Meropenem for treating KPC-producing Klebsiella pneumoniae bloodstream infections: Should we get to the PK/PD root of the paradox?

Abstract

The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) ≥16 mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2 g every 8 hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1×MIC and T > 40% 4×MIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024 mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1×MIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64 mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32 mg/L.

Mortality Associated with Bacteremia Due to Colistin-Resistant Klebsiella pneumoniae with High-Level Meropenem Resistance: Importance of Combination Therapy without Colistin and Carbapenems

“…These data suggest that meropenem would be ineffective when the strain exhibits high-level resistance. In fact, meropenem (2 g every 8 h in extended infusion) did not reach any pharmacokineticpharmacodynamic target in 19 patients with infections due to KPC-producing K. pneumoniae with meropenem MICs of Ͼ16 mg/liter in a recent study (16). Additionally, a recent study found a higher rate of failure for the carbapenem-colistin combination in patients with KPC-producing K. pneumoniae bacteremia caused by isolates highly resistant to colistin and doripenem (17).…”

Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae

“…This means that screening approaches in these settings should include broth microdilution methods (29,30), with a cutoff MIC for meropenem of 64 mg/liter (14). This may allow identifying the proportion of strains with an MIC of Յ64 mg/liter for meropenem, whose frequency may vary greatly from hospital to hospital (13,31,32). It is worth noting that the frequency was as high as 89.3% among the 169 KPC-Kp clinical isolates included in this study.…”

“…Data from Tumbarello et al (4) and Daikos et al (9) support the supposition that an EI of meropenem at 6 g/day may work in these cases, with a higher mortality rate when MICs are higher. The possibility that this approach might be feasible even against KpC-Kp infections due to strains with higher meropenem MICs is still to be demonstrated (12,13). In this regard, we recently showed that high-dose CI (HDCI) meropenem, in combination with other antimicrobials with activity against Gram-negative bacteria, was effective in the treatment of KPC-Kp infections (mainly of the bloodstream) due to strains with a meropenem MIC of up to 64 mg/liter (14).…”

Dose Optimization of Colistin Combinations against Carbapenem-Resistant Acinetobacter baumannii from Patients with Hospital-Acquired Pneumonia in China by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model

“…However, it is controversial to use %T ϾMIC (40%) as the target. It was reported in the clinical study that %T Ͼ4MIC should be over 40% to achieve clinical success (25,26). This study showed meropenem 2 g with 8-h infusion (%T ϾMIC , 90%) combined with colistin did not show better efficacy at 24 h compared with 3-h infusion (%T ϾMIC , 51%) using apparent MIC calculation for each regimen.…”

“…In this study, the maximum concentrations of meropenem regimen with 1 g and 2 g with 3-h prolonged infusion reached 16.5 and 32.9 mg/liter (24). It is very hard to achieve the PK/PD target for the highly resistant strains with an MIC of Ն32 mg/liter (25). The synergistic combination therapy can decrease the apparent MICs of both antibiotics and, therefore, increase the possibility of reaching targets for A. baumannii.…”