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Colistin and Polymyxin B testing in Carbapenemase producing Enterobacteriaceae


Carbapenems, such as imipenem and meropenem are often considered as the last resort treatment for nosocomial infections caused by multi-resistant Gram-negative organisms. Hence, the recent reports of resistance to carbapenems in Enterobacteriaceae are of great concern. This  may be mediated by 3 mechanisms: hyperproduction of an AmpC type cephalosporinase combined with decreased drug permeability through the outer membrane, decreased affinity of penicillin-binding proteins that constitute target proteins for carbapenems, and carbapenem-hydrolyzing beta lactamases, the latter being most common. Carbapenem-resistant Enterobacteriaceae (CRE) is usually resistant to all β-lactam agents as well as most other classes of antimicrobial agents such as fluoroquinolones, aminoglycosides, and co-trimoxazole. Several isolates are susceptible to amikacin or gentamicin however most remain susceptible to colistin and tigecycline. Thus the antimicrobial treatment options are very restricted and hence worrisome. Tigecycline is effective but treatment failures have been documented Furthermore, it is not recommended for treating urinary tract infections due to its low urine concentration. This leaves polymyxins (colistin) as the sole therapeutic alternative associated with the need for reliable susceptibility methods to predict the clinical response After being almost forgotten for more than 20 years, the recent increase in the use of colistin is a consequence of emerging multidrug-resistant Gram negative bacteria particularly in intensive care units because of the resultant high mortality rate, and the limited number of therapeutic options available. In the 1970s, the CLSI published the breakpoints of susceptibility for colistin and polymyxin B. However, at that time the procedures for standardization of susceptibility testing, the establishment of interpretative breakpoints and the definition of quality control strain guidelines were less rigorous.
In 2007, the CLSI has again provided guidance for the susceptibility testing of polymyxins in non enterobacteriaceae. However currently there were no CLSI recommendations for Enterobacteriaceae. The BSAC has never provided breakpoints for polymyxin B, possibly because this drug is not available in the UK for systemic administration. Nevertheless, colistin MIC breakpoints are provided for Enterobacteriaceae; ≤4 mg/L as susceptible and ≥8 mg/L as resistant. Because of limited pharmacokinetic and pharmacodynamic data, it is still unclear as to which breakpoint is most appropriate. Hence for colistin / polymyxin, an MIC test should be used and it appears that isolates with MICs ≤2 µg/ml could be considered susceptible. The laboratory should determine if additional testing should be performed following consultation with the patient’s physician. Considering the increasing use of polymyxins to treat infections due to multidrug resistant Gram-negative infections in many countries, it is important to evaluate different susceptibility testing methods to this class of antibiotic.


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