High-intensity meropenem combinations with polymyxin B: new strategies to overcome carbapenem resistance in Acinetobacter baumannii

Abstract

Objectives: The pharmacodynamics of polymyxin/carbapenem combinations against carbapenem-resistant Acinetobacter baumannii (CRAB) are largely unknown. Our objective was to determine whether intensified meropenem regimens in combination with polymyxin B enhance killing and resistance suppression of CRAB.

Methods: Time-kill experiments for meropenem and polymyxin B combinations were conducted against three polymyxin B-susceptible (MIC of polymyxin B = 0.5 mg/L) CRAB strains with varying meropenem MICs (ATCC 19606, N16870 and 03-149-1; MIC of meropenem = 4, 16 and 64 mg/L, respectively) at 10⁸ cfu/mL. A hollow-fibre infection model was then used to simulate humanized regimens of polymyxin B and meropenem (2, 4, 6 and 8 g prolonged infusions every 8 h) versus N16870 at 10⁸ cfu/mL over 14 days. New mathematical mechanism-based models were developed using S-ADAPT.

Results: Time-kill experiments were well described by the mathematical mechanism-based models, with the presence of polymyxin B drastically decreasing the meropenem concentration needed for half-maximal activity against meropenem-resistant populations from 438 to 82.1 (ATCC 19606), 158 to 93.6 (N16870) and 433 to 76.0 mg/L (03-149-1). The maximum killing effect of combination treatment was similar among all three strains despite divergent meropenem MIC values (E_max = 2.13, 2.08 and 2.15; MIC of meropenem = 4, 16 and 64 mg/L, respectively). Escalating the dose of meropenem in hollow-fibre combination regimens from 2 g every 8 h to 8 g every 8 h resulted in killing that progressed from a >2.5 log₁₀ cfu/mL reduction with regrowth by 72 h (2 g every 8 h) to complete eradication by 336 h (8 g every 8 h).

Conclusion: Intensified meropenem dosing in combination with polymyxin B may offer a unique strategy to kill CRAB irrespective of the meropenem MIC.

Figure 1.

Mechanism-based model for the synergy of meropenem and polymyxin B against three A. baumannii strains studied at high bacterial inocula of ∼10⁸ cfu/mL. The model contained two populations: the first population was meropenem susceptible and polymyxin B resistant (MEM^s/PMB^r), whereas the second population was resistant to both antibiotics (MEM^r/PMB^r). Bacterial killing terms (i.e. arrows) were only included for the effect of meropenem as 1.55 mg/L polymyxin B displayed negligible killing in time–kill experiments. Synergy was implemented by assuming that polymyxin B permeabilized the outer membrane of A. baumannii and thereby enhanced the target site concentration of meropenem. The presence of 1.55 mg/L polymyxin B decreased the meropenem concentration required to achieve half of maximal killing against the meropenem-susceptible and meropenem-resistant populations as listed in Table 2. MEM, meropenem and PMB, polymyxin B.

Figure 2.

Observed (symbols) and model fitted (lines) viable counts for time–kill experiments involving meropenem alone (a–c) and in combination with 1.55 mg/L polymyxin B (d–f) against A. baumannii strains ATCC 19606 (a and d), N16870 (b and e) and 03-149-1 (c and f). MIC values of meropenem are listed for each strain. MEM, meropenem; PMB, polymyxin B. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

PK/PD analyses from the time–kill experiments for each strain plotted as LRA (a–c) or LRC (d–f) as a function of meropenem concentration. Data for meropenem alone are represented by black circles, whereas data for meropenem in combination with 1.55 mg/L polymyxin B are represented by white diamonds. Each plot was fitted with a Hill-type function or linear equation (panels a and c for LRA). Parameter estimates for combination treatments are listed in Table 3. MEM, meropenem; PMB, polymyxin B.

Figure 4.

HFIM counts for the total bacterial population of N16870, as well as polymyxin B- and meropenem-resistant subpopulations, during 14 days of antibiotic exposure in monotherapy and in combination. A polymyxin B regimen simulating 1.43 mg/kg q12h alone was investigated. Meropenem dosing schemes of 2, 4, 6 and 8 g q8h administered as a 3 h prolonged infusion (3 h PI) were investigated as monotherapies and in the presence of the polymyxin B regimen. MEM, meropenem; PMB, polymyxin B; PAPs—counts on agar imbued with meropenem or polymyxin B. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 5.

Observed (symbols) and model fitted (lines) total population counts for strain N16870 investigated in the HFIM. Meropenem was studied as either a 2, 4, 6 or 8 g q8h regimen in the absence (left) or presence (right) of a polymyxin B regimen consisting of 2.22 mg/kg at time 0 h, followed by 1.43 mg/kg q12h thereafter. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 6.

The relationship between meropenem AUC over 24 h and the AUCFUs of the total bacterial populations throughout the 14 day HFIM experiments is shown for meropenem alone (black circles) and meropenem in combination with polymyxin B (white diamonds) in (a), whereas (b) displays the relationship between bacterial killing and the percentage of time the meropenem concentration was >4× the MIC (MIC = 16 mg/L, 4× the MIC = 64 mg/L). Combination regimens were fitted with a Hill-type function, whereas meropenem monotherapies are shown as line plots. PAPs—counts on agar imbued with meropenem.

Figure 7.

Resistance plots that graphically summarize either the beneficial suppression of carbapenem resistance or the deleterious amplification of resistance conferred with meropenem dose escalation. The AUCFU of A. baumannii subpopulations capable of growing on 16 mg/L meropenem (black circles) and 32 mg/L meropenem (white diamonds) throughout the 14 day HFIM experiments were normalized by the AUCFU of the total population for each meropenem regimen. Using Equation (1), the LRAs were then calculated for meropenem monotherapies (a) and polymyxin B combinations (b) and plotted as a function of meropenem 24 h AUC. Increasing meropenem exposure without polymyxin B induced the expansion of meropenem-resistant subpopulations. In contrast, escalating meropenem concentrations in combination with polymyxin B increased meropenem resistance at lower exposures (2 and 4 g q8h regimens) and reduced meropenem resistance at higher exposures (6 and 8 g q8h regimens).