Risk factors for suboptimal target attainment of commonly used ß-lactam antibiotics in older adults: a prospective cohort study.

Abstract

OBJECTIVES: Age-related pathophysiological changes may impact the pharmacokinetics and pharmacodynamics (PK/PD) of ß-lactam antibiotics, potentially resulting in suboptimal concentrations in older adults. This study evaluated PK/PD target attainment with current intravenous amoxicillin-clavulanate and piperacillin-tazobactam dosing regimens in older adults, identified risk factors for target non-attainment, and assessed the prevalence of toxic concentrations. METHODS: This was a prospective, observational PK study in geriatric inpatients (≥75 years) who were treated intravenously with amoxicillin-clavulanate (1 g/0.2 g q6h as a 30-minute infusion) or piperacillin-tazobactam (4 g/0.5 g q6h as a 3-hour infusion). Trough blood samples were collected in steady-state conditions. Target attainment was evaluated against a 100%fT > MIC target. Risk factors for target non-attainment were identified by multivariable logistic regression analysis. Toxicity thresholds were defined as total Cmin concentrations of 80 mg/L for amoxicillin and 157.2 mg/L for piperacillin. RESULTS: Seventy-four patients (median age (IQR): 87 years (83-90)) were included. The PK/PD target was achieved in 15 of 35 and 33 of 39 patients for amoxicillin-clavulanate and piperacillin-tazobactam, respectively. Multivariable logistic regression analysis revealed an effect of comorbidity burden, assessed by the Cumulative Illness Rating Scale-Geriatric (CIRS-G), and estimated glomerular filtration rate that explained 23.8% of target non-attainment (P < 0.05). Receiver operator characteristic curves identified an eGFR of 67 mL/min/1.73m2 as a threshold associated with an increased risk of target non-attainment. Toxicity thresholds were never exceeded in this study. CONCLUSIONS: Health status and renal function, rather than chronological age, play a significant role in target non-attainment among older adults. Further research is required to delineate predictors for interpatient variability in PK and develop evidence-based dosing strategies. TRIAL REGISTRATION: Registration in ClinicalTrials.govTrial registration number: NCT04436991Registration date: 16/06/2020.

AI evidence extraction

Main findings

Among 74 geriatric inpatients (median age 87 years), the 100% fT>MIC PK/PD target was achieved in 15/35 patients receiving amoxicillin-clavulanate and 33/39 receiving piperacillin-tazobactam. Comorbidity burden (CIRS-G) and estimated glomerular filtration rate were associated with target non-attainment (model explained 23.8%; P<0.05), with an eGFR threshold of 67 mL/min/1.73m2 linked to increased risk. Toxicity thresholds were not exceeded.

Outcomes measured

• PK/PD target attainment (100% fT>MIC)
• Risk factors for PK/PD target non-attainment (multivariable logistic regression)
• Prevalence of toxic concentrations (Cmin thresholds for amoxicillin and piperacillin)

{
    "study_type": "cohort",
    "exposure": {
        "band": null,
        "source": null,
        "frequency_mhz": null,
        "sar_wkg": null,
        "duration": null
    },
    "population": "Geriatric inpatients (≥75 years) treated intravenously with amoxicillin-clavulanate or piperacillin-tazobactam",
    "sample_size": 74,
    "outcomes": [
        "PK/PD target attainment (100% fT>MIC)",
        "Risk factors for PK/PD target non-attainment (multivariable logistic regression)",
        "Prevalence of toxic concentrations (Cmin thresholds for amoxicillin and piperacillin)"
    ],
    "main_findings": "Among 74 geriatric inpatients (median age 87 years), the 100% fT>MIC PK/PD target was achieved in 15/35 patients receiving amoxicillin-clavulanate and 33/39 receiving piperacillin-tazobactam. Comorbidity burden (CIRS-G) and estimated glomerular filtration rate were associated with target non-attainment (model explained 23.8%; P<0.05), with an eGFR threshold of 67 mL/min/1.73m2 linked to increased risk. Toxicity thresholds were not exceeded.",
    "effect_direction": "unclear",
    "limitations": [],
    "evidence_strength": "insufficient",
    "confidence": 0.66000000000000003108624468950438313186168670654296875,
    "peer_reviewed_likely": "yes",
    "keywords": [
        "older adults",
        "geriatric inpatients",
        "beta-lactam antibiotics",
        "amoxicillin-clavulanate",
        "piperacillin-tazobactam",
        "pharmacokinetics",
        "pharmacodynamics",
        "target attainment",
        "fT>MIC",
        "renal function",
        "eGFR",
        "CIRS-G",
        "toxicity threshold",
        "prospective observational study"
    ],
    "suggested_hubs": []
}

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