JAC Advance Access originally published online on January 28, 2008
Journal of Antimicrobial Chemotherapy 2008 61(3):636-642; doi:10.1093/jac/dkm511
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Original research |
Comparison of once-, twice- and thrice-daily dosing of colistin on antibacterial effect and emergence of resistance: studies with Pseudomonas aeruginosa in an in vitro pharmacodynamic model
1 Facility for Anti-infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University, Melbourne, Australia 2 Division of Laboratory Medicine, Women's and Children's Hospital, North Adelaide, Australia 3 Department of Pharmacy, Women's and Children's Hospital, North Adelaide, Australia 4 Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
* Corresponding author. Tel: +61-3-9903-9061; Fax: +61-3-9903-9629; E-mail: roger.nation{at}vcp.monash.edu.au
Received 13 June 2007; returned 24 October 2007; revised 3 October 2007; accepted 4 December 2007
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Abstract |
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Objectives: The optimal dosing regimen for colistin methanesulphonate (CMS) against Pseudomonas aeruginosa is unknown. CMS is converted in vivo to its active form, colistin. We evaluated three colistin dosage regimens in an in vitro pharmacokinetic/pharmacodynamic model.
Methods: Three intermittent dosage regimens involving 8, 12 and 24 h dosage intervals (Cmax of 3.0, 4.5 or 9.0 mg/L, respectively) were employed. Antibacterial activity and emergence of resistance were investigated over 72 h using two strains of P. aeruginosa: ATCC 27853 and 19056. The areas under the killing curves (AUBC0–72) and population analysis profiles (AUCPAP) were used to compare regimens.
Results: No difference in bacterial killing was observed among different regimens. For ATCC 27853, substantial killing was observed after the first dose with less killing after subsequent doses irrespective of regimen; regrowth to between 5.95 and 7.49 log10 cfu/mL occurred by 72 h (growth control 7.46 log10 cfu/mL). AUCPAPs at 72 h for the 12 hourly (4.08 ± 1.54) and 24 hourly (4.16 ± 2.48) regimens were substantially higher than that for both the growth control (1.63 ± 0.08) and 8 hourly regimen (2.30 ± 0.87). For 19056, bacterial numbers at 72 h with each regimen (1.32–2.75 log10 cfu/mL) were far below that of the growth control (7.79 log10 cfu/mL); AUCPAPs could not be measured effectively due to the substantial killing.
Conclusions: No difference in overall bacterial kill was observed when the recommended maximum daily dose was administered at 8, 12 or 24 h intervals. However, the 8 hourly regimen appeared most effective at minimizing emergence of resistance.
Keywords: colistin methanesulphonate , dosage regimens , pharmacokinetics , pharmacodynamics , multidrug resistance
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Introduction |
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The world is facing a growing threat from multidrug-resistant (MDR) microorganisms, especially Gram-negative bacteria,1–3 and several institutions have already experienced outbreaks of MDR Gram-negative bacteria resistant to all commercially available antibiotics except the polymyxins.4–8 The result has been the increasing use of colistin (also known as polymyxin E) as an agent of last resort for treating infections caused by MDR Gram-negative organisms.4,9–11 However, knowledge of the pharmacokinetics (PK) and pharmacodynamics (PD) of colistin is limited, and resistance to the polymyxins has recently emerged.12–16 With few new therapeutic options becoming available in the foreseeable future, particularly for Pseudomonas aeruginosa,2 solid PK/PD data on colistin are urgently needed. Such information will be crucial in determining optimal dosing strategies to maximize the clinical benefit of, minimize the development of resistance to, and prolong the usefulness of this increasingly important therapeutic option.
Colistin is available commercially as colistin sulphate (hereafter referred to as colistin) and sodium colistin methanesulphonate (CMS). Owing to reduced toxicity when compared with colistin,17,18 CMS is used parenterally whereas colistin is primarily used topically. The formation of colistin in vivo following parenteral administration of CMS has been demonstrated in both rats19 and humans.20,21 Recently, we established that CMS is an inactive prodrug of colistin.22
Due to the limited knowledge of the PK and PD of colistin and CMS, confusion surrounds the optimal dosing regimen that maximizes antibacterial activity and minimizes the emergence of resistance.8,10 At present, 8,7,23–25 1224 and 24 hourly26,27 dosage regimens of CMS are all used clinically in patients with normal renal function. The aim of this study was to evaluate the PD of colistin against P. aeruginosa in terms of antibacterial activity and emergence of resistance. This was achieved by simulating, in an in vitro PK/PD model, the PK of colistin formation in humans administered three clinically relevant dosage regimens of CMS, including the currently recommended regimens.28,29 Given that the antibacterial activity of CMS results from its hydrolysis to colistin,22 the PK/PD parameters used to describe the activity of ‘colistin’ must be based on the concentrations of colistin present, not CMS. The PK parameters (Cmax and t1/2) used in our studies were based on reliable clinical PK data for colistin.30 This study was not designed to determine the optimal PK/PD index for colistin.
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Bacterial strains and media
Two strains of P. aeruginosa were employed in this study: a reference strain, ATCC 27853 (American Type Culture Collection, Rockville, MD, USA) and a clinical isolate, 19056 (mucoid) from a patient with cystic fibrosis. The MICs of colistin (sulphate), as determined by broth microdilution,31 were 1 mg/L for ATCC 27853 and 0.5 mg/L for 19056; both strains were stored in tryptone soy broth (Oxoid Australia, West Heidelberg, Victoria, Australia) with 20% glycerol (Ajax Finechem, Seven Hills, NSW, Australia) at –80°C in cryovial storage containers (Simport Plastics, Boloeil, Quebec, Canada). Prior to each experiment, strains were subcultured onto horse blood agar (Media Preparation Unit, The University of Melbourne, Parkville, Australia) and incubated at 35°C for 24 h. One colony was then selected and grown overnight in 10 mL of cation-adjusted Mueller–Hinton broth (CAMHB; Oxoid, Hampshire, England) from which early log-phase growth was obtained.
Colistin sulphate was purchased from Sigma-Aldrich (Lot: 095K1048, St Louis, MO, USA; 20 195 U/mg). Immediately prior to each experiment, colistin stock solutions were prepared using Milli-Q water (Millipore Australia, North Ryde, NSW, Australia), sterilized by a 0.22 µm Millex-GP filter (Millipore, Bedford, MA, USA), and then stored at 4°C before use; colistin is stable under these conditions.32 All other chemicals were from suppliers previously described.33
The studies examined the effect of three different colistin dosing regimens (discussed subsequently) on microbiological response and emergence of resistance and were conducted over 72 h using a one-compartment in vitro PK/PD model. Briefly, the system consisted of four sealed reservoirs (compartments) each containing 100 mL of CAMHB (Ca2+ 23.0 mg/L and Mg2+ 12.2 mg/L) and a magnetic stir bar to ensure adequate mixing. Each experiment was conducted using three replicates, with the remaining (drug-free) reservoir acting as a control to define growth dynamics in the absence of colistin. All reservoirs were heated in paraffin oil to 37°C throughout the experiment. A peristaltic pump (Masterflex® L/S®, Cole-Parmer, USA) was used to deliver sterile (drug-free) CAMHB from a separate sealed reservoir into each of the four compartments at a predetermined rate (0.3 mL/min), displacing an equal volume of CAMHB into a waste receptacle. This produced a t1/2 of 4 h for colistin administered into the central reservoirs; this approximates the t1/2 determined in cystic fibrosis patients with normal renal function.20 At the beginning of each experiment, a 1.0 mL aliquot of early log-phase bacterial suspension, obtained from overnight culture, was inoculated into each reservoir giving 
106 cfu/mL. Colistin was administered to each treatment reservoir to achieve the desired Cmax as described below and in Table 1. Serial samples (1 mL) were collected aseptically from each reservoir via a rubber septum-sealed port for viable cell counting and population analysis profiles (PAP), as well as determination of colistin concentrations (discussed subsequently).
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Three intermittent colistin dosage regimens were simulated (Table 1). At the beginning of each experiment, the appropriate loading dose of colistin (sulphate) was injected into three of the four reservoirs followed by intermittent maintenance doses at 8, 12 or 24 h intervals. The 8 hourly dosage regimen closely simulated the expected plasma unbound peak (Cmax = 3 mg/L)20 and trough (Cmin = 0.75 mg/L) concentrations of colistin at steady state when CMS is administered 8 hourly according to the manufacturer's recommendations [5 mg/kg/day of colistin base activity; Coly-MycinTM M Parenteral package insert (Monarch Pharmaceuticals, Bristol, TN, USA)] in patients with normal renal function. The 12 and 24 hourly dosage regimens were designed to achieve higher Cmax values (Table 1) with extended dosage intervals.
Microbiological response and the emergence of resistance to colistin
Sampling times are shown in Table 1. Viable counting and PAP were conducted immediately after sampling by spiral plating (WASP2 spiral plater, Don Whitley Scientific Ltd, UK) 50 µL of appropriately diluted sample (using 0.9% saline) onto either nutrient agar (viable counting in in vitro PK/PD model) or Mueller–Hinton agar (PAP), followed by incubation at 35°C for 24 h. PAP plates were impregnated with colistin (sulphate) at 0, 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 mg/L; these concentrations were chosen after consideration of the MICs and the colistin concentrations typically achievable in plasma after intravenous CMS administration in patients.20 Enumeration was performed using a ProtoCOL colony counter (Don Whitley Scientific Ltd); the limit of detection was 20 cfu/mL.
Determination of colistin concentration in CAMHB
Samples (250 µL) collected from the in vitro PK/PD experiments were placed in 1.5 mL microcentrifuge tubes (NeptuneTM, CLP, Mexico) and immediately stored at –80°C until analysis. Concentrations of colistin were measured using HPLC.33,34 The assay range for colistin was 0.10–6.00 mg/L; samples were diluted when the expected colistin concentrations were higher than the upper limit of quantification. Analysis of quality control samples with nominal concentrations of 0.40 and 4.00 mg/L had measured concentrations of 0.34 ± 0.03 mg/L (n = 26) and 4.27 ± 0.29 mg/L (n = 26), respectively; a quality control sample with nominal concentration of 9.00 mg/L was used to assess the accuracy and reproducibility of the dilution step and had a measured concentration of 9.51 ± 0.13 mg/L (n = 6).
Microbiological response to each regimen was examined graphically and quantified by calculation of the area under the killing curve of log10 cfu/mL from 0 to 72 h (AUBC0–72); this area was normalized by dividing by the initial inoculum (i.e. log10 cfu/mL at time zero). Changes in the PAP for ATCC 27853 were examined descriptively and quantified by calculating the area under the PAP curve (AUCPAP) normalized by the respective PAP inoculum.AUBC0–72 and AUCPAP were calculated using the linear trapezoidal rule. Unless otherwise indicated, data are expressed as mean ± SD.
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Colistin concentrations achieved for each simulated dosage regimen
For the 8, 12 and 24 hourly dosage regimens (Table 1), the mean measured concentrations immediately after dosing were 3.44 ± 0.38 (n = 6), 4.63 ± 0.34 (n = 6) and 9.30 ± 1.58 (n = 6) mg/L for the targeted Cmax values of 3.0, 4.5 and 9.0 mg/L, respectively. The mean colistin t1/2 across all experiments determined from the measured concentrations was 4.13 ± 0.49 h (n = 18) for the targeted value of 4 h.
The time-course profiles of bacterial numbers achieved with all dosage regimens for each strain are shown in Figure 1. Substantial differences in total killing were observed between the two strains, with the clinical isolate 19056 exhibiting greater kill than ATCC 27853. All dosing regimens for both strains resulted in extensive bacterial killing to the limit of detection (>5 log10 reduction in cfu/mL) within 1–2 h of the first administration of colistin.
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For ATCC 27853, regrowth after the initial administration of colistin occurred within 6 h with all regimens (Figure 1a), despite the colistin concentrations at this time (
1.0, 1.6 and 3.2 mg/L for the 8, 12 and 24 hourly dosage regimens, respectively) remaining at or above the MIC of 1 mg/L. Although bacterial numbers declined after each subsequent administration of colistin, the extent of the decrease was less and generally never attained the undetectable levels observed following the first colistin dose. In addition, following the small decrease in bacterial numbers, regrowth occurred after each dose, as was observed after the first dose. At 72 h, bacterial numbers for the 24 hourly dosage regimen were virtually superimposable with those for the growth control, whereas those for the 8 and 12 hourly regimens were 1.5 and 0.7 log10 cfu/mL below the control, respectively (Figure 1a). The general similarities in time-courses for bacterial response to each regimen are reflected in small differences in AUBC0–72 values (Table 2).
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Compared with ATCC 27853, regrowth for clinical isolate 19056 occurred more slowly after initiation of all colistin regimens and to a much lower extent (Figure 1b). It was not possible to detect regrowth with any of the regimens until 24 h. Thereafter, regrowth of bacteria was detected with each regimen. At 72 h, the cfu/mL for all regimens were >5 log10 lower than for the corresponding growth control (Figure 1b). At the end of the treatment period, the maximum difference in cfu/mL between the three dosage regimens was
1.25 log10 units. The general similarities in time-courses for bacterial response to each regimen are again reflected in small differences in AUBC0–72 (Table 2). Emergence of resistance to colistin
For both ATCC 27853 (Figure 2) and the clinical isolate 19056 (data not shown), the PAP after exposure to the conditions within the in vitro model for 72 h, but in the absence of colistin (i.e. growth controls), closely matched those observed at time zero (baseline). At baseline or following 72 h incubation in the model for ATCC 27853, no sub-populations able to grow in the presence of 4 mg/L colistin and above were detected; for clinical isolate 19056, the corresponding value was 0.5 mg/L. The AUCPAPs at baseline and 72 h for clinical isolate 19056 were 0.50 ± 0.04 (n = 3) and 0.85 ± 0.22 (n = 3), respectively.
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The emergence of resistance in ATCC 27853 during treatment with colistin is shown in the PAP (Figure 2); also included in the figure are the AUCPAPs. For the 8 hourly dosage regimen, no growth was detected above 4 mg/L colistin at 48 h, whereas by 72 h, the growth was detected in the presence of colistin up to 6 mg/L (Figure 2a). For the 12 hourly dosage regimen, no growth was detected above 3 mg/L at 48 h; at 72 h, there was a very substantial change in the PAPs (Figure 2b) such that
0.14% of the population was able to grow at 4 mg/L and growth was detected at 10 mg/L. For the 24 hourly dosage regimen, the PAP curve after 48 h moved to the right and growth was detected in the presence of 5 mg/L colistin (Figure 2c). By 72 h, there was evidence of further emergence of resistance with growth detected in the presence of 10 mg/L colistin. For clinical isolate 19056, no growth was detected in the PAP at any colistin concentration for any of the dosage regimens (data not shown). |
Discussion |
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A lack of information on the PK and PD of colistin and CMS has led to confusion regarding the optimal dosing schedule.10 The product information for CMS recommends a maximum daily dose of 5 mg/kg/day (colistin base activity) in two to four divided doses in patients with normal renal function,28,29 although once-daily dosing has also been reported recently.26,27 Simulated regimens in the in vitro PK/PD model were chosen based on the PK of colistin generated from CMS in humans with normal renal function20 and allowed for an unbound fraction of colistin in human plasma of approximately 0.5 (P. J. Bergen, J. Li and R. L. Nation, unpublished results). Thrice-daily dosing (8 h dosage interval, Table 1) is the regimen most commonly reported in the literature.7,9,23–25,35,36 A larger unit dose of colistin was administered to simulate a 12 h dosage interval24 (Table 1). A 24 h dosage interval (Table 1) simulated a regimen which has recently been used clinically26,27 but has no corresponding recommendation for renally healthy patients in the product information.
Both bacterial strains were susceptible to colistin prior to drug exposure (MICs 1 and 0.5 mg/L for ATCC 27853 and 19056, respectively), and each dosage regimen produced colistin concentrations that exceeded the MIC for substantial percentages of the dosage interval (Table 1). With each strain, the first exposure to colistin caused rapid and extensive killing to the limit of detection (Figure 1). However, regrowth was observed with all regimens. For ATCC 27853, regrowth was detected with each regimen no later than 6 h after the initial administration of colistin, despite the concentrations at this time (1.0, 1.6 and 3.2 mg/L for 8, 12 and 24 hourly dosage regimens, respectively) remaining at or above the MIC of 1 mg/L. For the clinical isolate 19056, the initial killing activity of colistin was more sustained, which is consistent with its lower MIC (0.5 mg/L). Simulated colistin concentrations with the 8 and 12 hourly dosage regimens remained above the MIC for this isolate throughout the treatment period (Table 1), whereas with the 24 hourly regimen, the MIC was exceeded for 17 h (70%) of the dosage interval; the pattern of regrowth seen with this regimen, however, was not dissimilar to that of the other regimens. Indeed, regrowth with the 24 hourly regimen was detected 6 h after the 48 h dose, when colistin concentrations were significantly above the MIC (6.4x MIC). Thus, regrowth of the clinical isolate occurred with all regimens in the presence of colistin concentrations above the MIC, as was the case with the reference strain.
For each strain, overall bacterial killing and regrowth throughout the experimental period were generally similar among the three regimens (Figure 1 and Table 2). The AUC/MIC ratios for each strain were similar across each regimen, whereas the corresponding Cmax/MIC and t > MIC values differed substantially (Table 1). Although this study was not designed to elucidate the PK/PD index most closely related to antibacterial effect of colistin, the similar time-courses of overall bacterial numbers suggest that AUC/MIC is likely to be more important than Cmax/MIC and t > MIC. The same conclusion was reached for polymyxin B from studies conducted in an in vitro PK/PD model with once-, twice- and thrice-daily dosing against P. aeruginosa.37 Appropriately designed studies will be required to differentiate more definitively among the three PK/PD indices as the determinant of overall antibacterial effect.
The similarity of the time-courses of overall bacterial numbers across the regimens for a given strain may lead to the conclusion that the three regimens were equally effective. The PAP, however, provided very important information on the relative emergence of resistance across the treatment period with the three regimens. With PAP, the similarity of the profiles generated in control groups for both strains at baseline and 72 h demonstrated that incubation in the in vitro model in the absence of colistin did not appreciably alter the proportion of resistant sub-populations. In contrast to growth controls, the proportion of resistant sub-populations present in the reference strain following colistin administration varied with both time and regimen. We recognize that interpretation of PAP may be influenced by inoculum. As the bacterial numbers at 24 h with each regimen were substantially lower than for any other PAP samples, it is not possible to make meaningful comparison between this and other time points. In contrast, in those cases where there was a substantial change in the PAP, indicated by a ‘shift to the right’ and reflected by increases in AUCPAPs, the PAP inoculum was close to that of the corresponding growth controls. At 48 h, resistant sub-populations were found only with the 24 hourly dosage regimen, where growth was detected at 5 mg/L colistin (Figure 2c); the ratios of AUCPAP for the 8, 12 and 24 hourly dosage regimens to the AUCPAP for growth control at 48 h (data not shown in Figure 2) were 1.06, 1.08 and 1.95, respectively. By 72 h, resistant sub-populations were present with each regimen, but to a lesser extent with the conventional 8 h dosage interval (AUCPAP ratios of 1.41, 2.50 and 2.55 for 8, 12 and 24 h dosage intervals, respectively). Due to the low bacterial numbers present at 24, 48 and 72 h for the clinical isolate, it was not possible to use PAP to determine whether resistant sub-populations emerged.
Although the three colistin regimens led to generally similar patterns of overall bacterial numbers across the 72 h treatment period, the PAP for ATCC 27853 revealed that the emergence of resistant sub-populations increased as the dosage interval for colistin increased. Tam et al.37 examined the antibacterial effect of polymyxin B against P. aeruginosa using three dosage regimens analogous to those of the present study (once, twice and thrice daily) in an in vitro PK/PD model. Although the extent of overall regrowth after 4 days of polymyxin B dosing was similar for each regimen, the proportion of the total population that was resistant (defined as ability to grow at 3x MIC) was substantially lower for the thrice-daily regimen when compared with the other two regimens. Although the latter observation was not commented upon,37 it is in agreement with the findings of the present study with colistin, i.e. that a longer dosage interval is associated with greater emergence of resistant sub-populations.
Despite exhibiting concentration-dependent killing, colistin possesses little or no post-antibiotic effect (PAE) at clinically relevant concentrations.30 In the present study, as the dosage interval increased, colistin concentrations remained above the MIC for a smaller proportion of the treatment period (Table 1). For ATCC 27853, colistin concentrations with the 8, 12 and 24 hourly dosage regimens remained above the MIC for 80%, 72% and 53% of the 72 h treatment period, respectively. With this strain, although the time-course of bacterial numbers was generally similar among the three regimens, in the two regimens which employed the greater dosage intervals (12 and 24 h), the emergence of resistance, as revealed by PAP, was substantially greater and occurred earlier than for the conventional 8 hourly regimen (Figure 2). It is also noteworthy that the bacterial load at 24, 48 and 72 h (the only common pre-dose sampling time across the three regimens) was greater with the 24 hourly dosage regimen than the other regimens (Figure 1a). In the absence of a substantial PAE, the emergence of resistant sub-populations appears to be favoured by extended dosage intervals leading to protracted periods of colistin concentrations below the MIC. This is an important observation given recent reports involving administration of CMS in higher, less frequent doses26,27 and would suggest that moves towards 24 h and other extended dosage intervals may be detrimental.
In conclusion, the emergence of resistance to colistin is of great concern given CMS is often the last available therapeutic option for treatment of infections caused by MDR Gram-negative bacteria. By simulating the PK of colistin formation in humans administered CMS, we have shown little difference in the overall pattern of bacterial killing and regrowth between three clinically relevant dosage regimens. However, we have also shown that dosing regimens incorporating higher doses of colistin administered less frequently produced greater emergence of resistance than the conventional thrice-daily regimen. This sends a strong warning about the potential negative consequences of moving prematurely to extended-interval dosing. Future studies are warranted to define the prevalence of strains in which resistance is likely to be selected by such dosage regimens. In addition, it will be important to identify the primary PK/PD index determining efficacy and preventing the emergence of resistance.
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This work was supported by the Australian National Health and Medical Research Council. J. L. is an Australian National Health and Medical Research Council R. Douglas Wright Research Fellow.
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We do not have any financial, commercial or proprietary interest in any drug, device or equipment mentioned in this paper.
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Acknowledgements |
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The assistance of Ms Roxanne Owen and Mr Chun-Hong Tan of the Facility for Anti-infective Drug Development and Innovation, Monash University, Melbourne, is gratefully acknowledged.
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References |
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