Ceftazidime-Avibactam in CRRT: Pharmacokinetics in a Critically Ill Infant with Sepsis

Abstract

A new cephalosporin/β-lactamase inhibitor combination, ceftazidime-avibactam, has received significant attention for its use in treating infections due to multidrug-resistant Gram-negative pathogens. Its use is challenging in pediatric patients treated with continuous renal replacement therapy because of alterations in pharmacokinetic profiles in this population. The authors present a case report of a 6-month-old female with SCID who develops sepsis due to Stenotrophomonas maltophilia after undergoing stem cell transplantation. She continued on CRRT for fluid overload but received ceftazidime-avibactam therapy with suboptimal plasma concentrations as therapeutic drug monitoring disclosed an inability to attain pharmacokinetic/pharmacodynamic (PK/PD) targets. Clearance rates were significantly higher than those reported in adult studies and thus posed a threat to treatment efficacy and resistance. This study reiterates the use of individualized dosing and therapeutic drug monitoring in pediatric CRRT and throws open a much larger space for future research into optimal dosing strategies for ceftazidime-avibactam in this susceptible population.

Introduction

Ceftazidime-avibactam is an innovative third-generation cephalosporin-based combination with β-lactamase inhibitor, tailored to address the emerging challenge of antimicrobial resistance. It is crucial in multi-drug resistant Gram-negative infections; but it is notoriously troublesome in critically ill patients, especially with those on CRRT. This case report will center on the pharmacokinetics of ceftazidime-avibactam in a 6-month-old girl receiving CRRT for fluid overload, where the intricacies in dosing strategies to be optimized in pediatric patients are challenging in severe infections.

Case Presentation

A 6-month-old female patient with a history of severe combined immunodeficiency comes into the hospital with sepsis. She has a bloodstream infection due to Stenotrophomonas maltophilia. The patient recently received stem cell transplantation for SCID. She was extremely ill at presentation to the PICU, required mechanical ventilation, and required aggressive fluid resuscitation. On presentation to the hospital, her initial laboratory findings revealed multi-organ dysfunction with elevated inflammatory markers, acute kidney injury, and fluid overload. She therefore initiated CRRT on Day 2 of admission to manage fluid overload and maintain stability in hemodynamics.

Background and Rationale for Therapy

Stenotrophomonas maltophilia is a Gram-negative bacterium notorious for its inherent resistance to most antibiotics, including carbapenems; thus, infections due to this organism are very challenging to treat. The choice of ceftazidime-avibactam was based on the former's broad-spectrum activity against Gram-negative pathogens and the latter's ability to overcome β-lactamase-mediated resistance. While its use has increased in pediatric cases, the pharmacokinetics of this combination in patients on CRRT, particularly children, are still relatively understudied. CRRT affects the clearance of drugs profoundly, and dosing strategies based on adult literature often do not apply to pediatric patients, as seen in this case.

Pharmacokinetics and Drug Monitoring

To optimize the patient's therapy, ceftazidime-avibactam was administered at a dose of 30 mg/kg of ceftazidime and 7.5 mg/kg of avibactam every 8 hours via a 2-hour infusion. Therapeutic drug monitoring (TDM) was employed to assess drug concentrations and ensure that PK/PD targets were being met. The drug levels were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS), allowing precise quantification of ceftazidime and avibactam concentrations in plasma.

However, despite the adjusted dosing regimen, the patient’s drug concentrations failed to reach the desired PK/PD targets. The total clearance rates were 1.7 L/h and 3.02 L/h for ceftazidime and avibactam, respectively, both significantly higher than values reported in the adult literature. The CRRT clearance of ceftazidime ranged from 28.8% to 60%, while for avibactam, it was 14% to 33%. These findings suggest that standard dosing may be insufficient in pediatric patients undergoing CRRT, potentially leading to subtherapeutic drug levels, treatment failure, and the risk of developing resistance.

Challenges in Dosing and Achieving PK/PD Targets

Adequate antimicrobial exposure is challenging to attain in children with impaired renal function, particularly in those receiving CRRT. In this instance, drug clearance was greater than predicted, necessitating adjustment of the dosing strategy because of the drugs' small molecular size and susceptibility to removal through extracorporeal systems during pediatric CRRT. Another challenge to dosing strategies is the dynamically changing nature of renal function in critically ill children.

Failure to achieve PK/PD targets in this case highlights the necessity of tailoring dosing regimens. Standard dosing timings used in children on CRRT cannot, therefore, be assumed applicable to everyone. Due to drug clearance, dosing may need to be more frequent, or continuous infusion might be necessary to maintain adequate therapeutic concentrations. Continuous infusion of ceftazidime-avibactam is an alternative strategy that will guarantee better drug exposure as it maintains more stable plasma concentrations that lead to better target attainment, especially in patients who have fluctuating renal function.

Potential Implications of Suboptimal Drug Levels

Subtherapeutic drug levels in patients with severe infections, such as sepsis, can have significant clinical consequences. In this case, the inability to reach therapeutic concentrations of ceftazidime-avibactam raises concerns about the potential for treatment failure and the emergence of resistant bacterial strains. Stenotrophomonas maltophilia is already a challenging pathogen due to its intrinsic resistance mechanisms, and suboptimal antibiotic exposure may further drive the development of resistance.

Emerging resistance to ceftazidime-avibactam could have profound implications for the management of multidrug-resistant infections, especially in immunocompromised patients like this one. The patient's underlying condition of severe combined immunodeficiency further complicates the situation, as any delay in effective antimicrobial therapy could lead to rapid clinical deterioration. Close monitoring of drug levels and early intervention in the event of subtherapeutic concentrations are therefore critical in managing such high-risk patients.

CRRT and Drug Clearance

CRRT, while life-saving in cases of acute kidney injury and fluid overload, complicates the pharmacokinetics of many drugs, including antimicrobials. The clearance of drugs during CRRT is influenced by several factors, including the characteristics of the filter, blood flow rates, and the drug’s molecular weight, protein binding, and volume of distribution. In this case, the higher clearance rates observed for both ceftazidime and avibactam suggest that CRRT was removing a significant proportion of the administered drug, necessitating a reevaluation of the dosing regimen.

Studies have shown that drug clearance during CRRT can vary widely depending on the specific modality used (e.g., continuous venovenous hemofiltration, continuous venovenous hemodialysis), highlighting the need for tailored dosing strategies. In pediatric patients, who have different physiologic parameters compared to adults, this variability is even more pronounced. Therefore, TDM is essential in guiding dosing adjustments to ensure that therapeutic drug levels are maintained.

Treatment Outcome

Despite the challenges in achieving optimal drug concentrations, the patient showed clinical improvement with the resolution of sepsis by Day 14 of therapy. Her hemodynamic status stabilized, and she was successfully weaned off CRRT by Day 10. However, given the subtherapeutic levels of ceftazidime-avibactam observed throughout her treatment, it is likely that other factors, such as the patient's immune recovery post-transplant and supportive care measures, played a role in her recovery.

The case highlights the importance of individualized antimicrobial dosing in pediatric patients receiving CRRT. Although the patient ultimately had a positive outcome, the risk of treatment failure due to suboptimal drug levels was significant, emphasizing the need for ongoing research into optimal dosing strategies for this population.

Discussion

This case study will serve to illustrate some of the challenges associated with infection management in critically ill pediatric patients, particularly those receiving CRRT. The pharmacokinetics of ceftazidime-avibactam in children are largely undefined. Therefore, standard dosing regimens are likely inadequate for patients receiving renal replacement therapy. Higher doses or continuous infusion strategies may be necessary to meet the PK/PD targets to achieve effective antimicrobial therapy.

TDM is of particular value in determining therapy when drugs undergo altered clearance due to CRRT. Further studies on the pharmacokinetics of ceftazidime-avibactam in pediatric populations will be necessary for the development of evidence-based dosing recommendations in the future. In the meantime, clinicians need to continue to vigilantly monitor drug levels and be prepared to adjust dosing as an individual's needs dictate.

Conclusion

Therapeutic drug levels are challenging to achieve in critically ill pediatric patients undergoing CRRT with the pharmacokinetics of ceftazidime-avibactam. This case emphasizes the need for individualized dosing, TDM, and higher doses or continuous infusion to prevent treatment failure and antimicrobial resistance. Further studies should be undertaken to optimize dosing strategy targeting such vulnerable patient populations for the treatment of life-threatening infections, such as those caused by Stenotrophomonas maltophilia.

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