Abstract
The aim of this article is to demonstrate extreme interindividual variability of piperacilin/tazobactam (PIP/TAZO) pharmacokinetics in critically ill morbidly obese patients and to emphasize the need for the practice of routine PIP/TAZO plasma concentrations measurement in order to ensure optimal efficacy and safety of antibiotic therapy.
Keywords: critical illness, morbid obesity, piperacillin/tazobactam (PIP/TAZO), therapeutic drug monitoring (TDM)
1. INTRODUCTION
Piperacillin/tazobactam—a combination of beta‐lactam antibiotic (BLA) with beta‐lactamase inhibitor—exhibits a broad‐spectrum activity against aerobic gram‐positive and gram‐negative bacteria and anaerobes. Piperacillin inhibits bacterial cell wall synthesis by binding to penicillin‐binding proteins, ultimately leading to bacterial lysis and cell death. Tazobactam acts as an inhibitor of bacterial beta‐lactamases. Like other beta‐lactam antibiotics, PIP/TAZO demonstrates time‐dependent pharmacodynamics. That means the main predictor of antimicrobial efficacy is the cumulative percentage of time over the dosing interval in which the free (unbound) antimicrobial concentration remains above the minimum inhibitory concentration (MIC) of an offending pathogen (fT > MIC). 1 , 2 , 3
As opposed to aminoglycosides and glycopeptides, the practice of routine measurement of BLA plasma concentrations has not yet been put into practice, and TDM has been conventionally used as a tool for minimizing the risk of toxicity in drugs with a narrow therapeutic window or with non‐linear pharmacokinetics. 4 However, recent studies suggest that standard BLA dosing regimens do not lead to reaching therapeutic concentrations in a significant number of critically ill patients. Thus, in an effort to improve the achievement of PK/PD goals and therapeutic outcomes, a growing interest in the use of TDM in optimizing BLA dosing has currently been raised. 5
Critically ill obese patients represent an ever‐expanding but understudied group of patients who display significant alterations of pharmacokinetic and pharmacodynamic parameters of some antibiotics, including beta‐lactams, as a result of complex changes associated with obesity. 6 , 7 , 8 Increased distribution volume Vd and augmented renal clearance C1 lead to alteration of plasma half‐life t/2, which may consequently result in difficulty in reaching the pharmacodynamic target in ICU, that is, reaching the concentrations of four times the MIC at the end of the dosing interval (100% fT > 4× MIC). 9
This report presents case studies of the first four patients enrolled in the monitoring process meeting the criteria of grade 2 and 3 obesity (BMI ≥35 kg/m2) and treated with piperacillin/tazobactam from a research project focusing on therapeutic drug monitoring of selected beta‐lactam antibiotics in critically ill patients. The project has been carried out in intensive care units of the Na Homolce Hospital.
The blood samples were taken from a peripheral venous catheter into lithium‐heparin tubes exactly twenty‐four hours after the therapy initiation (in steady‐state) just before administering the succeeding dose (cmin) and were immediately transported to the laboratory, where they were centrifuged and frozen at −70°C. For each sample, all possible drug incompatibilities or drug interactions were noted. Plasma concentrations of PIP/TAZO were determined at the Motol University Hospital (Prague, Czech Republic) using validated high‐performance liquid chromatography (HPLC) followed by UV detection. Considering the research nature of the project, the samples were analyzed once a week only; therefore, the determined concentrations were not available in real time. Hence, they could not serve as a guide for adjusting the dosage during the patients' therapy, but they were used for post hoc analysis. This analysis implies that, despite the chosen maximum dosage of PIP/TAZO in the context of the patients' renal functions, the measured PIP/TAZO plasma concertation in obese patients did not display any degree of dependency, as shown in the following simplified case reports.
2. CASE REPORTS
2.1. 1st Case: RRT and Overdosing
A 45‐year‐old obese female patient (175 cm, 113 kg, BMI 36.9 kg/m2) suffering from diabetes with multiple complications, with severe cardiac history, COPD and chronic renal insufficiency, treated in dialysis center was brought in by ambulance because of a fever of around 38°C with gradually increasing shortness of breath. Upon her arrival, due to progressively worsening dyspnea with low oxygen saturation level (74%) without the effect of conservative therapy, orotracheal intubation was performed, mechanical ventilation was initiated, and the patient was admitted to ICU.
Subsequent to the initial management of the patient, cardiology consultation was requested and resulted in finding of old myocardial infarction secondary to ischemia, without the need for intervention. During the first week of the patient's ICU stay, her condition stabilized, she was successfully weaned from mechanical ventilation and catecholamine support was discontinued.
Rapid clinical deterioration of an already alert and relatively stable patient occurred on the tenth day of the hospitalization together with a suddenly developing high fever. Laboratory tests detected significantly elevated inflammatory markers (PCT 3.83 ng/mL, CRP 177.3 mg/L, total leukocytes 25 × 109/l). The not‐improving, malodorous defects located on both lower limbs in the area of diabetic foot were identified as a suspected focus of the infection, and therefore, antibiotic therapy with PIP/TAZO at a dose of 4,5 g per 8 h (in the context of iHD) was initiated. Pseudomonas aeruginosa (MIC 4 mg/L), Enterobacter cloacae (MIC 1.5 mg/L), Klebsiella pneumoniae (MIC 2 mg/L), and Peptostreptococcus species (MIC 0.048 mg/L) were verified in the wound swab culture specimen. Considering the patient's weight, poor antibiotic penetration into the target tissue and microbiological findings (Pseudomonas aeruginosa), the initial dosing was kept above common renal dosage adjustment guidelines. The plasma concentration of PIP/TAZO 24 h after the first dose was 272.2 mg/L. However, no signs of toxicity (neurotoxicity, hematotoxicity, hepatotoxicity) were observed during the therapy despite the supratherapeutic plasma concentration.
Clinical condition of the patient gradually improved, body temperature and levels of inflammatory markers declined, wound drainage significantly decreased, and dry necrosis developed. After a week, PIP/TAZO antibiotic therapy was discontinued; the patient did not show clinical signs of infection. In stable condition, she was transferred to the ICU department of the district hospital for further treatment.
2.2. 2nd Case Report: ARC and Underdosing
A 51‐year‐old morbidly obese patient (184 cm, 145 kg, BMI 42.8 kg/m2), up to this point treated only with arterial hypertension, was admitted via acute internal ambulance, and due to the clinical findings of perforated appendicitis, he was indicated for an urgent revision of the abdominal cavity.
Without delay, empiric antibiotic therapy PIP/TAZO at a dose of 4.5 g per 4 h was initiated and gentamicin 480 mg as a single dose was administered. The antibiotic therapy was targeted at assumed Enterobacteriaceae (ECOFF Escherichia Coli 8 mg/L, standard 1–2 mg/L) and anaerobic strains. In the admission laboratory tests, the level of CRP was 188.3 mg/L, total leucocytes count was 16 × 109/l, serum creatinine was 89 μmoL/L; otherwise, there were no abnormalities. As a result of respiratory insufficiency, the patient was intubated in the immediate post‐surgery course and then transferred to ICU for further treatment.
24 h after the antibiotic therapy initiation, the determined level of PIP/TAZO was 1.2 mg/L (with actual creatinine clearance 2.57 mL/s, based on 24‐hour collection of urine). No growth was detected after aerobic and anaerobic incubation in the perioperatively collected secretion and swab specimens. Therefore, antibiotics remained in the medication regimen due to therapeutic uncertainty and severity of the primary diagnosis.
The spontaneously ventilating and verbally communicating patient was transferred to the surgical department on the third postoperative day. In the following days, intestinal transit restored, inflammatory markers rapidly decreased and surgical wounds healed per primam intentionem. On the fifth day, antibiotic therapy was discontinued and on the tenth day after the surgery, the patient was discharged without clinical or laboratory signs of infection and in an overall good condition. The extremely low concentration of PIP/TAZO (1.2 mg/L) could not reach the desired PK/PD target, that is, the concentration of four times the MIC over the entire dosing interval.
2.3. 3rd Case: Renal Insufficiency
A 72‐year‐old monstrously obese (180 kg, 170 cm, BMI 62.3 kg/m2) polymorbid man was found somnolent by his family. An ambulance was called, and the patient, still spontaneously ventilating, was taken to an acute admissions ward. An initial CT scan of the head and brain was performed with the finding of a massive subarachnoid hemorrhage in the basal cisterns. The patient was administered prothrombin complex twice, followed by an immediate transport to the neurosurgical ICU. Due to the rapid progression of the neurological deficit and the deterioration in the level of consciousness, the already soporous patient was urgently intubated and connected to mechanical ventilation. The source of the bleeding was a rupture of pericallosal artery aneurysm resulting in intracerebral hematoma. Considering the extremely unfavorable prognosis, no intervention was indicated, and a conservative therapy was decided at the ICU.
A check CT scan showed a massive subacute subdural hematoma with midline shift and presumably bilateral pansinusitis the following day. Elevation of inflammatory markers (CRP 132.9 mg/L and leukocytes 12.3 109/l) was detected in the laboratory. Purulence, gram‐positive cocci in chains and gram‐negative rods were found in the maxillary sinus puncture.
An intravenous antibiotic therapy with amoxicillin clavulanate was initiated. Due to an allergic reaction (allergic exanthema), antibiotic therapy was modified to PIP/TAZO at a dose of 4.5 g every 4 h, based on the microbiology tests result (Klebsiella pneumoniae, MIC 6 mg/L, and Proteus mirabilis, MIC 0.19 mg/L) at GFR 0.47 mL/s (creatinine clearance from a 24‐hour urine collection). The high initial dose was chosen due to the extreme weight of the patient, the poor availability and penetration of the target compartment (cavity) and the high MIC of the infectious pathogen (Klebsiella pneumoniae). The current GFR value has not been considered a sufficient reason for dose reduction, which is usually approached in patients with GFR below 0.3 mL/s only. 11 The found PIP/TAZO concentration 24 hours after the initiation of therapy was 83.3 mg/L.
During the following week, there was a decrease in inflammatory parameters, and on Day 9, the antibiotic therapy was discontinued with negative culture controls. However, the patient's overall prognosis (14 days without sedation, no improvement of consciousness, initial intracerebral hemorrhage, grade 5 Hunt‐Hess scale) remained extremely unfavorable, and treatment options were gradually exhausted; the patient was indicated for palliative care.
2.4. 4th Case: Adequate Plasma Concentration in ARC
A 48‐year‐old female obese patient (158 cm, 104 kg, BMI 41.7 kg/m2) with known congenital lung stenosis after surgical valvulotomy with hard‐to‐heal wound formation and chronic mediastinitis and osteomyelitis was scheduled to be admitted for cardiovascular surgery.
Within the elective procedure (homograft replacement of the pulmonary valve, tricuspid valve annuloplasty and closure of the patent foramen ovale), signs of chronic inflammation with an abscess cavity around arteria pulmonalis sin. were found. Abscess drainage was performed with microbiological findings of gram‐negative rods, and antibiotic escalation was indicated from prophylactic to therapeutic administration. PIP/TAZO at a maximum dose of 4.5 g every 4 h was chosen according to the results of cultivation and PCR in an obese patient with normal renal function.
24 h after the antibiotic therapy initiation, the plasma concentration was determined to be 24.7 mg/L; creatinine clearance validated by 24‐hour urine collection was 2.25 mL/s. Achromobacter xylosoxydans (MIC 4 mg/L) sensitive to PIP/TAZO was identified in perioperatively collected tissue samples by MALDI‐TOF mass spectrometry. Due to the CT finding of fluid at the site of the original abscess and the risk of recurrence, long‐term administration of PIP/TAZO was indicated.
The patient remained afebrile throughout the hospitalization, with decreasing laboratory markers of inflammation, the wound healed per primam intentionem. On the tenth day after the surgery, the patient was transferred to the internal department of the district hospital in an overall good condition with an ongoing ATB therapy.
3. DISCUSSION
Currently, massive data from RCTs determining PK changes of PIP/TAZO in critically ill obese patients are not available, and only results of smaller studies and individual case reports have been published. 8 , 10 , 12 , 13 Due to the absence of clinical data regarding the optimal PIP/TAZO dosing in this subpopulation, PIP/TAZO dose adjustments have so far been made on the basis of an expert judgment. However, this case series demonstrates the extreme variability of PIP/TAZO plasma concentrations in morbidly obese patients and their very difficult predictability, complicated by various degrees of renal insufficiency or, on the contrary, augmented renal clearance. Although further research is needed in this area, the first four cases of morbidly obese patients enrolled in the monitoring process clearly indicate the need for precise measurement of PIP/TAZO levels to ensure optimal efficacy and safety of the therapy.
We conclude from the first case report that the measurement of PIP/TAZO plasma concentrations and individual dose adjustment based on the found concentration should be performed after the first dose of PIP/TAZO, that is, prior to the generally accepted 24‐hour high‐dose (“loading” dose) PIP/TAZO initial therapy termination. The described experience points to the risk of reaching extremely high, up to potentially toxic plasma concentrations of PIP/TAZO in critically ill obese patients, especially those with impaired function of the organs of excretion. Only an early implementation of TDM will allow us to detect supratherapeutic concentrations of the antibiotic and respond immediately by adjusting the dose, thus ensuring the safety of therapy.
The second case report confirms our conclusions, especially in the context of morbid obesity and augmented renal clearance, which can lead to ultra‐fast antibiotic elimination even at maximum dosing, that is, PIP/TAZO 4.5 g every 4 h. As Newman et al. 10 and Sturm et al. 12 also argue, the use of standard dosing regimens in critically ill morbidly obese patients may result in inadequate antibiotic exposure in a large portion of this population. Without the implementation of early TDM, obese patients, and especially those with ARC, face a significant risk of minimum inhibitory concentrations non‐achievement and antibiotic treatment failure, particularly if they suffer from infections caused by resistant pathogens with high MIC values. Monitoring of PIP/TAZO plasma concentrations is therefore considered necessary in these cases. As a possible strategy in the event of finding sub‐MIC concentrations, we suggest considering the administration of PIP/TAZO via prolonged infusion 14 , 15 , 16 and possibly further dose escalation according to plasma concentrations, clinical response, and MIC values of the offending pathogen.
The third case, alongside with the first two case reports, brings us to the conclusion about the need for early implementation of TDM. In this case, knowing the plasma concentrations of PIP/TAZO after the first dose would lead to consideration of the possibility of reducing the maximum dose to the standard dose, that is, 4.5 g every 6 h, which would probably be sufficient in view of the current state of renal function (GFR 0.47 mL/s), despite the patient's extreme obesity (BMI 62,3 kg/m2).
The last case report then leads us to a similar finding as described by Deman et al. in a case study of a patient with BMI 55 kg/m2, 13 that shows that despite significant differences in pharmacokinetic parameters of morbidly obese patients compared to healthy volunteers (see Summary of Product Characteristics), the PK/PD target was surprisingly achieved, which correlates with a positive clinical outcome. The performance of TDM here would serve to verify the adequacy of dosing of the chosen regimen and thus the effectiveness of antimicrobial therapy, which is absolutely crucial in the first 24 hours and at the same time otherwise difficult to evaluate.
Out of the four cases described above, a predefined PD target of 100% fT > 4×MIC (concentration 24.7 mg/L, MIC l.4 mg/L) was reached only once (25%) in the first 24 hours of PIP/TAZO therapy. Once (25%) a sub‐MIC concentration was found (1.2 mg/L, MIC of the presumed offending pathogen 1–2 mg/L) and two patients (50%) exceeded 10 times the MIC (272.2 mg/L, MIC 4 mg/L and 83.3 mg/L, MIC 6 mg/L, respectively), which is associated with the risk of systemic toxicity. 6
In accordance with Jung et al. 8 we suggest that critically ill obese patients represent a high‐risk group in terms of unpredictability of PIP/TAZO plasma concentrations, exposing them to the risk of overdosing and toxicity or, conversely, underdosing and PD target non‐achievement leading to treatment failure. Given the fact that early and adequate antibiotic therapy is a key intervention in successful management of infection in intensive care setting, 17 , 18 there is a strong need for performing TDM of PIP/TAZO in critically ill obese patients immediately after the first administered dose. In the context of the above‐discussed effect of early reaching of sufficient antibiotic plasma concentrations on clinical outcome, we propose maximization of PIP/TAZO dose at baseline to rapidly saturate increased Vd in obese patients, determining PIP/TAZO levels just after this initial maximum dose, and immediate individual dose adjustment based on found plasma concentration of the antibiotic. When finding sub‐inhibitory concentrations of PIP/TAZO in critically ill obese patients, especially in the case of high MIC values of the infectious agent, it may be necessary to consider prolonged infusions, which are more likely to reach PD targets ( 16 , 19 ).
4. LIMITATIONS
Within the limitations of the research project, antibiotic levels were determined ex post, that is, they were not available in real‐time and could not be used for dose adjustments. The analysis of these case reports leads us to further intensive data collection with the aim of introducing a validated analytical method with the possibility of real‐time adaptive feedback. Due to the limited number of patients, definitive conclusions from the presented case series could not be drawn and confirmation of our first experience, which we present here, will be possible only on the basis of the analysis of a larger group of patients. However, we believe that our findings may still be beneficial and will contribute to the introduction of routine TDM of beta‐lactam antibiotics into clinical practice.
5. CONCLUSION
Despite the worldwide increase in the practice of TDM of antibiotics, the current state of knowledge does not provide definitive evidence of BLA dosing in critically ill obese patients, and dose adjustments have so far only been made on the basis of an expert judgment. As demonstrated by the examples from clinical practice, critically ill obese patients show extreme interindividual variability of pharmacokinetics, which results in high difficulty, if not unpredictability, of beta‐lactam antibiotics levels. Patients with high BMI are thus at risk not only of insufficient BLA concentrations, which may result in treatment failure, but also of high BLA exposures associated with potential systemic toxicity. Accurate determination of pharmacokinetic changes in obese critically ill patients is becoming a prerequisite for optimizing current unsuitable “one‐size‐fits‐all” dosing regimens. By introducing a validated analytical method for determining serum BLA concentrations and routinely performing TDM using PK‐software, clinical efficacy is maximized and risks resulting from insufficient or excessive dosing are minimized.
A definitive assessment of the clinical benefit of TDM of BLA remains an area for future study. However, we believe that our first experience may contribute to the further research.
AUTHOR CONTRIBUTIONS
Marie Mieresová: Resources; writing – original draft. Kateřina Balážová: Investigation; resources. Jan Kubele: Supervision; validation. Dalibor Černý: Data curation; formal analysis. Milada Halačová: Conceptualization; methodology; writing – review and editing.
FUNDING INFORMATION
The project was supported by the Ministry of Health, Czech Republic—conceptual development of research organization (NNH, 00023884), IG 168601.
CONFLICT OF INTEREST STATEMENT
The authors declare no competing or potential conflict of interest.
INFORMED CONSENT
Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy. The study protocol was approved by the Institutional Ethics Committee of Na Homolce Hospital.
ACKNOWLEDGEMENT
The sponsorship for this study was covered by the Ministry of the Health of the Czech republic. The authors would like to express their sincere thanks to all of the nurses and support stuff of the Na Homolce Hospital for their assistance in all of our clinical research.
Mieresova M, Balazova K, Kubele J, Cerny D, Halacova M. Piperacillin/Tazobactam in critically ill morbidly obese patients: A case series: The first One‐Centre experience with TDM . Clin Case Rep. 2023;11:e7032. doi: 10.1002/ccr3.7032
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.