Data supporting dosing recommendations for CMS from prospective studies continue to be scarce. Although some data describing the PK of CMS and formed colistin in critically ill patients are available (29
), the studies included only 14 and 18 patients, respectively, and all 32 patients had creatinine clearance values greater than 40 ml/min; none of the patients was in receipt of renal replacement therapy. Thus, the patient populations were not representative of the full range of critically ill patients who may require intravenous administration of CMS for treatment of a Gram-negative infection. Neither of these previous studies (29
) provided maintenance dosing suggestions for CMS in critically ill patients. The current study describes the disposition of the prodrug, CMS, and formed colistin in 105 critically ill patients, including 12 on intermittent hemodialysis and 4 on continuous renal replacement therapy. Of the 105 patients, 69 had CrCL of less than 40 ml/min/1.73 m2
. Based upon population PK analysis and a thorough search for covariates in the disposition of CMS and formed colistin, we have been able to develop dosing suggestions for various categories of critically ill patients.
Across the two previous PK studies of critically ill patients (29
), 30 patients received a CMS dose of 9 million units (MU) per day, while the remaining two patients received 6 and 4 MU per day; this corresponds to a range of CBA doses of about 120 to 270 mg/day, although clearly the majority of patients received the highest dose. In the present study, there was about a 5.5-fold range in the physician-selected daily dose of CMS (75 to 410 mg CBA) across the patients, with a clear trend for lower doses to be prescribed for patients with low CrCL (A). There was an ~20-fold range in the AUC0-24
and corresponding Css,avg
values for formed colistin (B; see also B). Close examination of the data in both panels of is instructive. First, it reveals the important role of renal function as a determinant of the plasma concentrations of the active antibacterial, formed colistin; as discussed below, CrCL was an important covariate in the population PK model developed in this study. Second, it is evident that in patients with moderate to good renal function, administration of a daily dose of CBA at the upper limit of the current product-recommended dose range (300 mg CBA per day) (2
) was not able to generate plasma colistin concentrations that would be expected to be reliably efficacious.
Our final (best-fit) population PK model was linear, with two compartments for CMS and one compartment for colistin. This structural model was similar to that used by Plachouras et al. (31
) to describe the disposition of CMS and formed colistin in 18 critically ill patients; in the study by Markou et al. (29
), plasma concentrations of formed colistin only were quantified in 14 patients and the resultant concentration-time profiles were subjected to noncompartmental analysis. In the current population PK analysis, the volume of the central compartment for CMS was modeled as a function of weight and, as discussed in more detail below, the clearances for CMS and colistin were modeled as functions of CrCL. The volume of distribution and clearance of formed colistin were conditioned on fm, which in the current analysis represents the unknown fraction of the nonrenal clearance of CMS resulting in formation of colistin. In the study by Plachouras et al. (31
), the reported clearance and volume of distribution for colistin were conditioned on a different fm, the fraction of the total CMS dose that was converted to colistin. The results from the current and previous study agree well when we adjust the fm in our study to mirror the one used by Plachouras et al. (31
); under these circumstances, in patients with CrCL values of at least 40 ml/min/1.73 m2
, the geometric mean apparent clearance of colistin in our study was 10.8 liters/h with an intersubject variability of 76.5%, compared to 9.09 liters/h with an intersubject variability of 59% in the earlier study (31
Renal function, expressed as CrCL, was an important covariate for the clearance of both CMS and colistin in our population PK model. In renally healthy individuals, the prodrug, CMS, is predominantly cleared by renal excretion, with only a relatively small fraction of a dose converted to the active antibacterial, colistin (23
); thus, total clearance of CMS is expected to decline with CrCL. At first thought it may seem surprising that CrCL was an important covariate for the clearance of formed colistin, because following direct administration of colistin in animal studies, it is cleared predominantly by nonrenal mechanisms, with only a very small fraction of the administered dose recovered in urine in unchanged form (24
). The explanation for CrCL being a covariate for the apparent clearance of formed colistin in this study lies in the somewhat unusual overall disposition of CMS and formed colistin. As mentioned above, only a small fraction of an administered dose of CMS is converted to colistin (23
); since CMS is cleared predominantly by renal excretion, as CrCL declines a progressively larger fraction of a dose of CMS will be converted to colistin, although we cannot discount the possibility of an associative decrease in the actual clearance of colistin as renal function declines. The practical consequence of this rather complex interplay of dispositional processes for administered CMS and formed colistin and the impact of renal function thereon are clearly evident in . Not surprisingly, CrCL was the major PK factor involved in the CMS maintenance dosing algorithm for generation of a target plasma concentration of formed colistin (, equation 10). Neither of the previous PK studies of critically ill patients found CrCL to be a covariate for the clearance of formed colistin (29
); similarly, CrCL was not a covariate for the clearance of administered CMS (31
). It is very likely that the inability to detect relationships between renal function and clearances of CMS and colistin in the previous studies was the result of the small sample sizes (14 and 18 patients) and the relatively narrow range of CrCL values (>40 ml/min) for the enrolled patients (29
). We also found body size to be a relevant covariate affecting the volume of the central compartment for CMS; as a consequence, suggested CMS loading doses are a function of body weight (). We did not, however, find any significant trends in clearance of either CMS or colistin against body size, and thus we were not able to propose a weight-based maintenance dosing algorithm for CMS.
Since the physician-selected CMS maintenance doses in this study provided a substantive variance in AUC0-24 (and corresponding Css,avg) for colistin (), we developed a dosing algorithm incorporating renal function to estimate the suggested CMS maintenance dose (expressed as mg CBA per day) required to reach a target Css,avg for colistin (, equation 10). CrCL as a covariate explained ~60% of the variability in the “ideal” maintenance dose of CBA required to achieve a given target Css,avg for colistin (). Further improving on this precision would require identification of additional PK covariates and/or development of an adaptive feedback control algorithm for colistin (individual optimization based on PK/PD/TD principles). The maintenance dosing algorithm performed satisfactorily when it was applied to patients not on any renal replacement and those on HD, using a colistin Css,avg target of 2.5 mg/liter, corresponding to a steady-state colistin AUC0-24 of 60 mg·h/liter. Similarly, the suggested CMS maintenance dose for patients on CRRT () performed well when applied to the 4 patients in this category.
It is noteworthy that the CMS maintenance dose required to achieve each 1.0 mg/liter of the colistin Css,avg
target in patients on CRRT (192 mg CBA per day) () is very similar to that required in a patient with a CrCL of ~100 ml/min/1.73 m2
(, equation 10). This may seem surprising given that colistin is predominantly nonrenally cleared in individuals with normal kidney function (26
). The explanation most likely relates to the mechanisms involved in the renal handling of colistin in the presence of intact kidney function in comparison with the extracorporeal clearance mechanisms in operation in CRRT. The renal handling of colistin involves very extensive tubular reabsorption; this serves to retain in the body a very large fraction of the filtered load of colistin, and it contributes to an extremely low fraction excreted unchanged in urine (24
). In contrast, following clearance by diffusion and/or convection in a CRRT cartridge, there is no carrier-mediated mechanism to return colistin from dialysate to blood perfusing the cartridge.
This and other (15
) studies have also shown that CMS and colistin are efficiently cleared during intermittent HD; the magnitudes of extracorporeal clearances of CMS and colistin in this study are in accord with those reported elsewhere (15
). Even when a dialysis session occurs toward the end of a CMS dosage interval, a substantial amount of CMS and colistin would be cleared, necessitating a supplemental dose of CMS to maintain a colistin Css,avg
similar to that occurring on a nondialysis day; a larger supplemental dose would be required if administered during dialysis compared with dosage after the session (). Because of the large fluctuations in plasma CMS concentrations during a dosage interval (), a much larger amount of CMS would be cleared if dialysis occurs early in a dosage interval. For this reason, it is suggested that dialysis is best conducted toward the end of a CMS dosage interval.
It is important to provide caveats about the loading and maintenance dose suggestions for CMS in . When computing the absolute loading dose of CBA from the result of applying equation 9 (), the lower of either the actual or ideal body weight should be used. In addition, there is little experience with using (single daily) doses of CMS greater than the current upper limit in the product information (300 mg CBA), and the potential impact of large loading doses of CMS on renal function is not known. Thus, at this time we suggest caution in the use of a loading dose greater than 300 mg CBA. In relation to suggested maintenance doses, the algorithm (, equation 10) predicts the need for increasingly high CMS maintenance doses as CrCL increases, and dependent upon the desired colistin Css,avg
, this may generate suggested CMS daily doses above the upper limit (300 mg CBA per day) in the current product labeling (2
). For example, if targeting a colistin Css,avg
of 2.5 mg/liter, a patient with a CrCL of 70 ml/min/1.73 m2
would require 337.5 mg CBA per day. In such patients (i.e., with moderate to good renal function), it is theoretically possible to use daily doses of CMS higher than 300 mg CBA per day to generate a desired target colistin Css,avg
similar to those occurring with lower maintenance doses of CMS in patients with poorer kidney function (). However, increasing the daily dose of CBA beyond the current upper limit daily dose in patients with relatively good renal function comes at the expense of presenting a larger mass of CMS to the kidneys, with the potential for intrarenal conversion to colistin (23
), which may increase the possibility of nephrotoxicity. This is not an insignificant risk given the rate of nephrotoxicity even with the currently recommended CMS dosage regimen. In the present study, of the 89 patients not on renal replacement, all but two had been prescribed a CMS maintenance dose of 300 mg CBA per day or less, and 43/89 (48%) had a rise in serum creatinine of >50%, of which, for 27/43 (63%), levels remained elevated at the end of the study; these findings are similar to those reported for other studies (10
). Thus, care is needed in the use of the maintenance dosing algorithm for patients with moderate to good renal function and/or when it is desired to target a relatively high colistin Css,avg
target, circumstances where the algorithm-suggested daily dose of CBA may be substantially greater than 300 mg/day. At this time, we do not recommend use of the algorithm for patients with CrCL of >70 ml/min/1.73 m2
unless it is appropriate to target a low Css,avg
The PK data for critically ill patients obtained in the current study were integrated with PD data for A. baumannii
and P. aeruginosa
in murine thigh and lung infection models (12
). In undertaking these translational analyses, because of the absence of information on plasma binding of colistin in critically ill patients, we utilized PD parameter estimates for total (i.e., unbound plus bound) colistin in plasma in the murine models and linked them with the colistin Css,avg
(i.e., total plasma concentration) expected to be achieved in the individual critically ill patients from algorithm-predicted maintenance doses targeting a colistin Css,avg
of 2.5 mg/liter. This approach assumes that the “average” unbound fraction in infected mice is similar to that in infected humans. We chose a colistin Css,avg
of 2.5 mg/liter (corresponding to a target AUC0-24
of 60 mg·h/liter) for two reasons: first, it was similar to the median Css,avg
of 2.36 mg/liter in the 105 patients with the physician-selected maintenance doses of CMS; second, against 3 strains each of A. baumannii
and P. aeruginosa
in murine thigh and lung infection models, a ratio of AUC0-24
to MIC of 60 was generally associated with an effect somewhere between stasis and 1-log kill, with the exception of P. aeruginosa
in thigh infection, where a smaller effect was observed (unpublished data from references 12
for data based on the total plasma colistin concentration). From the results of these analyses, it appears that the above maintenance doses (and resultant colistin Css,avg
) would not be reliably effective against isolates with MICs greater than 0.5 mg/liter ( and ). It is our opinion that in order to achieve dosage regimens with a high probability of safety and efficacy, it appears that colistin might best be used as part of a highly active combination. This is especially likely to be the case for patients with moderate to good renal function, for whom, as discussed above, it is not possible to achieve colistin Css,avg
values that are likely to be reliably effective without administration of maintenance doses of CMS which may increase the risk of nephrotoxicity.
In conclusion, this is the first study to report the results of population PK modeling for more than 100 critically ill patients with a diverse range of renal functions, including those requiring intermittent hemodialysis or continuous renal replacement therapy. Our modeling revealed that creatinine clearance was an important covariate in the clearance of both CMS and formed colistin. As a result, we have developed the first scientifically based dosing suggestions for CMS to generate a desired target steady-state plasma concentration of formed colistin in various categories of critically ill patients. Our current results suggest that because of the inability to achieve adequate plasma concentrations of formed colistin with CMS monotherapy, CMS/colistin might best be used as part of a highly active combination, especially when treating an infection caused by an organism with an MIC of >0.5 mg/liter in a patient with a creatinine clearance of >70 ml/min/1.73 m2. The loading and maintenance dosing suggestions reported herein should be regarded as interim; they will be refined as we complete recruitment to a total of 238 critically ill patients and also model the pharmacodynamic and toxicodynamic endpoints.