Sepsis
Sepsis
Sepsis
1 Infectious Disease and Clinical Microbiology, Gazi University School of Medicine, Ankara, Türkiye
2 Emergency Departments, Atatürk Sanatoryum Training and Research Hospital, Ankara, Türkiye
3 Department of Internal Medicine, Division of Intensive Care Medicine, Gazi University School of Medicine, Ankara, Türkiye
4 Department of Nephrology, Gazi University School of Medicine, Ankara, Türkiye
ABSTRACT
Objective: This study aimed to investigate the relationship between procalcitonin (PCT)
kinetic and estimated glomerular filtration rates (eGFR) in critically ill patients who had
Gram-negative primary bloodstream infection (GN-BSI) and responded to the antimicrobial
therapy.
Materials and Methods: This single-centered study was retrospective and observational.
Critically ill GN-BSI patients over 18 years old who had clinical and microbiological re- Corresponding Author:
sponses to antibiotic treatment were included in the study. Patients were divided into two Hasan Selçuk Özger
groups according to eGFR (eGFR <30 mL/min/1.73m2 and ≥30 mL/min/1.73m2) and com-
E-mail:
pared for PCT kinetic at seven different measurement points as initial, first, third, fifth,
[email protected]
seventh, tenth, and fourteenth days.
Results: The study included 138 patients. Initial PCT levels were higher in patients with Received: May 03, 2024
eGFR <30 mL/min/1.73m2 (4.58 [1.36-39.4] ng/mL) than in eGFR ≥30 mL/min/1.73m2 (0.91 Accepted: July 26, 2024
Published: September 26, 2024
[0.32-10.2]) (p<0.001). This elevation was present at all measurement points (p<0.05). The
decrease in PCT values by ≥30% (26.0% vs 47.9%; p=0.024) on the third day and ≥50% (69.2% Suggested citation:
vs 76.6%; p=0.411) on the fifth day was less in the low eGFR (<30 mL/min/1.73m2) group. The Özger HS, Çorbacıoğlu ŞK,
effect of low GFR on serum PCT kinetic was present in both fermenter and non-fermenter Boyacı-Dündar N, Yıldız M,
GN-BSIs but was more prominent in the fermenter group. Helvacı Ö, Altın FB, et al.
Changes of procalcitonin kinetics
Conclusion: Serum PCT levels during therapy were higher in patients with low eGFR. Early
according to renal clearance in
PCT (<5 days) response was not obtained in non-fermenter GN-BSI patients with low eGFR. critically ill patients with primary
Antibiotic revision decisions should be made more carefully in patients with low eGFR due Gram-negative bloodstream
to high initial PCT levels and slow PCT kinetic. infections. Infect Dis Clin
Microbiol. 2024;3:206-15.
Keywords: procalcitonin, kinetics, renal clearance, critically ill patients
DOI: 10.36519/idcm.2024.363
This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License. 206
Procalcitonin Kinetics in Gram-Negative Bloodstream Infections
P
rocalcitonin (PCT) is a biomarker frequently fection, infectious agents, and severity of infection
used in the diagnosis and prognosis of infec- also affect PCT kinetics and increase the uncertainty
tion (1-4). The lack of optimum cut-off values between renal clearance and PCT kinetics (13).
and the high serum PCT levels in some non-infec-
tious conditions restrict its clinical use (3-5). There- This study evaluated the relationship between
fore, PCT use is not recommended regardless of PCT kinetic and estimated glomerular filtration
clinical parameters (6). This limitation in clinical rates (eGFR) in critically ill patients with primary
use has led to PCT kinetic evaluations rather than Gram-negative primary bloodstream infections
predictions based on single PCT measurements. (GN-BSIs) who had clinical and microbiological re-
The clinicians use PCT kinetics to predict the op- sponses to antibiotic therapy.
timal duration of antibiotic therapy without worse
clinical outcomes (5). However, due to heteroge- MATERIALS AND METHODS
neous patient groups and confounding factors on
PCT kinetics, there are different published results This study was a single-center, retrospective, and
and recommendations for the effect of PCT on the observational-analytic study conducted at Gazi Uni-
optimal antibiotic therapy duration (7, 8). versity Hospital between January 2019 and Decem-
ber 2022. It included all adult patients (≥18 years)
Acute or chronic renal failure is one of the main with GN-BSIs who had clinical and microbiological
confounders of PCT kinetics (9, 10). In renal failure, responses to appropriate antibiotic therapy. Patients
altered immune responses to infection, ongoing in- with breakthrough bloodstream infections (BSIs)
flammation, and altered PCT clearance affect serum during antibiotic therapy, patients who had an anti-
PCT levels. Compared to patients with normal renal biotic change due to a proven or possible secondary
clearance, the PCT values accepted for the diagnosis infection in any other site or therapy failure, and pa-
of infection are higher than the standard PCT lim- tients without follow-up PCT were excluded.
it. However, the relationship between renal clear-
ance, PCT kinetic, and its clinical effects remains Renal function was assessed according to eGFR lev-
unknown. The acceptable PCT decreases cut-off els. eGFR was calculated based on creatinine, age,
and time interval for PCT response in these patients gender and race via the Chronic Kidney Disease
are unclear (11, 12). This uncertainty and more vari- Epidemiology Collaboration (CKD-EPI) 2009 calcu-
able PCT kinetic may lead to unnecessary antibiot- lator (14). Patients were divided into two groups ac-
ic revisions and therapy extensions in renal failure cording to their eGFR levels. Clinical response was
patients compared to patients with normal renal defined as the resolution of infection signs (such
as fever, hypotension, and leukocytosis). Microbial
response was defined as sterilization of blood cul-
ture under antibiotic therapy (15). Breakthrough
HIGHLIGHTS BSIs were defined as isolating the same or different
• Baseline, follow-up and final serum procalcitonin microorganisms in blood culture during antibiotic
(PCT) levels were higher in patients with low esti- therapy. Therapy failure was defined as the need
mated glomerular filtration rates (eGFR). to revise antibiotic therapy due to a lack of clinical
• PCT kinetic was slow in patients with low GFR and microbiological response. According to antimi-
levels, especially in non-fermenter Gram-nega- crobial susceptibility testing, appropriate antibiotic
tive primary bloodstream infections. treatment was defined as using at least one effec-
• Early PCT evaluation was not suitable for PCT re- tive antibiotic as empirical or definitive treatment.
sponse in patients with low GFR levels.
• PCT response should be delayed until the fifth Age, gender, comorbid diseases, Charlson comorbidi-
day of antibiotic therapy in these patients. ty index (CCI), systemic inflammatory response syn-
drome (SIRS), sequential organ failure assessment
Comorbidities n (%)
Microorganism, n (%)
eGFR: Estimated glomerular filtration rates, IQR: Interquartile range, CCI: Charlson comorbidity index,
SIRS: Systemic inflammatory response syndrome, SOFA: Sequential organ failure assessment score,
BSI: Bloodstream infections, GN: Gram-negative, MDR: Multidrug resistance.
a
Klebsiella spp., n=42; E. coli, n=26; Enterobacter spp., n=7; Proteus spp., n=7; Morganella spp., n=1, Rautella spp.,
n=1; Serratia spp., n=1.
b
Acinetobacter baumannii, n=25; Pseudomonas aeruginosa, n=14; Stenothrophomonas maltophilia, n=5; Ralstonia
paucula, n=3; Delfia avidovorans, n=3; Burkholderia cepacia, n=2; Sghingomonas spp., n=1.
(SOFA) scores, blood culture results, empiric and tar- according to their lowest eGFR level within 14 days.
geted antibiotics, duration of antibiotic treatments, These two groups were compared for PCT kinetic.
and clinical outcomes (intensive care unit stay and The procalcitonin test was measured quantitative-
mortality) were recorded. The first day of the appro- ly in serum samples using the electrochemilumi-
priate antibiotic therapy was considered day zero. nescence immunoassay “ECLIA” (Elecsys® BRAHMS
Blood PCT, C-reactive protein (CRP), creatinine lev- PCT; Roche Diagnostics Inc., USA) method.
els, and eGFR values were measured and recorded
for 14 days from day zero. Patients were divided into The study primarily aimed to evaluate the effect of
eGFR <30 mL/min/1.73m² and ≥ 30 mL/min/1.73m², renal clearance on PCT kinetics in patients with GN-
This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License. 208
Procalcitonin Kinetics in Gram-Negative Bloodstream Infections
Final PCT level, ng/mL, median (IQR: 25-75%) 0.62 (0.29-1.63) 0.21 (0.09-0.7) 0.001
GN-BSI: Gram-negative bloodstream infections, PCT: Procalcitonin, ΔPCT: Delta procalcitonin, eGFR: Estimated
glomerular filtration rates, IQR: Interquartile range.
ªThe highest PCT values on days 0-1 and above the normal limit value (>0.5 ng/mL) were included in the analyses.
b
Insufficient power to assess the statistical significance of the difference between groups (Power: 0.12 with 0.05
type 1 error and 0.20 type 2 error)
Table 3. PCT kinetics according to eGFR in patients with fermenter and non-fermenter GN-BSIs.
PCT, ng/mL, median (IQR: 25-75%), levels in patients with fermenter GN-BSIs
PCT, ng/mL, median (IQR: 25-75%, levels in patients with non-fermenter GN-BSIs
GN-BSI: Gram-negative bloodstream infections, PCT: Procalcitonin, ΔPCT: Delta procalcitonin, eGFR: Estimated
glomerular filtration rates, IQR: Interquartile range.
ªThe highest PCT values on days 0-1 and above the normal limit value (>0.5 ng/mL)
were included in the analyses.
b
Insufficient power to assess the statistical significance of the difference between groups
(Power: 0.46 with 0.05 type 1 error and 0.20 type 2 error).
c
Insufficient power to assess the statistical significance of the difference between groups
(Power: 0.11 with 0.05 type 1 error and 0.20 type 2 error).
d
Insufficient power to assess the statistical significance of the difference between groups
(Power: 0.32 with 0.05 type 1 error and 0.20 type 2 error).
e
Insufficient power to assess the statistical significance of the difference between groups
(Power: 0.11 with 0.05 type 1 error and 0.20 type 2 error).
This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License. 210
Procalcitonin Kinetics in Gram-Negative Bloodstream Infections
This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License. 212
Procalcitonin Kinetics in Gram-Negative Bloodstream Infections
sary antibiotic revisions. However, in the fermenter eGFR and did not measure actual GFR (29). All eGFR
BSI subgroup with a low eGFR level, the sharp PCT formulas known to us are validated in stable pa-
decrease on the third day may be helpful for an ear- tients without acute kidney injury (AKI), and they
ly response. tend to overestimate eGFR when AKI is present. To
tackle this issue, some researchers suggest using
In clinical practice, serum PCT is generally used for newer indicators of AKI such as kidney injury mol-
optimal antibiotic therapy duration apart from its ecule-1 (KIM-1), neutrophil gelatinase-associated
diagnostic and prognostic use. In their meta-anal- lipocalin (NGAL) and others, but their success and
ysis, Heilmann et al., PCT-guided antibiotic therapy triumph over eGFR is not well established (30, 31).
in patients with renal failure resulted in an approx- Furthermore, measuring the actual GFR is a cum-
imately two-day reduction in antibiotic use without bersome process which can only be employed in
increasing mortality risk. However, measurement studies with a prospective design and intent (32).
times of PCT and PCT cut-offs for antibiotic thera- However, to minimize the effect of eGFR’s well-
py optimization were quite different in the studies known constraints on our work, we demonstrated
included in the meta-analysis (28). This heteroge- creatinine trends, which are more valuable than a
neity in the meta-analysis does not allow recom- single estimate of kidney function (33). Another lim-
mendations for clinical practice. In our study, final itation related to the retrospective and descriptive
serum PCT levels at the end of antibiotic therapy study design is missing data in PCT serial measure-
were above normal limits in patients with low eGFR ments. This may cause the sample size to change
in the fermenter and non-fermenter GNs-related in each comparison and increase the risk of type 2
BSIs. In a PCT-guided antibiotic therapy approach, errors. Another limitation of our study is that since
these high final PCT values may lead to unneces- PCT values were not normally distributed, pairwise
sarily longer antibiotic therapy. Therefore, in opti- comparisons could be made at the measurement
mizing antibiotic therapy duration in patients with points instead of mixed ANOVA between the study
low eGFR, changes in PCT kinetics should be eval- groups.
uated together with the resolution of clinical infec-
tion signs instead of the final PCT level. In conclusion, according to our study results, serum
PCT levels were higher in patients with low eGFR
Our study had some limitations. First of all, despite at baseline, during, and at the end of therapy. Early
the strict inclusion criteria, all confounding factors PCT response evaluation should not be performed,
that may affect PCT kinetics could not be exclud- especially in these patients with non-fermenter
ed due to the retrospective study design. Although GN-BSIs, as the PCT response is delayed until the
we determined some criteria to exclude other ac- fifth day. Considering high PCT levels and slower
tive infections that may affect PCT kinetics, these PCT kinetics in patients with low eGFR may reduce
infections may not have been wholly excluded. Our unnecessary antibiotic revisions and extensions.
study used the CKD-EPI 2009 formula to calculate
Ethical Approval: The Ethics Committee of Gazi University F.B.A., Ö.H.; Analysis and/or Interpretation – H.S.Ö., M.Y., F.B.A.,
approved the study on January 23, 2024, with decision number Ş.K.Ç; Literature Review – H.S.Ö., M.Y., F.B.A., Ö.H.; Writer – H.S.Ö.,
2024-196. Ş.K.Ç, N.B.D., G.A., Ö.H., M.T.; Critical Reviews – G.A., M.T., M.D.,
N.B.D., Ö.H.
Informed Consent: N.A.
Conflict of Interest: The authors declare no conflict of interest.
Peer-review: Externally peer-reviewed
Financial Disclosure: The authors declared that this study has
Author Contributions: Concept – H.S.Ö.., Ş.K.Ç., N.B.D.., Ö.H.;
received no financial support.
Design – H.S.Ö., Ş.K.Ç, M.D., G.A., M.T.; Supervision – H.S.Ö., Ş.K.Ç,
M.D., M.Y., F.B.A.; Data Collection and/or Processing – H.S.Ö., M.Y.,
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