Increased β-Lactams dosing regimens improve clinical outcome in critically ill patients with augmented renal clearance treated for a first episode of hospital or ventilator-acquired pneumonia: a before and after study

Critically ill patients are at risk to develop ventilator- or hospital-acquired pneumonia (HAP-VAP), which has been associated with impaired outcomes, prolonged duration of mechanical ventilation, increase in the length of stay, and the healthcare costs [1]. In this context, appropriate antibacterial exposure is essential to improve the chances of clinical success and reduce the risk for selection of drug-resistant strains [2].

According to current practice, β-lactams are the most commonly prescribed antimicrobial agents for treatment of HAP-VAP [1]. β-Lactam antibiotics exhibit time-dependent bacterial killing, such as maximum bacterial killing occurs when the free drug concentration at the site of infection persistently exceeds 4 times the minimum inhibitory concentration (MIC) of the pathogen throughout the dosing interval (100%fT_>4xMIC) [3]. On the other hand, optimizing antimicrobial therapy remains a complex challenge given the wide and unpredictable variability of β-lactam antibiotic concentrations in critically ill patients [4].

A “one dose fits all” approach can especially be problematic in patients with augmented renal clearance (ARC), potentially leading to subtherapeutic drug exposure and higher rates of clinical failure when conventional dosing regimens are used [5‐9]. In this context, several studies previously suggested that higher than licensed β-lactam dosing regimens would be necessary to improve empirical pharmacokinetic/pharmacodynamic (PK/PD) target attainment rates in patients with ARC [10, 11]. However, evidence on clinical outcome is still controversial [12, 13].

We thus hypothesized that higher than licensed dosing regimens of β-lactams may be safe and effective in reducing the rate of therapeutic failure and HAP-VAP recurrence in critically ill patients with ARC. The main objective was to compare the clinical outcome of ARC patients treated by conventional or increased β-lactam dosing regimens for a first episode of HAP-VAP.

Our study reports the interest of optimizing dosing strategies of antimicrobial agents in critically ill patients with augmented renal clearance. This is a major concern as inadequate antimicrobial therapy has been associated with the acquisition of antimicrobial resistance, therapeutic failure, and mortality in patients with severe sepsis or septic shock [17]. Early attention to appropriate β-lactam dosing may thus improve outcomes given the marked increase in success rates when the free concentration remains above 4 times the MIC throughout the entire dosing period (100%fT_>4xMIC) [3, 9].

On the other hand, several studies have suggested a strong association between ARC, subtherapeutic β-lactam plasma concentrations, and higher rates of therapeutic failure when conventional dosing regimens are used [5‐11]. ARC has been reported in approximately 16 to 100% of patients, depending on the population investigated and the definition of ARC [18]. Although most studies have defined ARC by an enhanced CL_CR ≥ 130 ml/min/1.73m², we arbitrarily chose a cut-off of ≥ 150 ml/min for increasing β-lactam dosing regimens. Indeed, the threshold of CL_CR defining ARC should rely on the inherent risk of antibiotic underexposure depending of the type of β-lactam, dosing regimen, and modalities of administration. For β-lactams administered by continuous infusion, a previous study suggested that no underdosing was observed for CL_CR ≤ 170 ml/min [9]. Thresholds higher than 130 ml/min have also been reported for β-lactams administered by intermittent infusion (150 ml/min for ceftriaxone, up to 190 ml/min for amoxicillin-clavulanic acid) [11, 19]. Interestingly, the same threshold was also suggested by Roberts et al., the vast majority of patients with CL_CR values > 150–160 ml/min requiring a dose increase to reach trough or steady-state concentrations at four times MIC of the known pathogen [20].

Our antibiotic therapy protocol was thus in accordance with previous studies which suggested that higher than licensed dosing regimens would be necessary in patients with ARC. Piperacillin-tazobactam has been the most studied antibiotic in this context, where previous studies demonstrated that standard intermittent dosing regimens were unlikely to achieve optimal antibiotic exposure [21‐23]. Although other studies suggested a significant improvement of PK/PD target attainment rates when extended or continuous infusions are used, patients with CL_CR ≥ 150–170 ml/min remained at risk for empirical underexposure [9, 10]. In this context, higher than licensed doses of piperacillin-tazobactam (20 g/2.5 g/day by continuous infusion) allowed attaining the empirical PK/PD target in 100% patients with CL_CR ≥ 150 ml/min, without excessive dosing [12].

Data on other β-lactams in patients with ARC are scarce. For ceftriaxone, we previously demonstrated high rates of empirical target underdosing in patients with CL_CR ≥ 150 ml/min. In this context, Monte Carlo simulations suggested a dose of 2 g twice a day to achieve a 100% fT_>MIC when targeting a theoretical MIC at the upper limit of the susceptibility range [11]. Dosing simulations for amoxicillin-clavulanic acid also supported the use of increased dosing regimens (2 g four times daily) for ARC patients when using a target MIC of 8 mg/l and a pharmacodynamic target of 50% fT_>MIC, with little accumulation of clavulanic acid [21, 24]. Considering cefazolin, only an ancillary pilot study suggested a higher rate of underdosing in ARC patients, especially when PK/PD targets were adjusted to the inoculum effect [25].

Finally, some β-lactam antibiotics were not adjusted in the treatment period as no data had previously demonstrated that ARC patients may benefit for enhanced dosing regimen of meropenem, ceftazidime, or cefepime. Concerning meropenem, various Monte Carlo simulation studies suggested that 2000 mg q8h either by extended (180-min infusion) or continuous infusion allowed achieving PK/PD targets even with CL_CR of 130–250 ml/min [26]. In a former study, ARC (CL_CR ≥ 170 ml/min) was not associated with an increased rate of subexposure (fT_<4xMIC) for those antibiotic agents administered 6 g/day continuously [9]. However, this study was impaired by a small sample size of ARC patients treated by ceftazidime or cefepime and did not allow any conclusion about the optimal dosing regimen in ARC patients treated by ceftazidime and cefepime for less-susceptible pathogens. This reason might explain the observed difference concerning the type of initial broad-spectrum antimicrobial therapy (ceftazidime or cefepime and/or piperacillin ± tazobactam) between both periods in the present study. Patients empirically treated by meropenem, ceftazidime, or cefepime were not excluded for the analysis as most of them underwent antibiotic de-escalation that could require dose-adjustment in the treatment period.

A prompt recognition of ARC is thus of paramount importance for optimizing empirical antibiotic dosing regimens. However, commonly used formulas frequently misclassify ARC and may underestimate the risk of β-lactam underdosing [27, 28]. Although several screening tools have shown adequate predictive abilities for identifying patients with ARC, 24-h measured CL_CR must remain the reference and should be monitored daily in at-risk patients [29, 30]. On the other hand, dose adaptations solely based on CL_CR are probably not sufficient to achieve target therapeutic concentrations [31]. The relationship between CL_CR and drug concentrations is probably far more complex and dose-adaptions are probably best guided by a validated Population PK model and not by CL_CR alone [32]. Moreover, a special attention should be granted to detect dose-dependent neurotoxicity, especially when using higher than licensed doses of β-lactams [33]. Intra-patient variability of CL_CR and drug concentrations over time must require subsequent dose adjustment guided by CL_CR values, pathogen susceptibility, and therapeutic drug monitoring [34]. However, the safety of increased dosing regimens in ARC patients has been reported in previous studies, all the reported concentrations being significantly under the supposed toxic cutoff [12, 13]. Currently, therapeutic drug monitoring is required to adjust daily regimens in critically ill patients.

Several limitations should be considered. First, the main limitation relied on the retrospective before–after design that could lead to selection and interpretation bias. Even if there were no known significant changes to our local procedures, our results may be driven by the preferential use of increased dosing regimens of piperacillin-tazobactam. However, the propensity score matching allowed reducing the effects of confounding covariates directly influencing the choice of probabilistic or documented antibiotic therapy. Furthermore, we aimed to focus on HAP-VAP as they meet widely used criteria for diagnostic and management, where therapeutic failure is not related to inadequate surgical source control. Second, the rate of antibiotic side effects is very limited, although probably related to an underreporting in the medical records. Finally, the study design did not allow adequate MIC determination and therapeutic drug monitoring. Only pharmacological dosing could confirm the association between higher rates of PK/PD target attainment and lower rates of therapeutic failure in critically ARC patients treated by increased β-lactam dosing regimens.

Higher than licensed dosing regimens of β-lactams may be safe and effective in reducing the rate of therapeutic failure and HAP-VAP recurrence in critically ill ARC patients treated for a first episode of HAP-VAP.