Colistin hetero-resistance in multidrug-resistant Acinetobacter baumannii clinical isolates from the Western Pacific region in the SENTRY antimicrobial surveillance programme.

BACKGROUND: Multidrug-resistant Acinetobacter baumannii has presented a global medical problem. Emergence of colistin resistance, including hetero-resistance, has been increasingly reported. This study examined the susceptibility to colistin of multidrug-resistant A. baumannii from the Western Pacific region. METHODS: A total of 30 isolates were studied from 10 clinical centres in various countries. MICs were measured against 21 antibiotics by broth microdilution. Colistin population analysis profiles (PAPs) (0, 0.5, 1, 2, 3, 4, 5, 6, 8 and 10mg/L) were determined. Time-kill kinetics of colistin against 3 isolates (2 colistin-susceptible (one of which was colistin hetero-resistant) and 1 colistin-resistant) were studied over a wide range of concentrations and development of resistance was monitored by measurement of colistin PAPs after 24-h exposure. RESULTS: All the isolates were highly multiresistant. Colistin MICs were 0.5-2mg/L except one isolate which had an MIC of 128mg/L. Seven isolates were colistin hetero-resistant with subpopulations growing at >2mg/L. For the 2 colistin-susceptible isolates examined, >3log killing was observed within 3h even at 0.5x MIC. Interestingly, >3log killing was also observed with the colistin-resistant isolate within 1h even at 0.5mg/L. Regrowth occurred at 24h for both colistin-susceptible and -resistant isolates. Emergence of resistance to colistin after 24-h exposure was confirmed by PAP. CONCLUSION: Colistin was very active against A. baumannii based upon MICs and initial killing in time-kill studies. Hetero-resistance in this group of A. baumannii isolates was less common than in previous studies. Nevertheless, care is required with colistin monotherapy for A. baumannii infections.

In vitro pharmacodynamics of colistin against multidrug-resistant Klebsiella pneumoniae.

BACKGROUND: Resistance to colistin is emerging in multidrug-resistant Gram-negative bacteria and no solid pharmacodynamic data are available for colistin against Klebsiella pneumoniae. METHODS: Twenty-one multidrug-resistant clinical K. pneumoniae isolates from 16 different clinical sites worldwide were employed. The genetic relatedness of these isolates was examined with PFGE. In vitro pharmacodynamic properties of colistin (sulphate) were investigated by studying the MICs, mutation prevention concentrations, time-kill kinetics, population analysis profiles and the post-antibiotic effect (PAE). Time-kill was studied with three clinical isolates plus ATCC 13883 at concentrations ranging from 0.5 to 64x MIC. The PAE was examined after 20 min of exposure of these isolates. RESULTS: The 22 isolates belonged to 18 different PFGE groups. For susceptible isolates, colistin MICs ranged from 0.125 to 1 mg/L. Six isolates were colistin-resistant with MICs of >/=32 mg/L. Colistin heteroresistance was observed in 15 of 16 isolates considered colistin-susceptible based on MICs. For susceptible isolates, colistin showed extremely rapid killing; however, regrowth was observed as early as 2 h after treatment and substantial regrowth at 24 h even at concentrations up to 64x MIC for some isolates. Colistin exhibited no or very modest PAE against the isolates tested. CONCLUSIONS: The data suggest that monotherapy with colistin methanesulfonate, the parenteral form of colistin, and long dosage intervals may be problematic for the treatment of infections caused by multidrug-resistant K. pneumoniae, particularly for colistin-heteroresistant strains. Further investigation on combination therapy of colistin with other antibiotics is warranted.

Antibiograms of multidrug-resistant clinical Acinetobacter baumannii: promising therapeutic options for treatment of infection with colistin-resistant strains.

Multidrug-resistant Acinetobacter baumannii infection has presented a global medical challenge. The antibiograms of paired colistin-susceptible and -resistant strains revealed increased susceptibility of colistin-resistant strains to most tested antibiotics, including those that are active against only gram-positive bacteria. Synergy between colistin and rifampicin was observed in the colistin-susceptible strains. The ability to form biofilm in the colistin-resistant strains was significantly lower (P<.001) than in the parent strains. Our study provides valuable information for potential expansion of our current therapeutic options against colistin-resistant A. baumannii infection.

In vitro pharmacodynamics of colistin against Acinetobacter baumannii clinical isolates.

BACKGROUND: Colistin is being increasingly used for treatment of infections caused by multidrug-resistant Gram-negative bacteria, including Acinetobacter baumannii. METHODS: The in vitro pharmacodynamic properties of colistin (sulphate) were investigated by studying the time-kill kinetics and the post-antibiotic effect (PAE) against multidrug-resistant, including colistin heteroresistant, A. baumannii. Time-kill was studied with four multidrug-resistant clinical isolates at concentrations ranging from 0.5 to 64 x MIC. The PAE was examined after 20 min exposure with five clinical isolates, including the four in the time-kill study, plus ATCC 19606. RESULTS: Colistin showed extremely rapid killing in a concentration-dependent manner; but re-growth was observed as early as 3 h and substantial re-growth at 24 h even at concentrations up to 32 x MIC or 64 x MIC for some isolates. Colistin exhibited modest PAE of 1.0, 2.3 and 3.5 h at 16, 32 and 64 x MIC, respectively, against ATCC 19606. Surprisingly, negative PAE (range: -0.8 to -8.15 h) was observed for all of the five clinical isolates. CONCLUSIONS: These findings suggest that monotherapy with colistin methanesulphonate, the parenteral form of colistin, and long dosage intervals (e.g. 24 h) may be problematic for treatment of infections caused by colistin heteroresistant A. baumannii.

Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii.

Multidrug-resistant Acinetobacter baumannii has emerged as a significant clinical problem worldwide and colistin is being used increasingly as "salvage" therapy. MICs of colistin against A. baumannii indicate its significant activity. However, resistance to colistin in A. baumannii has been reported recently. Clonotypes of 16 clinical A. baumannii isolates and ATCC 19606 were determined by pulsed-field gel electrophoresis (PFGE), and colistin MICs were measured. The time-kill kinetics of colistin against A. baumannii ATCC 19606 and clinical isolate 6 were investigated, and population analysis profiles (PAPs) were conducted. Resistance development was investigated by serial passaging with or without exposure to colistin. Five different PFGE banding patterns were found in the clinical isolates. MICs of colistin against all isolates were within 0.25 to 2 microg/ml. Colistin showed early concentration-dependent killing, but bacterial regrowth was observed at 24 h. PAPs revealed that heteroresistance to colistin occurred in 15 of the 16 clinical isolates. Subpopulations (<0.1% from inocula of 10(8) to 10(9) CFU/ml) of ATCC 19606, and most clinical isolates grew in the presence of colistin 3 to 10 microg/ml. Four successive passages of ATCC 19606 in broth containing colistin (up to 200 microg/ml) substantially increased the proportion of the resistant subpopulations able to grow in the presence of colistin at 10 microg/ml from 0.000023 to 100%; even after 16 passages in colistin-free broth, the proportion only decreased to 2.1%. This represents the first demonstration of heterogeneous colistin-resistant A. baumannii in "colistin-susceptible" clinical isolates. Our findings give a strong warning that colistin-resistant A. baumannii may be observed more frequently due to potential suboptimal dosage regimens recommended in the product information of some products of colistin methanesulfonate.