In settings where CR gram-negative bacteria are endemic, colonization and infection rates by these bacteria are high among SOT recipients. Implementation of enhanced ICM in all related units of a hospital, although challenging, reduces colonization rates by CR gram-negative bacteria.

Limited pharmacokinetic (PK) data suggest that currently recommended pediatric dosages of colistimethate sodium (CMS) by the Food and Drug Administration and European Medicines Agency may lead to suboptimal exposure, resulting in plasma colistin concentrations frequently <2 mg/L. We conducted a population PK study in 17 critically ill patients 3 months-13.75 years (median 3.3 years) old, who received CMS for infections caused by carbapenem-resistant Gram-negative bacteria. CMS was dosed at 200,000 IU/kg/d [6.6 mg colistin base activity (CBA)/kg/d, 6 patients], 300,000 IU/kg/d (9.9 mg CBA/kg/d, 10 patients) and 350,000 IU/kg/d (11.6 mg CBA/kg/d, 1 patient). Plasma colistin concentrations were determined using ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry. Colistin PK was described by a one-compartment disposition model including creatinine clearance, body weight and the presence or absence of systemic inflammatory response syndrome (SIRS) as covariates (p<0.05 for each). The average colistin plasma steady-state concentration (Css,avg) ranged from 1.11-8.47 mg/L (median 2.92 mg/L). Ten patients had Css,avg ≥2 mg/L. The presence of SIRS was associated with decreased apparent clearance of colistin (47.8% of that without SIRS). The relationship between the mg/day of CBA to achieve each 1 mg/L of plasma colistin Css,avg and creatinine clearance (mL/min) was described by linear regression with different slopes for patients with and without SIRS. Nephrotoxicity, probably colistin-unrelated, was observed in one patient. In conclusion, administration of CMS at the above doses improved exposure and was well tolerated. Apparent clearance of colistin was influenced by creatinine clearance and the presence or absence of SIRS.

Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) can cause biofilm-related bloodstream infections associated with significant morbidity and mortality worldwide. We investigated the bactericidal activities of colistin (CST), rifampin (RIF), meropenem (MEM), gentamicin (GEN), and tigecycline (TGC) alone and that of CST in combination with RIF, MEM, GEN, or TGC against CR-Kp mature biofilms. Twenty CR-Kp blood isolates were derived from an equal number of bloodstream infections in adult patients. Biofilm formation was assessed by staining with 0.4% crystal violet and measuring the optical density spectrophotometrically at 545 nm. Biofilm damage was measured as the percent reduction of metabolic activity by an XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt] assay. The MIC50 for biofilms was determined as the minimum concentration that caused ≥50% bacterial damage compared to that for untreated controls. Antibacterial drug interactions were analyzed by the Bliss independence model. Four of the 20 CR-Kp isolates were biofilm producers. Biofilm MIC50s of CST, RIF, MEM, GEN, and TGC for these isolates were 64, 8, >256, 128, and 8 mg/liter, respectively. Synergistic interactions were observed at 32 to 64 mg/liter of CST combined with 0.25 to 4 mg/liter of RIF, at 32 mg/liter of CST combined with 0.007 to 0.25 mg/liter of MEM, and at 16 to 32 mg/liter of CST combined with 16 to 64 mg/liter of TGC. The synergy was highest for CST plus RIF, with a mean ΔE ± standard error (SE) of 49.87% ± 9.22%, compared to 29.52% ± 4.97% for CST plus MEM (P < 0.001) and 32.44% ± 6.49% for CST plus TGC (P < 0.001). Indifferent results were exhibited by CST plus GEN. None of the combinations exhibited antagonism. These drug interaction findings, especially those for CST with RIF, may be of importance in the treatment of biofilm-related CR-Kp infections.

No abstract

The presence of different antimicrobial susceptibility profiles does not preclude the possibility that two CR K. pneumoniae or A. baumannii isolates are clonally related.