Treatment of Infections Caused by Gram-negative Pathogens: Current Status on the PK/PD of Parenteral and Inhaled Polymyxins in Patients

Abstract

Polymyxins are increasingly used as a last resort for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria in patients. Over the last decade, significant progress has been made in understanding the pharmacokinetics/pharmacodynamics/toxicodynamics (PK/PD/TD) of parenteral and inhaled polymyxins. This mini-review provides an overview of the chemistry, different dose definitions of polymyxins, and the latest research on their clinical use, toxicities, preclinical and clinical PK/PD after intravenous and inhalation administration. Optimizing the PK/PD/TD of polymyxins in patients is critical to maximize their efficacy while minimizing toxicities and the emergence of resistance.

Introduction

Polymyxin B and polymyxin E (also known as colistin) belong to a group of polypeptide antibiotics that were approved in the late 1950s for the treatment of Gram-negative bacterial infections [1]. In the 1970s, polymyxins were ‘abandoned’ because of nephrotoxicity and neurotoxicity, largely due to the lack of information on their pharmacokinetics/pharmacodynamics/toxicodynamics (PK/PD/TD). However, since the late 1990s, increasing resistance to other antibiotics and a lack of new antibiotics reaching the clinic [2, 3] have forced clinicians to use polymyxins as the last resort for infections caused by multidrug-resistant (MDR) Gram-negative pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae [4–6]. These MDR Gram-negative bacteria commonly cause hospital-acquired pneumonia (HAP) in critically-ill patients and chronic pulmonary infections in patients with cystic fibrosis (CF) [7]. For intravenous administration and inhalation, polymyxin B is available in its sulfate form, while colistin is the most commonly in the form of an inactive prodrug, colistin methanesulfonate (CMS; also known as colistin sulfonyl methate, colistimethate, and colistimethanesulfate) [1, 8, 9]; to date colistin sulfate for intravenous admonistration is only available in China [10]. Up until the last two decades, our understanding of the PK/PD/TD of intravenous and inhaled polymyxins in treating pulmonary infections was scarce. This review provides an overview on the latest pharmacological knowledge of intravenous and inhaled polymyxins and how this knowledge has improved their use in critically-ill patients and patients with pulmonary disease (such as cystic fibrosis). For detailed dosing recommendations, please refer to our recently published guideline for polymyxins [11].

Chemistry of Polymyxins

Polymyxins consist of a cyclic heptapeptide ring with a tripeptide side chain and a fatty acyl group (Figure 1). They are amphipathic because of the hydrophobic segments (fatty acyl group and positions 6/7) and L-α,γ-diaminobutyric acid (Dab) residues [5]. At least 10 polymyxins (A, B, C, D, E [colistin], F, M, P, S and T) have been discovered, of which only polymyxin E and B are used clinically [1, 8]. Polymyxin B and colistin differ by a single amino acid at position 6 and both have two major components which account for >80% of their commercial products (Figure 1) [1, 12]. It should be noted that CMS undergoes conversion to form a complex mixture of colistin and a large number of partially sulfomethylated derivatives both in vitro (even at −20°C) and in vivo [1, 13]. The physicochemical instability of CMS causes significant challenges for PK/PD measurements and therapeutic drug monitoring (TDM) [1].

Figure 1.

Chemical structures of polymyxin B and colistin, and their two major components. Figure adapted from Sivanesan et al. [70] with permission from the American Chemical Society.

Commercial Products and Clinical Indications

There are many commercially available parenteral formulations globally, including Colomycin^® (Teva UK Limited) and Coly-Mycin M Parenteral^® (JHP Pharmaceuticals, Rochester, USA) [1]. Unfortunately, products in Europe and North America are labelled very differently with respect to the CMS content and caution is required when comparing the results in the literature. Colomycin^® is labelled in international units (IU), while Coly-Mycin M is labelled in colistin based activity (CBA); notably, CBA is also an activity unit even though it appears as a mass unit [1, 14]. Because of this difference, the total recommended daily doses for the two types of products differ significantly. For more details on the unit conversion and recommended dosage regimens, please refer to our reviews [1, 14, 15].

In the past four decades, the parenteral formulation of CMS has been reconstituted with saline for nebulization in CF patients in Europe [16]. Recently, CMS dry powder formulations for pulmonary delivery have been marketed as Promixin^®, Tadam^® and Colobreathe^® (Table 1). Dosage regimens of CMS nebulization for patients with CF are empirically determined [17]. For the parenteral CMS products in the US, inhalation is not listed in the product information and off-label use often occurs.

Table 1.

Comparison of the inhaled CMS commercial products

	Tadim®	Promixin®	Colobreathe®
Manufacturer	Phebra	Profile Pharma Limited	Penn Pharmaceutical
Formulation	Powder for nebuliser solution	Powder for nebuliser solution	Dry powder for inhalation
Active ingredient	CMS	CMS	CMS
Labelled content per vial	1 MIU which is equal to ~33.3 mg CBA or ~80 mg CMS	Each vial contains 1 MIU which is equivalent to ~33.3 mg CBA or ~80 mg of CMS	Each capsule contains 1,662,500 IU (equal to ~50 mg CBA) of CMS
Recommended dose	Adults, adolescents and children >2 years: 30 – 60 mg CBA two or three times daily	Adults, adolescents and children ≥ 2 years: 30 – 60 mg CBA two to three times per day (max 180 mg CBA/day) Children < 2 years: 15–30 mg CBA twice daily (max 60 mg CBA/day)	Adults and children of ≥ 6 years: One capsule twice daily

^Aone million IU = ~ 33.3 mg CBA = ~80 mg of the chemical CMS [1].

The clinical use of nebulized polymyxin B is off-label and is even more limited than inhaled CMS [18]. In a study conducted in Brazil, 19 patients (14 pneumonia and 5 tracheobronchitis) were treated with inhaled polymyxin B (500,000 IU/12 h) [18]. In pneumonia, both inhaled and intravenous polymyxin B was administered and clinical cure occurred in 10 (53%) patients, improvement in 8 (42%), and failure in 1 patient. This is the largest study to date using inhaled polymyxin B to treat nosocomial pneumonia caused by multidrug-resistant Gram-negatives [18]. Assessment of the safety and efficacy of nebulized polymyxin B in patients is urgently required to develop scientifically-based dosing recommendations.

Colistin sulfate (Asia Pioneer Pharmaceuticals Company, Shanghai, China) is only available for clinical use in China, and the dosage regimen is 10,000–20,000 IU/kg/day (500,000 IU per vial, 6,500 IU/mg) divided into 2 or 3 doses according to the standards formulated by the State Food and Drug Administration (SFDA) of China [1]. The availability of colistin sulfate presents significant challenges to infectious diseases clinicians in China, as its pharmacological characteristics are similar to polymyxin B sulfate, but not CMS. Furthermore, the terms of colistin and CMS are often used interchangeable wrongly; therefore, when clinicians determine the dose of colistin sulfate, great caution is required to avoid significant prescription errors.

Clinical Pharmacokinetics of Polymyxins

Intravenous Administration of Polymyxins

Several studies investigated the PK of CMS and formed colistin in plasma following intravenous CMS administration in healthy volunteers, CF and critically-ill patients (Supplementary Table S1). Irrespective of the patient groups, one- and two-compartment models with first-order conversion best described the disposition of CMS and formed colistin in humans, respectively [19]. Following intravenous infusion of CMS in patients, a gradual formation of colistin in plasma is evident with C_max achieved within ~0.75–7 h after the start of the infusion or ~1–4 h after the completion of infusion [20–22]. The V_d of CMS and formed colistin is significantly larger in critically-ill patients than in healthy volunteers and CF patients [19–22], which is likely due to changes to the distribution kinetics in different disease states. Following intravenous administration of CMS in critically-ill patients, the half-lives of CMS and formed colistin were ~2.2 h and ~5.9–18.5 h, respectively [20, 23]. Consistent with the observation in rodents, a relatively similar V_d (L/kg) was observed for both CMS (V_ss = 0.19 L/kg) and colistin (V/f_m = 0.17 L/kg) [24]. As the terminal half-life of formed colistin was longer than that of CMS, the elimination of formed colistin following intravenous CMS administration in humans and rats is not rate limited by the formation from CMS [24]. With the currently recommended dosage regimens the C_ss,avg of formed colistin in plasma is approximately ~2.3 mg/L in critically-ill patients [15]. After intravenous infusion of CMS, intra-renal formation of colistin is also noted in humans; approximately 70% of the CMS dose was recovered in urine as CMS and ~30% as formed colistin across 24 h in healthy volunteers [24].

An inverse relationship has been noted between the average steady-state concentration (C_ss,avg) of formed colistin and creatinine clearance (CrCL) [19]. This is because a reduction in the renal clearance causes a decrease in CMS clearance, which in turn leads to the increased availability of CMS to form colistin systemically [8]. Evidently, elimination of colistin itself is not affected by renal impairment, with a terminal half-life of 10–13 h across a wide range of CrCL values [8]. It should be noted that this inverse relationship was absent in the studies by Mohamed et al. [23] and Plachouras et al. [20], which was most likely due to the small sample size (n = 10 and 18, respectively) and narrow range of CrCL values (41 – 126 mL/min in [20]).

Most of the clinical PK data on polymyxins involves CMS/colistin, and far fewer studies examine the PK of polymyxin B [8, 19, 25–29] (Supplementary Table S2). Sandri et al. reported the first polymyxin B population PK model with a C_ss,avg of 2.79 ± 0.9 mg/L (range, 0.68 – 4.88 mg/L) and mean half-life of 11.9 h in critically-ill patients [30]. Polymyxin B (0.45–3.38 mg/kg/day) was predominantly cleared by non-renal pathway(s) and there was no relationship between its total body clearance and renal function in critically-ill patients. Total body weight was also not identified as a statistically significant covariate in several other population PK models for critically-ill patients [26, 29]. Recently, a potential association between renal function (in form of CrCL) and polymyxin B clearance was identified in 9 adult cystic fibrosis patients [31]. The findings must be interpreted with caution due to limited sample size and the observation nature of the study [31]. Further clinical trials are urgently needed to better characterize the impact of renal function on polymyxin PK in patients.

In summary, the different PK of polymyxin B versus CMS in patients after intravenous administration has significant pharmacological implications [1]. Firstly, the slow and low conversion of CMS to colistin in vivo often causes suboptimal plasma concentrations of colistin in the first dosing interval, even with a loading dose [1]. Secondly, in patients with good renal function it is very difficult to achieve total plasma concentrations of formed colistin higher than 2 mg/L, even with the upper limit of the currently recommended daily dose; fortunately, the PK of polymyxin B does not seem to be affected by renal function in critically-ill patients [30]. Thirdly, based on the current pharmacological information, the dosage regimen of CMS in patients with poor renal function may require adjustment, but not polymyxin B in terms of PK/PD considerations [11]. Collectively, for intravenous administration, current literature shows that polymyxin B has superior PK/PD characteristics in plasma than CMS because of the rapid and reliable attainment of desired drug exposure in critically-ill patients. The PK of intravenous polymyxins in other populations have been discussed in the recently published polymyxin book [1]. It should be noted that due to the significantly higher urinary recovery, intravenous CMS is advantageous than polymyxin B for the treatment of urinary tract infection.

Clinical Pharmacokinetics of Inhaled Polymyxins

In the last decade, significant progress has been made in understanding the PK of inhaled polymyxins in humans, with the majority of inhalation use occurring in people with CF (Supplementary Table S3). In a PK study of nebulized CMS in 30 CF patients, two puffs of albuterol were given immediately followed by 60 mg CBA of CMS via a PARI LC Star^® nebulizer [32]. Serum colistin A concentrations gradually increased to 0.178 ± 0.018 mg/L with T_max,serum of 1.47 ± 0.16 h. The sputum colistin concentration (~40 mg/L) peaked 1 h post nebulization, being 20 times higher than the MIC breakpoint for P. aeruginosa (2 mg/L) [5, 14]. Sputum concentration is not a true predictor of drug exposure in the lungs. Epithelial lining fluid (ELF) represents extracellular sites of the lungs where bacteria replicate; hence, ELF concentration is a much better surrogate for lung exposure of drugs to predict the clinical efficacy [33]. In a subgroup of 8 CF patients, nebulized CMS was administered via the PARI eFlow nebulizer [32]. No significance difference was observed in the PK between PARI LC Star vs. PARI eFlow systems.

Yapa et al. were the first to compare concentrations of CMS and formed colistin in plasma and sputum following intravenous and pulmonary administration of CMS in CF patients [34]. Each of the 6 patients received (1) a single dose of nebulized CMS (60 mg CBA), (2) a single dose of nebulized CMS (120 mg CBA), and (3) a single intravenous dose of CMS (150 mg CBA) over 45 min. A minimum washout period of 3 days was implemented between each treatment. Nebulization of CMS resulted in a much higher exposure of CMS and formed colistin (AUC_{Sputum,FormedColistin,0–12h} = 24.3–122 mg∙h/L) in the sputum compared with that from intravenous administration (<LOQ of 0.125 mg/L). The systemic bioavailability of CMS was very low in patients following nebulization (7.93 ± 4.26% and 5.37 ± 1.36% for 60 and 120 mg CBA, respectively), and formed colistin was not detected in the plasma. Only approximately 2–3% of the nebulized CMS dose was detected in urine samples at 24 h. It is evident that pulmonary nebulization of CMS can achieve much higher lung exposure than intravenous administration, while with minimal systemic exposure [32, 34–36].

Currently, the use of nebulized CMS is off-label in the United States and there are only a few case studies in neonates with ventilator-associated pneumonia (VAP) infected with P. aeruginosa or A. baumannii [37–39]. However, the dosage regimens reported in such case studies were not evidence-based and differed considerably. Recently, Nakwan et al. investigated the PK of nebulized CMS in neonates with VAP caused by A. baumannii and K. pneumoniae [40]. Six neonate patients received a single dose of CMS (4 mg CBA/kg in 4 mL) via ultrasonic nebulizers over 15 min. Following nebulization, colistin concentrations in lung aspirate remained above 2 mg/L over 12 h. After 12 h, colistin concentrations in lung aspirate fell below 2 mg/L in 50% of the subjects. Similar to the observations in adult patients, low systemic exposure of formed colistin was observed in these neonates (AUC_Plasma/AUC_{tracheal aspirate} = 3.8 ± 2.6%).

In summary, irrespective of patient groups, pulmonary administration of polymyxins is able to achieve much higher exposure in the lungs than occurs with intravenous administration, yet with much lower systemic bioavailability. This is of clinical importance, as low systemic bioavailability could potentially minimize nephrotoxicity and neurotoxicity. It should be noted that little is known about the impact of the inhalation device and patient characteristics on the PK of nebulized polymyxins, and comprehensive population PK models are needed to characterize the extent of potential patient- and device-specific differences for inhaled polymyxins.

Systemic and Pulmonary Toxicities

Polymyxin-associated toxicities include nephrotoxicity, neurotoxicity, hyperpigmentation and pulmonary toxicity. Nephrotoxicity is the most common side effect and the dose-limiting factor for intravenous CMS and polymyxin B [1]. The incidence of nephrotoxicity (CMS, 30–60%; polymyxin B, 40–60%) is much higher than that of neurotoxicity (0–7%) [1]. Hyperpigmentation has been increasingly reported in patients receiving intravenous polymyxin B, but not CMS [1].

Several recent toxicodynamic studies have suggested that polymyxin-induced nephrotoxicity is related to the total daily dose, duration of therapy, and plasma concentration [41–47]. In a retrospective cohort study, despite the overall incidence of CMS-induced nephrotoxicity being higher than of polymyxin B-induced nephrotoxicity (60.4% vs. 41.8%, respectively; p=0.02) [48], the results of multivariate and comparative analyses demonstrated that, with the currently recommended dosage regimens, CMS was not significantly associated with an increased risk of nephrotoxicity when compared to polymyxin B [46, 49]. Furthermore, high-dose polymyxin B (total daily dose of ≥ 250 mg and/or a dose of >3.0 mg/kg daily) is not necessarily associated with an increased risk of nephrotoxicity [50]. Most importantly, polymyxin-induced nephrotoxicity usually occurs following two to five days of treatment and is reversible upon cessation of the therapy [51, 52].

The exact mechanism of polymyxin-induced nephrotoxicity remains unclear; however, the extraordinary accumulation of polymyxins in renal tubular cells via transporters (e.g. megalin and peptide transporter-2 [PEPT2]) play a key role [1]. Recent animal studies suggest that polymyxin-induced nephrotoxicity is also mediated by oxidative stress, leading to tubular cell apoptosis and eventually renal dysfunction [53]. Co-administration of various agents such as ascorbic acid, N-acetylcysteine, melatonin, and heme oxygenase-1 with intravenous CMS has demonstrated nephroprotective activity in rats [1]; however, such protective effects have not been shown in patients receiving intravenous CMS [54]. Further clinical studies are warranted to develop novel approaches to attenuate polymyxin-induced nephrotoxicity.

Inhalation of polymyxins has the potential to minimize the risk of nephrotoxicity and neurotoxicity, and is probably a safer route to treat pulmonary infections than parenteral administration. In adults, inhaled polymyxins may cause chest tightness, cough and transient decreases in lung function (manifested as a decrease in forced expiratory volume in 1 s [FEV₁]) [55]. Very rarely, hypersensitivity pneumonitis, hypotension and neuromuscular toxicity (manifested as apnea and respiratory failure) can occur in patients following nebulized CMS (30–60 mg CBA every two to three times daily) [55]. Nakwan et al. investigated the safety of nebulized CMS (4 mg CBA/kg) in eight neonates with VAP and reported that none experienced systemic or pulmonary toxicity [40]. Although the effect of nebulized CMS on pulmonary function has been reported in the literature, the results are difficult to interpret since different studies employ different nebulizers with varying nebulizing efficiency and, more importantly, no comparisons have been performed with placebo groups. Well-designed prospective clinical studies are urgently needed to elucidate the factors contributing to the pulmonary toxicity (e.g. cough and bronchospasm) arising from nebulized polymyxins and to develop potential protective strategies. Very limited information is available on the mechanism of polymyxin-induced pulmonary toxicity. Recent in vitro studies revealed that polymyxins can accumulate in human lung epithelial cells and cause oxidative stress, mitochondrial damage and apoptosis [56]. Further mechanistic studies are warranted to develop novel approaches for the optimization of polymyxin inhalation therapy.

Pharmacokinetics/Pharmacodynamics of Parenteral and Inhaled Polymyxins

PK/PD relationships of antibiotics can be classified into three different indices: the ratio of the area under the unbound concentration-time profile to minimum inhibitory concentration (fAUC/MIC), the ratio of unbound peak plasma concentration to MIC (fC_max/MIC), and the percentage of time that the unbound plasma concentration exceeded the MIC (%fT_>MIC). The PK/PD index approach is currently the gold standard to guide dosing regimens for antibiotics, including polymyxins, for various types of infections [57].

In the past decade, the PK/PD indices for systemically administered colistin and polymyxin B were identified in vitro and in infected mice to guide dosing regimens for critically-ill patients. Using a one-compartment in vitro model, the antimicrobial efficacy of systemically administered colistin against P. aeruginosa was best correlated with fAUC_Plasma/MIC [58]. More recently, studies with mouse thigh infection models have shown that fAUC/MIC is best correlated with the antimicrobial efficacy against P. aeruginosa, A. baumannii and K. pneumoniae following subcutaneous administration of colistin and polymyxin B (Figure 2); no major differences in the efficacy between colistin and polymyxin B were observed [59, 60]. To achieve 1-log₁₀ CFU/mL killing in the mouse thigh infection model, an fAUC_Plasma/MIC of approximately 3.5–13.9 is required for P. aeruginosa and A. baumannii, whereas a higher value of ~3.72–28.0 is required for K. pneumoniae [59, 60]. In the mouse thigh infection model, an fAUC_Plasma/MIC of approximately 7.4 – 17.6 is required to achieve 2-log₁₀ CFU/mL killing by polymyxins against P. aeruginosa and A. baumannii, while it is not possible against K. pneumoniae [59, 60]. A similar set of PK/PD targets for P. aeruginosa was also obtained using an in silico PK/PD model [61]. Considering the C_ss,avg of formed colistin and polymyxin B (ranging from 2.3 to 2.8 mg/L) and their plasma binding in humans (~50–60%), the current dosage regimens of CMS and polymyxin B may not be efficacious for isolates with MICs >2 mg/L. Unfortunately, subcutaneous administration of colistin and polymyxin B only showed minimal efficacy against lung infections caused by P. aeruginosa where the required fAUC/MIC for bacteriostasis is not clinically feasible; no efficacy was observed against A. baumannii and K. pneumoniae [59, 60]. This is very likely due to the low maximal tolerant doses of polymyxins, low ELF drug exposure following parenteral administration, and their binding to lung surfactant [62]. In brief, from the PK/PD point of view, intravenous polymyxin B and CMS in patients may be problematic for pulmonary infections caused by P. aeruginosa, A. baumannii and K. pneumoniae due to poor PK in the ELF. Nevertheless, several clinical papers in the literature demonstrated favorable clinical outcomes (e.g. clinical cure rate) with intravenous polymyxin B and CMS in patients and well-designed prospective clinical trials are required [1].

Figure 2.

Relationship between bacterial load in thighs and lungs at 24 h infected with P. aeruginosa ATCC 27853 (A-B), A. baumannii ATCC 19606 (C), A. baumannii N-16870.213 (D) and K. pneumoniae FADDI-KP032 (E-F) versus fAUC/MIC in neutropenic infected mice. R² is the coefficient of determination. The broken line represents the mean bacterial burden in the tissue at the start of treatment. Figure adapted from Cheah et al. [59] and Landersdorfer et al. [55] with permission from the Oxford University Press.

Considering the PK advantages of inhaled polymyxins for lung infections, we employed a neutropenic mouse lung infection model to elucidate the PK/PD indices of inhaled colistin against P. aeruginosa (ATCC 27853, PAO1 and FADDI-PA022; MIC = 1 mg/L for all strains), A. baumannii (ATCC 19606, 248–01-C.248, and N-16870.213; MIC = 1, 1, and 0.5 mg/L, respectively) and K. pneumoniae (ATCC BAA 2146, M320445, and BM1; MIC = 0.5, 1, and 0.25 mg/L, respectively) (Figure 3) [63, 64]. It is evident that AUC/MIC in ELF (AUC_ELF/MIC) and plasma (fAUC_Plasma/MIC) were the most predictive PK/PD determinants for the efficacy of inhaled colistin against P. aeruginosa, A. baumannii and K. pneumoniae. The AUC/MIC targets required to achieve stasis against the three species were 684–1,050 in ELF. Inhaled polymyxin B displays similar PK/PD characteristics (AUC/MIC targets required for stasis against the three P. aeruginosa strains were 1,326–1,506 in ELF) to those of inhaled colistin in vivo [65]. The high AUC_ELF/MIC targets required for bacteriostasis with inhaled colistin and polymyxin B may indicate the difficulty in delivering the drug molecules to the alveolar due to potential blockage of subsegmental bronchi by the infection.

Figure 3.

The relationship between the Log₁₀CFU/Lung at 24 h versus the PK/PD indices for epithelial lining fluid (ELF) (A) AUC_ELF/MIC, (B) C_{max, ELF}/MIC, and (C) %T_{>MIC, ELF} and for plasma (D) fAUC_Plasma/MIC, (E) fC_{max, Plasma}/MIC, and (F) f%T_{>MIC, Plasma} following pulmonary administration of colistin. R² is the coefficient of determination. The broken line represents the mean bacterial burden in lungs at the start of treatment. Figure adapted from Lin et al. [63] with permission from the American Society for Microbiology.

The determined PK/PD index (fAUC/MIC) and the targets required for various magnitudes of bacterial killing serve as an important pharmacological tool that can be used in conjunction with Monte Carlo simulations to derive the probability of target attainment (PTA) and guide the selection of optimal dosage regimens in humans (Tables 2 and 3) [66]. According to the PTA calculations, a loading dose of 2.0–2.5 mg/kg for intravenous polymyxin B via a 1-h infusion was recommended for critically-ill patients [11]. To assist clinicians in treating critically-ill patients with intravenous CMS, a clinician-friendly dosing algorithm was developed based on the hitherto largest clinical PK/PD/TD study and PTAs [15]. Additionally, a smart phone app was developed (apps.apple.com/us/app/colistindose/id1336806844) using the first scientifically-based dosing recommendations of CMS [15] to help clinicians minimize potential description errors and optimize its clinical use. For inhaled polymyxins, no studies to date have utilized Monte Carlo simulations to calculate potential PTAs to recommend dosage regimens.

Table 2.

Suggested loading and daily doses of colistimethate for a target colistin C_ss,avg of 2 mg/L in various categories of critically-ill patients. Adapted from Nation et al. [15] with permission from the Clinical Infectious Disease.

Dose	Category of Critically-ill Patient	Dosing Suggestions
Loading Dose	All patient categories	Loading dose of CBA (mg) = Css,avg target (mg/L) × 2.0 × ideal body weight (kg). Maximum loading dose = 300 mg CBA.
Daily dose	Not receiving renal replacement therapy (RRT)	Daily dose of CBA (mg) = Css,avg target (mg/L) × 10(0.0048 × CrCl + 1.825).
	Receiving renal replacement therapy (RRT)	The baseline daily dose of colistimethate for a Css,avg of 2 mg/L in a patient with creatinine clearance of 0 mL/min is 130 mg/d of CBA (3.95 million IU/d). The supplement to the baseline daily dose needed during receipt of RRT is 10% of the baseline dose per 1 h of RRT.
	/Intermittent haemodialysis	Non-dialysis day: CBA dose of 130 mg/d (3.95 million IU/d), i.e., baseline dosing for a Css,avg of 2 mg/L. Dialysis day supplement: add 30% or 40% to baseline daily dose after a 3- or 4-h session, respectively.
	Sustained low-efficiency dialysis (SLED)	During SLED: add 10% per 1 h of SLED replacement to baseline daily dose for a Css,avg of 2 mg/L. Patient receiving a 10-h nocturnal SLED session each day and receiving colistimethate every 12 h, the dose would be (baseline CBA dose of 130 mg/d for a patient with creatinine clearance of 0 mL/min + supplemental dose comprising 10% of the baseline dose per h × 10 h). It is suggested that tie SLED session begin 1–2 h after the afternoon/evening dose; in such a case, it may be most convenient and safe to administer 130 mg CBA (3.95 million IU) every 12 h.
	Continuous renal replacement therapy (CRRT)	During CRRT: add 10% per 1 h of CRRT to the baseline daily dose for a Css,avg of 2 mg/L; the suggested CBA dose is 440 mg/d (~13 million IU/d).

Table 3.

Suggested loading and daily doses of polymyxin B in various categories of critically-ill patients. Adapted from Tsuji et al. [11] with permission from the American Colleague of Clinical Pharmacology.

Dose	Category of Critically-ill Patient	Dosing Suggestion*
Loading Dose	All patient categories	Loading dose of 2.0–2.5 mg/kg for polymyxin B, based on total body weight (TBW) (equivalent to 20,000–25,000 IU/kg) over 1 h
Daily Dose	All patient categories	1.25–1.5 mg/kg (equivalent to 12,500–15,000 IU/kg TBW) every 12 h is infused over 1 h
	Patient with renal impairment	Daily maintenance doses should not be adjusted
	Patients with renal replacement therapy	Both loading and daily maintenance doses should not be adjusted

^*Based upon the results from a limited number of patients.

Future Directions

Over the last two decades, the PK/PD of polymyxins has been well characterized using mouse infection models. However, the efficacy of intravenous CMS and polymyxin B has not been well demonstrated in critically-ill patients, and well-designed prospective clinical studies are urgently required for the optimization of their use and establishment of accurate susceptibility breakpoints. Although the PK/PD index based approach can guide the selection of optimal dosage regimens, mechanism-based PK/PD modeling (MBM) provides an enhanced quantitative understanding of the PK/PD relationship [67]. Recently, an MBM for inhaled colistin was developed based upon the PK/PD data in neutropenic mouse lung infection model to simultaneously describe the disposition of colistin and killing of bacteria (Figure 4) [68]. Combined with a previously published PK model of nebulized CMS [33, 69], this MBM was able to predict treatment outcomes of different clinically prescribed dosage regimens in patients. In line with previous clinical recommendations, deterministic simulations employing human PK data predicted that an inhalation dosage regimen of 60 mg CBA every 12 h is required to achieve a ≥2 log₁₀ CFU/Lung bacterial reduction in critically-ill patients with lung infections caused by MDR P. aeruginosa [68]. Together with therapeutic drug monitoring, the developed MBM may provide a valuable tool for optimizing inhalational dosage regimens in the clinic [67, 68]. Further clinical studies are warranted to validate and refine the MBM for polymyxins in patients.

Figure 4.

Schematic diagram of the MBM based on in vivo time-kill data. Figure adapted from Lin et al. [68] with permission from the American Society for Microbiology.

Conclusions

Polymyxins will remain as a last-line of defense against MDR Gram-negative ‘superbugs’ for many years to come. Although significant progress has been made over the past two decades in polymyxin pharmacology, significant gaps still remain, in particular regarding inhalation of polymyxins for the treatment of pulmonary infections. Understanding the PK/PD/TD of the polymyxins is critical to their optimal use in patients and minimizing the emergence of resistance; well-designed randomized clinical trials in different types of patients (e.g. obese, burn, and neonate patients) are desperately needed.

Highlights.

• Polymyxins are used as the last resort against MDR Gram-negative bacterial infections.

• fAUC/MIC is best correlated with the antimicrobial efficacy of polymyxins against Gram-negative pathogens.

• Well-designed randomized clinical are desperately needed.