1325 - Things that go Bump in the Night: Combating Klebsiella pneumoniae co-producing New Delhi metallo-beta-lactamase (NDM) and Mobile Colistin Resistance (MCR)

Background: The scourge of MBLs among Gram negatives, such New Delhi Metallo-beta-lactamase-producing Klebsiella pneumoniae, has resulted in an overwhelming need for new treatmens. Worryingly, additional acquisition of plasmid-mediated polymyxin resistance through the mcr gene can produce strains resistant to all last line agents. The novel combination of aztreonam (ATM, which is not an MBL substrate) with avibactam (AVI, to inhibit extended spectrum beta-lactamases that inactivate ATM) has been proposed to restore ATM activity.

Methods: K. pneumoniae SZ04 harboring bla_NDM-5, bla_CTX-M-55, and mcr-1 (MIC_ATM = 128 mg/L, MIC_{Polymyxin B} = 4 mg/L, MIC_Amikacin = 1 mg/L, MIC_{ceftazidime/avibactam} > 16/4 mg/L) was studied at two initial inoculum (10⁶ and 10⁸ cfu/mL) over 24h in static time kills (SCTK). Concentration arrays of 2-, 3-, and 4-drug combinations of low- and package insert-dose polymyxin B (PMB) ± low- and package insert-dose amikacin (AMI) ± package insert dosing of ATM/AVI were simulated in > 200 individual arms of SCTK. Data were summarized using the Log Ratio Area (LRA) which is calculated by integrating the area under the bacterial killing curve, normalizing to the growth control, then log-transforming. A Hill-type function was fit to the data in order to determine the maximum effect (E_max) and drug concentration for 50% effect (EC₅₀).

Results: When simulating the maximum free concentration of amikacin 15 mg/kg (52 mg/L) in combination with package insert concentrations of ATM/AVI, there was a marked reduction of 3.22 in the LRA compared to the growth control for the 10⁸ cfu/mL starting inocula. Combining ATM with low amikacin (0.813 mg/L) and polymyxin B (0.125 mg/L) resulted in a reduction in LRA of 4.32 at 10⁶ cfu/mL. Model fitting results showed a statistically significant difference in EC₅₀ to amikacin between low and high inocula at 1.24 and 18.1 mg/L, respectively. Combination of AMI with low-concentration PMB (0.125 mg/L) resulted in an increase in the E_max of amikacin to -5.68.

Conclusion: The use of ATM/AVI combinations is a promising option against MBL and MCR co-producing K. pneumoniae. Low-dose strategies of polymyxin or amikacin dosing in combination with ATM/AVI is merits further testing for future translation to the clinical setting to improve efficacy and optimize treatment.