceptibility tests were ready).
Overall, rapid reporting of the species identification
result (without antibiogram) caused adjustments in
empiric therapies of 36/179 (20%) bacteremia episodes. The
mean time between reporting of species results to the
ward and documented change of antibiotic therapy was
168 min (median 186 min, range 0–434 min).
Evaluating these 36 bacteremia episodes showed that
the adjustments led to a better therapy in 26/36 cases
(72%). Criterion for evaluating an adjustment as
reasonable was that the identified species was more likely
targeted with the antibiotic used than the previously used
therapy (evaluations for single cases are shown in the
supplementary material, Additional file 1: Table S1).
Among the 36 cases in which adjustments of antibiotic
treatment were performed after species identification,
therapeutic changes were more often performed, if S.
aureus was reported, as compared to all other pathogens
(13/41 vs. 23/152, p = 0.03).
The major aim of this study was to compare species
identification times for microorganisms from BCs using
a conventional diagnostic approach versus MALDI-TOF
MS based species identification from shortly incubated
Fig. 1 Effects of MALDI-TOF MS species identification on empiric antimicrobial therapy
Fig. 2 Pathogens in blood cultures included (n = 193). Microorganisms summarized under “others (each n = 1)”: Haemophilus influenzae,
Lactobacillus gasseri, Citrobacter freundii, Acinetobacter baumannii, Brevibacterium casei, Bacillus licheniformis, Salmonella serovar Typhi, Proteus
vulgaris group, Enterococcus casseliflavus, Bacillus simplex, Streptococcus gallolyticus, Raoultella ornithinolytica, Streptococcus dysgalactiae subsp.
equisimilis, Rothia dentocariosa, Rothia mucilaginosa, Streptococcus pneumoniae, Listeria monocytogenes, Streptococcus sanguinis, Moraxella osloensis,
biomass. Technically, the applicability, validity and
microbiological accuracy of this method has been
demonstrated before in a pilot study . In this study, we
found that the results of the pilot study held true in daily
routine. Performing MALDI-TOF MS of immature
cultures resulted in a significant reduction of the median
time until species identification for bacteria from BCs.
Particularly for fast growing Gram-negative
microorganisms, the median time until species identification was
reduced to less than three hours. However, compared with
our pilot studies the mean time until availability of
species results was slightly higher (5.9 h for Gram-positive
cocci and 2 h for Gram-negative rods in the study by
Idelevich et al. vs. 6.7 h for Gram-positive bacteria and
4.6 h for Gram-negative bacteria in this study) . This
is because in contrast to the pilot study, this data
assessment includes all BC cultures even if MALDI-TOF MS
was not performed on the same day (e.g. for cultures
detected in the late afternoon or on weekends where the
service hours of the laboratory were restricted). These
results are important as they show that the pilot studies
do not markedly overestimate the benefits of
MALDITOF MS of shortly incubated cultures when this
technique is applied in microbiological routine diagnostics.
The application of PCR-based BC diagnostic tests
has also resulted in a significant reduction of the time
until species identification  and, partly, results
were available even faster. However, major advantages
of the diagnostic approach evaluated here are that it
can be done without any additional consumable costs
and that it leads to cultivated microorganisms ready
for further characterization, in particular susceptibility
testing. The efforts regarding re-organizing workflows
of technical personnel and additional hands-on time
was limited in our hands and the intervention was
easy to implement in diagnostic routine. However, it
should be noted that this study was done in a
microbiological laboratory serving a single university
hospital. This limited the daily number of BC bottles,
which had to be processed and facilitated
communication of the results to the wards. In regional labs
with larger catchment areas and service for several
facilities, the implementation of this diagnostic
approach might be more challenging. However, recent
and future developments in the field of laboratory
automation including “smart” incubators and
automated growth detection may facilitate the approach
Besides the positive effects of performing MALDI-TOF
MS from immature biomass on the speed of diagnostics,
we also found that our lab infrastructure limits the
achievements made [5, 17, 18]. As the majority of BC bottles were
reported “positive” by the automated incubator outside the
service hours of the laboratory, the median time until
further processing of a BC bottle (i.e. microscopy and plating
on solid media) was >6 h. Besides offering longer service
hours, another option to solve this problem might be the
installation of BC incubators in areas of the hospital
available for clinical personnel so that BC bottles can be
continuously loaded into the systems . The second
infrastructural parameter assessed in this study was the time
between performing microscopy and report of this result
to ward. We are convinced that the 15 min interval
observed is a reasonable. Outliers (>1000 min for reporting
the microscopy results) were due to cases in which initial
microscopy failed to identify bacteria in the Gram stain
where they were actually present .
Besides evaluating the applicability of MALDI-TOF
MS-based diagnostics in laboratory routine, we aimed to
assess whether knowledge of the species (even without an
antibiogram) led to adjustments of antibiotic therapies.
We found that the clinicians changed empiric antibiotic
therapies in 20% of all cases after communication of the
species test result. This was more frequent than
adjustments made based on microscopy results alone (8%).
Hence, MALDI-TOF MS had an important clinical effect.
On the other hand, a majority of antibiotic therapies
remained unchanged. This could be explained by, first,
adherence to well-designed guidelines for empiric therapies
covering the reported species, second, difficulties of the
treating physicians to correctly interpret the species report
(without an antibiogram) with respect to how to adjust
empiric therapies in a way that they are more accurate
and sophisticated, or third, disregarding the diagnostic
finding. Detailed evaluations of the quality of single
therapeutic adjustments were difficult, as other diagnostic
findings than BC results, such as allergies to antibiotics, data
for organ insufficiencies and the overall prognosis of the
clinical case must be considered. This is a major limitation
of the retrospective study design. However, assessing the
quality of adjustments after species identification in a local
antibiotic stewardship team revealed that the majority of
adjustments was appropriate. Clinicians particularly made
adjustments for S. aureus bacteremia (32%), even if at this
stage, antibiograms were not yet available. This might be
due to the fact that at the UHM all patients are screened
at admission for nasopharyngeal carriage of MRSA and,
hence, MRSA bacteremia, which is mostly caused by
strains colonizing the nares prior to infection , is
rather unlikely, if a negative screening result from the nares
is available. Moreover, the proportion of MRSA on all S.
aureus isolates from BCs at our institutions followed the
nationally declining trend in Germany and was <15% in
2014 (EARS-net, http://ecdc.europa.eu/, own data not
shown). Interestingly, we found that in 11/13 S. aureus
bacteremia cases (and 72% of all cases in which
adjustments of antibiotic therapies were made) the modified
therapy included the microorganism better the initial
empiric regimen. Delport et al. recently reported positive
clinical effects of performing MALDI-TOF MS from
shortly incubated colonies. They observed in a pediatric
patient collective that antibiotics were earlier optimized
and the patients even had a favorable outcome and a
shorter length of stay .
Overall, more rapid species diagnostics led to
adjustments of empiric therapies in 20% and these adjustments
improved calculated therapies in 72%. Therefore, the
local antibiotic stewardship program shall focus on
improved communication of the more rapid species results,
maybe starting with a special emphasis of S. aureus
Additional file 1: Table S1. Evaluation of adjustments of antibiotic
therapies made by clinicians directly after species identification and
before availability of an antibiogram. (DOC 55 kb)
RK and EAI wrote the manuscript. JW, EAI and KB implemented MALDI-TOF MS
from shortly incubated cultures. RK, DH, CL, JW, KB and EAI evaluated the
antibiotic prescriptions within the local antibiotic stewardship team. All authors
read and approved the final manuscript.
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