Infectious Diseases II
| (4) | Around 2000, with the emergence of CRE, colistin use was reconsidered, given the |
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lack of treatment options.
| (5) | Dosing challenges |
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| (A) | Different products provide different dosing recommendations. |
| (B) | Colomycin injection is the brand primarily used in Europe. Dosed in international |
units (IU).
| (C) | Coly-Mycin is the brand primarily used in the United States. Dosing in colistin- |
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based activity
| (D) | 3 million IU of colistin is equal to about 100 mg of colistin-based activity. |
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| (6) | PK/PD |
| (A) | All colistin products, regardless of the dosing units, are administered as |
colistimethate, which is a prodrug. Colistimethate is hydrolyzed to the active
drug colistin.
| (B) | Colistimethate is excreted through renal clearance, whereas the active drug |
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colistin is cleared by nonrenal pathways. Hence, renal dysfunction leads to a
higher portion of colistimethate being present for hydrolysis into colistin, thus
increasing the final active drug concentration.
| (C) | PD parameter for maximal activity is area under the curve/MIC ratio. |
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| (D) | In the 1960s, the dosing recommendations and PK/PD parameters were largely |
unknown because the methods for evaluations were drastically different from the
current standards.
| (E) | Recent PK/PD evaluations show that traditional dosing methods are probably |
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insufficient to reach adequate serum concentrations to maximize PD target
attainment.
| (F) | Several studies have reported that a higher colistin dose is associated with |
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significant improvements in clinical outcomes.
| (G) | International consensus dosing recommendations |
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| • | 300 mg colistin base activity loading dose. |
| • | 300-360 mg colistin base activity divided every 12 hours, with adjustments |
made based on renal function / renal replacement therapy.
| (H) | Several ongoing investigations are evaluating the effects of high-dose colistin |
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regimens and the utility of using a loading dose.
| • | One study from South America is recruiting patients to evaluate the utility of a |
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200-mg loading dose.
| • | One study reported a 300-mg loading dose regimen, followed by 150 mg every |
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12 hours. This study was non-comparative, but it reported high rates of clinical
success.
| (7) | Because the PK/PD of colistin is unclear and little is known regarding the optimal |
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dosing regimen, colistin should be reserved for infections in which other treatment
options are not available. In such cases, it may be prudent to administer combination
therapy. Furthermore, many in vitro studies have shown synergy between colistin and
other antimicrobials.
| (8) | Resistance to colistin has been reported. In vitro studies also show that colistin |
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resistance develops quickly, which may be another rationale for providing combination
therapy. Clinicians should verify colistin susceptibility with their local microbiology
laboratory.
| (A) | Routine monitoring of colistin concentrations is currently infeasible. |
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| (B) | According to PK data, an MIC of 2 mcg/mL or less should be considered sensitive. |