Therapeutisches Drug Monitoring von Antibiotika-Dauerinfusion bei Intensivpatienten mit chronischem Nierenersatzverfahren
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Abstract
This study investigated the impact of different renal replacement therapy modalities on
the serum concentrations of the antibiotics piperacillin, meropenem, and vancomycin in
critically ill intensive care patients. The primary objective was to evaluate the influence of
RRT on achieving standardized pharmacokinetic target ranges. In addition, the study
assessed deviations from defined target ranges across different RRT modalities
(specifically CVVH, CVVHD, and CVVHDF) compared to patients without continuous renal
replacement therapy. Sex-specific differences in antibiotic serum concentrations and their
deviations from target ranges were also analyzed, as well as the effects of RRT modalities
on these concentrations. These objectives aimed to improve the understanding of the
complex interactions between drug properties, RRT methods, and patient-specific factors,
ultimately contributing to optimizing antibiotic therapy in critically ill patients.
IMPACT OF RENAL REPLACEMENT THERAPY
The largest deviations from target concentrations were observed in the CVVH and CVVHD
groups, mostly showing supratherapeutic levels beyond guideline recommendations. The
highest median deviation was found in female patients within the meropenem cohort
under CVVH therapy (171.0% median). Among male patients, the largest deviations
occurred in the vancomycin cohort under CVVH (91.5% median) and in the piperacillin
cohort under CVVHD (90.0% median). The CVVHDF group performed slightly better but
still showed deviations in 5 out of 8 scenarios. Patients not receiving RRT generally
remained within the defined target ranges.
In the piperacillin cohort, the PRISMAFLEX device produced the most favorable results in
male patients, whereas the multiFiltrate device led to significant overdosing. In females,
both devices resulted in supratherapeutic concentrations. Similarly, in the meropenem
cohort, both devices led to relevant deviations, particularly the multiFiltrate in female
patients. The duration of RRT also had an impact on concentration deviations. Relevant
deviations occurred under both continuous and intermittent RRT. In the piperacillin cohort,
continuous RRT appeared more favorable for female patients, whereas intermittent
therapy yielded better results in the meropenem cohort. In the vancomycin cohort,
outcomes varied depending on the administration method: intermittent therapy with
bolus application produced acceptable results in females, while continuous therapy via
syringe pump was more effective in males.
The choice of dialysis device and treatment duration significantly influenced antibiotic
serum concentrations, with variation depending on the antibiotic and the patient's sex. In
many cases, patients not receiving RRT had the lowest deviations. Continuous therapy
forms tended to produce more moderate deviations and thus more stable serum
concentrations.
SEX-SPECIFIC DIFFERENCES
The highest deviations were found in female patients, particularly in the meropenem
cohort under CVVH. Male patients had the highest deviations in the vancomycin cohort
(CVVH) and the piperacillin cohort (CVVHD). Additionally, sex-specific differences in ICU
length of stay and mortality were observed. Male patients had longer ICU stays in the
piperacillin and vancomycin cohorts, while female patients had longer ICU stays in the
meropenem cohort. In all cohorts, the median age of deceased male patients was higher
than that of deceased female patients.
Antibiotic serum concentrations were significantly influenced by the choice of dialysis
device and treatment duration, with notable differences depending on the antibiotic and
sex.
ANTIBIOTIC-SPECIFIC OBSERVATIONS
Serum concentrations of piperacillin and meropenem were predominantly above the
target range, while most vancomycin concentrations remained within target. In the
vancomycin syringe pump cohort, negative deviations were frequently observed,
indicating underdosing, whereas the bolus cohort showed mostly positive deviations,
suggesting overdosing. The highest mortality rate was recorded in the vancomycin cohort.
CLINICAL PRACTICE
Physicians often targeted higher concentration ranges than those defined in SOPs. This
likely reflects a cautious approach in clinical practice, driven by concerns about
subtherapeutic drug levels in critically ill patients.
In situations with increased physiological variability—such as sepsis, organ failure, or
ongoing RRT—more aggressive therapeutic strategies appear justifiable. This trend toward
individualized therapy aligns with current recommendations advocating dynamic
adjustment of targets based on patient-specific parameters and pharmacokinetic
variability. At the same time, it highlights a discrepancy between rigid protocols and realworld decision-making at the bedside.
PATHOGEN FINDINGS
The most frequently detected pathogens included Enterococcus spp., Enterococcus
faecium, Escherichia coli, Pseudomonas aeruginosa, coagulasenegative Staphylococcus spp., and Staphylococcus epidermidis. No clear association with
mortality was found for Enterococcus spp., Pseudomonas aeruginosa, or Staphylococcus
epidermidis. However, Enterococcus faecium and E. coli were associated with increased
mortality, though comorbidities likely also contributed.
COMORBIDITIES AND ORGAN FUNCTION
Cardiac conditions, bacterial infections, and renal insufficiency were common across all
cohorts. The highest rate of metabolic disorders occurred in the vancomycin cohort. Liver
values and inflammatory markers were elevated after initiation of antibiotic therapy.
Associations were found between low sodium levels and elevated serum concentrations in
the meropenem cohort, as well as between decreased blood count values and a wide
range of serum levels in the vancomycin cohort. The vancomycin cohort had the highest
mortality and longest hospital stays, while the piperacillin cohort showed lower mortality
despite pronounced thrombocytopenia and anemia.
In both the piperacillin and meropenem cohorts, lower deviations in serum concentrations
were observed on days without RRT, especially when residual kidney function was better
preserved. Older age was associated with greater deviations and more variability in serum
concentrations.
CONCLUSION AND OUTLOOK
The results underscore the complexity of antibiotic dosing in patients undergoing various
RRT modalities and highlight the importance of individualized monitoring and dose
adjustment. These findings suggest that individualized antibiotic dosing—especially in
female patients receiving RRT—is necessary. Future studies and clinical guidelines should
more closely examine and incorporate sex-specific differences and other patient-related
factors.
RECOMMENDATIONS FOR FUTURE RESEARCH
• Sex-specific differences: Further exploration of pharmacokinetic differences by
sex, including potential hormonal influences on antibiotic metabolism and
clearance.
• Age-related effects: In-depth investigation of age-dependent pharmacokinetics,
particularly in patients over 50, with the aim of developing age-adjusted dosing
strategies.
• Maintenance dose optimization: Studies to determine optimal maintenance
doses for different patient groups, considering age, sex, and residual kidney
function.
• Residual kidney function: Quantification of its influence on antibiotic
concentrations and development of predictive models for optimal dosing.
• Long-term studies: Monitoring of antibiotic resistance development under various
dosing strategies.
• Predictive modeling: Development and validation of individualized dosing
algorithms based on patient-specific characteristics.
These investigations could support the advancement of personalized antibiotic therapy in
patients receiving renal replacement therapy
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Except where otherwise noted, this item's license is described as Attribution 4.0 International