Continuous infusion of meropenem–vaborbactam for a KPC-3-producing Klebsiella pneumoniae bloodstream infection in a critically ill patient with augmented renal clearance

Antimicrobial resistance is increasing globally, resulting in longer hospital stays, higher medical costs, and increased mortality [1]. Fortunately, novel β-lactam/β-lactamase inhibitor combinations have been designed to target carbapenemase-producing Enterobacterales, which are among the most threatening resistant bacteria [1, 2].

Meropenem–vaborbactam is one of these novel antimicrobials, combining a carbapenem and a cyclic boronic acid β-lactamase inhibitor (inhibiting Ambler class A and C β-lactamases) with potent activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales [2]. It was first approved by the US Food and Drug Administration (FDA) in 2017 with an optimized dosing regimen of 2 g/2 g (2 g of meropenem + 2 g of vaborbactam) q8h as a 3-h infusion to treat pathogens with MIC ≤ 8 mg/L [2, 3]. It is worth noting that dosage adjustment is recommended in patients with impaired renal clearance (< 50 mL/min/1.73 m²); however, there is no recommendation in patients with augmented renal clearance (ARC) [2‐4]. For the latter, and in general for critically ill patients infected with carbapenem-resistant Enterobacterales, the use of continuous infusion (CI) could be interesting to limit therapeutic failures [5]. Indeed, like other β-lactams, meropenem–vaborbactam displays a predominantly time-dependent killing [2, 3]. Therefore, CI appears to be a promising dosing strategy to increase the likelihood of achieving the most optimized pharmacokinetic/pharmacodynamic (PK/PD) target [4, 8].

In September 2022, a 46-year-old man, weighing 77 kg, with a medical history of Child C cirrhosis, was hospitalized for 3 weeks in Portugal, for variceal haemorrhage. In October 2022, he was admitted to a French tertiary hospital for ascites and jaundice. He was rapidly treated with ceftriaxone for 7 days for an undocumented spontaneous bacterial peritonitis. The rectal swab performed upon admission was positive for a KPC-producing K. pneumoniae (strain A, Table 1). Between day 7 and 27, hepatic encephalopathy and three episodes of acute variceal bleed occurred, requiring intensive care unit (ICU) admission, two endoscopic variceal ligations, a transjugular embolization of rectal varices, a transjugular intrahepatic portosystemic shunt, and an additional course of ceftriaxone for 10 days.

On day 27, his condition worsened due to septic shock, empirically treated with meropenem and amikacin. The blood cultures, drawn for fever 1 day prior, were positive for an extended spectrum β-lactamase (ESBL)-producing K. pneumoniae (strain B, Table 1). On day 29, the patient was still febrile and in septic shock, and the antimicrobials were switched to ceftazidime–avibactam (2 g/500 mg bolus followed by 2 g/500 mg q8h as an 8-h infusion). On day 33, the blood cultures drawn on day 32 were positive for KPC-producing K. pneumoniae (strain C, Table 1). On day 34, as the patient still had fever and sepsis, antimicrobials were switched to the one with the lowest MIC. Meropenem–vaborbactam 2 g/2 g q6h as a 3-h infusion (8 g/8 g/day due to ARC at 140 mL/min/1.73 m²) was started and catheters were replaced. No septic focus was evidenced on computerized tomography (CT) scan and positron emission tomography (PET) scan. Meropenem through concentrations on days 36, 39 and 40 were 6.5 mg/L, 3.8 mg/L and 2.7 mg/L, respectively. On day 40, the dosing regimen was optimized to 1 g/1 g q4h as a 4-h infusion corresponding to a CI of 6 g/6 g/day. Meropenem steady-state concentrations were 8.4 mg/L, 16.8 mg/L and 14.9 mg/L, on days 42, 47 and 54, respectively (Fig. 1). Blood cultures drawn on day 35, 36 and 47 were negative and the patient was discharged to home at the end of treatment (day 61). There was no evidence of adverse effects, such as hypersensitivity reaction, neurotoxicity or acute kidney injury during treatment.

Interestingly, wgMLST showed that the KPC-3-producing K. pneumoniae strains A and C were not related (19.78% of sequence similarity) and belonged to international high-risk clones ST147 and ST11 (see Fig. 2 and Table 2). On the contrary, the KPC-3-producing K. pneumoniae strain C and the CTX-M-15-producing K. pneumoniae strain B isolated from the blood cultures were very similar (99.97%). They carried the same traT virulence gene on an IncFIB(K) plasmid. which encodes for an outer membrane protein of complement resistance and the same resistance genes on the IncFIA(HI1),IncR plasmid, except for the bla_KPC-3 gene harboured by an IncN plasmid.

To our knowledge, this is the first report of meropenem–vaborbactam administration by CI. The body of evidence suggests that CI of ß-lactams may be of interest in ICU patients with normal or ARC, to improve pharmacokinetic-target attainment, coverage of less-susceptible pathogens, bactericidal activity and outcomes [4, 8]. In accordance, we reported that only CI of meropenem–vaborbactam resulted in sustained concentrations above the MIC of susceptible pathogens throughout the whole dosing interval (100%ƒT > _MIC), taking into consideration the 8 mg/L breakpoint [2, 3]. There is no optimized pharmacokinetic target available in the literature for meropenem–vaborbactam. However, it is likely that the optimized targets for other beta-lactams, i.e. a free drug concentration above fourfold the MIC throughout the whole dosing interval (100%ƒT > _4xMIC), can be applied [9]. We found that the CI of meropenem–vaborbactam achieved concentrations between 8 and 16 mg/L, thus reaching the optimized pharmacokinetic target of 100%ƒT > _4xMIC, for MIC up to 4 mg/L [10]. In addition, vaborbactam exhibits concentration–time profiles, suggesting that a pharmacokinetic target higher than 100%ƒT > _4xMIC could enhance bactericidal activity in infections due to KPC-producing Enterobacterales [2]. Therefore, even at the lowest MICs, CI of meropenem–vaborbactam could be of interest.

The CTX-M-15-producing K. pneumoniae (strain B) and the KPC-3-producing K. pneumoniae (strain C), involved in the BSIs, shared the IncFIB(K) plasmid with the traT gene that encodes an outer membrane protein of complement resistance, allowing the bacteria to escape the host immune system [11]. WGS suggested that strain C probably picked up the plasmid IncFIA(HI1), IncR with the bla_KPC-3 gene, frequently described in Portugal [12, 13], from the KPC-3-producing K. pneumoniae (strain A) stool carriage. This case emphasizes the ability of K. pneumoniae to get new plasmids from other bacteria, which increases its resistance and virulence, and should prompt physicians to optimize drug selection and dosage in most severely ill patients [14].

Importantly, we reported that CI of meropenem–vaborbactam was feasible and safe when the daily dose was divided into six 4-h infusions in agreement with the manufacturer’s recommendations that meropenem–vaborbactam should not be infused for longer than 4 h, which is its stability limit at room temperature [2, 3, 15].

This study has limitations. First, the results presented in this case report need to be confirmed by larger studies. However, to our knowledge, this is the first clinical reference in the literature for the use of meropenem–vaborbactam CI. Second, we did not perform TDM of vaborbactam. Nevertheless, its pharmacokinetics seems to be comparable to that of meropenem [2]. Finally, we reported the effectiveness of meropenem–vaborbactam CI for bacteria with an MIC of 0.06 mg/L, and the effectiveness for bacteria with MICs up to 8 mg/L needs to be confirmed.