|Year : 2017 | Volume
| Issue : 2 | Page : 77-85
Colistin: Pharmacology, drug resistance and clinical applications
Parijat Das, Kasturi Sengupta, Gaurav Goel, Sanjay Bhattacharya
Department of Microbiology, Tata Medical Centre, Kolkata, West Bengal, India
|Date of Web Publication||26-Dec-2017|
Department of Microbiology, Tata Medical Centre, 14 Major Arterial Road (E-W), Newtown, Rajarhat, Kolkata - 700 156, West Bengal
Source of Support: None, Conflict of Interest: None
Colistin is an important antibiotic against multidrug-resistant (MDR) Gram-negative bacteria (GNB), particularly Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Although it is an old antibiotic, Colistin has emerged as an important agent in the treatment of GNB infections, especially those caused by MDR pathogens in hospitalised patients. Limited therapeutic option against Carbapenem-resistant Gram-negative bacilli (E. coli, Klebsiella, Pseudomonas and Acinetobacter) is one of the major problems in clinical practice. The current review discusses the pharmacology, toxicity, drug resistance, importance of therapeutic drug level monitoring and cost of one of the most important antibiotics in the current practice.
Keywords: Colistin, cost, drug resistance, generic brands, nephrotoxicity, neurotoxicity, pharmacodynamics, pharmacokinetics, pharmacology, Polymyxin, therapeutic drug monitoring
|How to cite this article:|
Das P, Sengupta K, Goel G, Bhattacharya S. Colistin: Pharmacology, drug resistance and clinical applications. J Acad Clin Microbiol 2017;19:77-85
|How to cite this URL:|
Das P, Sengupta K, Goel G, Bhattacharya S. Colistin: Pharmacology, drug resistance and clinical applications. J Acad Clin Microbiol [serial online] 2017 [cited 2018 Oct 22];19:77-85. Available from: http://www.jacmjournal.org/text.asp?2017/19/2/77/221503
| Introduction|| |
Polymyxins, a group of antibacterials that were discovered during 1947, are being used as one of the last options for the treatment of life-threatening Gram-negative sepsis. Currently, two different Polymyxins are available commercially, Polymyxin E (Colistin) and Polymyxin B. The history of Colistin discovery and use is shown in [Table 1].,
| Pharmacological Formulations|| |
There are two physical forms of Colistin available in the market: Colistin sulphate (tablets or syrup for oral use and powder for topical use), which is also available as an aqueous suspension solution for topical use in eyes, and Colistin methanesulphonate (Colistimethate sodium [CMS]) for parenteral use. The intravenous (IV) formulation can also be delivered by inhalation. [Table 2] represents the common difference between two Colistin forms.
Recommendation of Colistin as a therapeutic option for the treatment of ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) Gram-negative organisms has been already accepted by the American Thoracic Society Guidelines. IV Polymyxins have been evaluated for the treatment of serious infections by MDR Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae such as pneumonia, bacteraemia, abdominal infections, bone and joint infections, urinary tract infections (UTIs) and meningitis.
| Pharmacology|| |
Polymyxin is a white powder and its salts are soluble in water. By nature, it is an amphipathic molecule, having both hydrophobic (due to the fatty acid moiety) and basic properties (due to the 5 unmasked amino groups). Colistin has a molecular weight about 1200 Dalton (Da). It is a multi-component cationic polypeptide antibiotic with at least 30 of very closely related Decapeptides. Colistin is a combination of at least 85% Colistin A (Polymyxin E1) and about 15% Colistin B (Polymyxin E2). CMS is formulated by the use of a sulphomethylation technique where free amino groups are treated with formaldehyde, followed by sodium bisulphite to give the sulphomethyl derivative. [Table 3] highlights some of the main differences between these two groups. Sulphomethylation of CMS has been shown to minimise side effects without destroying antibacterial activity. The only difference between the structure of Polymyxin B and Colistin are in the amino acid components.
|Table 3: Major differences between Colistin and Polymyxin B, which may affect clinical outcomes|
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CMS has no microbiological activity. It acts as a pro-drug of Colistin which has no protein binding capacity. After administration of CMS, Colistin appears in plasma rapidly. Colistin is approximately 50% bound to human plasma proteins. After IV administration, it shows a serum peak level within 10 min which is higher than intra-muscular administration, but it declines more rapidly. The base of Colistin is more active than CMS. The available half-life of CMS is 1.5–2 h. Previous data suggested that the distribution of Colistin is very less in pleural cavity, lung parenchyma, bones and cerebrospinal fluid (15%–25%).
Route of administration
The route of administration of Colistin include:
- Intravenously as CMS
- Topically (as otic solution and powder for skin uses as Colistin sulphate)
| Mode of Action|| |
Generally, Polymyxins are bacteriostatic at low concentrations and bactericidal at high concentrations, with a relatively narrow spectrum of antibacterial activity against Gram-negative bacteria (GNB). The antimicrobial activity of Colistin is mainly specific for bacterial cell wall and cytoplasmic membrane. Colistin associates with the bacterial cell membrane through electrostatic interactions between cationic polypeptide (Colistin) and anionic lipopolysaccharide (LPS) molecules in the outer membrane of the GNB. Colistin displaces magnesium (Mg +2) and calcium (Ca +2) ions, of LPS, leading to a local disturbance of the outer membrane. Additional complexing with LPSs is facilitated by hydrophobic interactions between the lipid A portion of LPSs and the fatty acids of Colistin. The effects of this process increase the permeability of the cell envelope, leakage of cell contents and subsequently cell death.
| Mechanisms of Colistin Resistance|| |
Antimicrobial drug resistance against Colistin develops either through mutational or by adaptive mechanisms. A range of genetic mutations cause resistance to Colistin by altering the main target of Colistin's action, i.e., the outer membrane of GNB. [Table 4] represents all the possible mechanisms of Colistin resistance reported as of now.,,,,,,,,,,
| Emergence of Colistin Resistance in Klebsiella Pneumoniae|| |
Colistin resistance in Klebsiella pneumoniae (CRKP) is an emerging public health-related issue throughout the world. A report published by Biswas et al., 2012 on the emergence of Colistin resistance showed that there had been few reports for many decades from 1960 to 2011, but there has since been a steady increase in incidence of Colistin-resistant K. pneumoniae in the clinical setting in several countries of Europe, Americas and Asia.,,,
Several studies have recognised emergence of CRKP in clinical settings due to the current clinical use of Colistin/Polymyxin B and the transmission of CRKP polyclonal isolates found in hospitalised patients., While evidence suggested that, in humans, emergence of CRKP in vivo is most likely linked with the previous Colistin exposure, it is already known that CRKP can be found in patients not previously treated with Colistin., Most reports on CRKP have focused on patients infected with MDR bacteria being treated with Colistin and conclude that resistance developed after such treatment as most of the isolated bacteria also carry the carbapenemase gene. Recent molecular studies based on multi-locus sequence typing analysis showed a single clonal colonisation either by resistant or sensitive strains of K. pneumonia is common in patient population, whereas in healthy population, these strains were multi-clonal. These findings support the suggestion that prior treatment with Colistin will highly influence the risk of clonal CRKP among patients.
| Detection of Colistin Resistance in Stool Surveillance|| |
Increasing episodes of Carbapenem-resistant Gram-negative infections in hospital and community environment due to spread of MDR strains is a serious concern throughout the world. In developing countries, the problem is compounded by lack of proper surveillance strategies. A complete one-year analysis on clinical specimens in our hospital showed that the prevalence of CRKP is quite high (n = 24). These data also correlate with the chance of isolation of Carbapenamase-producing Klebsiella in surveillance culture before the detection of CRKP.
The results of surveillance should be linked with regional antibiotic policy. A successful policy requires proper antibiotic stewardship and with regular audit. This practice should update based on changing regional susceptibility patterns.
| Colistin Combinations: Where We Stand?|| |
Combining Colistin with other antibiotics seeking a synergistic activity looks promising. Combination therapy limits and suppresses bacterial resistance and covers a broad range of pathogens with greater efficacy. [Table 5] represents all the possible synergistic activity of Colistin combination therapy currently used worldwide. It has been reported previously that combination therapy of Colistin with other antibiotics (especially Carbapenems) significantly reduces mortality.
|Table 5: Outcome of patients with Carbapenemase-producing Klebsiella pneumoniae bloodstream infections according to treatment regimen|
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| Colistin Heteroresistance|| |
The term “heteroresistance” may be broadly defined as a mixed population of drug-resistant and drug-sensitive organisms in the same clinical specimen or culture. Around the world, different species of organisms have been already reported for their Colistin heteroresistance characteristic including A. baumannii, Enterobacter cloacae isolates, K. pneumoniae and P. aeruginosa.,,,
Because of the lack of standards for determining the heteroresistance property, the report of the incidence from different regions of the world varies greatly. Currently, Colistin resistance in Asia and Europe is considered to be more serious as compared to North and South America.
The pharmacokinetic/pharmacodynamic observations suggest that the mechanisms of heteroresistance in A. baumannii might be due to the loss of LPS and/or the two-component regulatory system (TCS) called PmrA/PmrB (which responds to pH, Mg ++ and Fe +3 and Polymyxins). Studies also show that instead of monotherapy with Colistin for A. baumannii, the use of combination therapy with Colistin/Carbapenem would be the best strategy as a treatment option. A recent study by Jayol et al., 2015 elucidating the mechanisms of Colistin heteroresistance in K. pneumoniae showed the role of PhoPQ TCS for Colistin heteroresistance. It is possible that routine antibiotic susceptibility testing (AST) methods in current use may be missing out heteroresistance.
| Clinical Indications of Colistin|| |
The use of IV administration of Colistin for the treatment of Gram-negative infections was initiated in the early 1950s; its use now is advisedly for the treatment of infections caused by the MDR GNB (suspected or confirmed Carbapenem-resistant Enterobacteriaceae/Pseudomonas/Acinetobacter species).
Colistin may be used in the treatment of VAP. Several comparative studies on the efficacy of IV Colistin therapy against VAP due to A. baumanii and P. aeruginosa have shown equal or even better results than standalone Carbepenem therapy in the treatment of VAP. Another study from Singapore General Hospital by Kwa et al., 2005 reported that treatment with nebulised Colistin for the infected MDR pneumonia by A. baumannii and P. aeruginosa showed a response rates around 57.1% and 85.7%, respectively.
Bacteraemia or sepsis
Several studies had shown that inadequate dose of antibiotics for the treatment of infection was an independent determinant of mortality, especially in critically ill patients. These authors also demonstrated that patients receiving inadequate dose of antibiotics had an in-hospital mortality rate of 52.1% due to sepsis, whereas the mortality come down to 12.2% if the patients were treated with adequate antibiotics therapy. In such cases, combination of Carbapenems, Colistin may be tried. A case study on sepsis associated with K. pneumoniae by Karabinis. et al., 2004 showed that patients with septic shock were successfully treated with Colistin.
Urinary tract infections
A recently reported retrospective hospital-based study from France Abat et al., 2015 recorded the prevalence of intrinsic Colistin-resistant bacteria (CRB) isolated from confirmed urinary tract infections cases over a period of five years. This study of 4847 intrinsic CRB isolates included 3150 Proteus spp., 847 Morganella spp., 704 Serratia spp. and 146 Providencia spp. Another prospective study from India reported that UTI caused by pandrug-resistant Acinetobacter complex also showed resistance to Tigecycline and Colistin. The inference from these studies is: Although Colistin is a broad spectrum antibiotic useful in the treatment of many GNB infections including those caused by MDR organisms, it cannot be relied upon to treat all UTIs.
| Selective Decontamination of the Digestive Tract|| |
Infections in the Intensive Care Units (ICUs) patients may be caused by potentially pathogenic microorganisms and colonisers of the oropharyngeal and digestive tract. A prophylactic antibiotic therapy through selective oropharyngeal decontamination (SOD) and selective decontamination of the digestive tract (SDD) have been used in many studies (especially outside India) to prevent infections by these microorganisms in ICU patients. The problem with this approach is the potential selection of resistant microorganisms, low efficacy of the approach in settings with high prevalence of antibiotic resistance, and additional cost of SOD and SDD.
| Colistin Dosing: in Patients With Normal and Abnormal Renal Function|| |
Scottish Antimicrobial Prescribing Group (NHS Scotland) states that “CMS is active against Carbapenemase-producing Enterobacteriaceae bacteria which achieve adequate serum levels to treat bloodstream infections. Traditional dosing regimens for CMS do not attain serum concentrations that would be sufficient for the treatment of infections caused by pathogens with minimum inhibitory concentrations (MICs) higher than 0.5 mg/L. Recent studies have shown that high-dose regimens (of Colistin) are more effective with no significant increase in nephrotoxicity. The Risk, Injury, Failure, Loss, and End-Stage kidney disease Criteria are used to monitor the renal impairment not only from Colistin but also from other nephrotoxic medicines.
Colistin doses in literature
CMS is a pro-drug of Colistin. Dosages are mentioned in two different units in the literature: million units (MU) and mg. The relation is as follows: 1 MU of Colistin = 80 mg of CMS; 100 mg of Colistin base activity (CBA) =240 mg of CMS = 3 MU of Colistin.
There is a difference between Colistin or CMS and CBA.
- For an average adult (with normal renal function), the loading dose of CMS/CMS (Colistin) is 6–9 MU; with subsequent maintenance doses of 4.5 MU administered every 12 h starting 12–24 h after the loading dose
- CMS is dissolved in 100 ml of normal saline and administered as an IV infusion over 30–60 min.
Body weight-based dosing of Colistin
- Use the lower of ideal body weight (IBW) or actual body weight (kg)
- IBW, in kilograms, is calculated as follows:
- Males: 50 + 2.3 × (height in inches exceeding 5 feet)
- Females: 45.5 + 2.3 × (height in inches exceeding 5 feet)
- For adults: >60 kg body weight: Up to 9 MU/day in severe infections
- For children ≤40 kg body weight or adults <60 kg body weight: 75,000–150,000 IU/kg/day divided into three doses
- For children with a body weight above 40 kg, use of the dosing recommendation for adults should be considered.
*Source: Adapted from http://www.medicines.org.uk/emc/medicine/23413#POSOLOGY.
- Use 9 MU of loading dose (LD)
- Exceptions; body weight <60 kg; renal impairment where 6 MU should be used as LD.
- First dose should be given 12–24 h after LD based on clinical condition, renal function (including urine output)
- Then, use 4.5 MU 12 hourly (for adults).
Monitoring of renal function
Ideally, before the first dose, a baseline serum creatinine should be checked, and urine output should be assessed. However, this may not always be possible in critical care settings, in which case clinical judgement must be used to decide on the loading dose. Renal function should be monitored daily for the first week and adjustments made accordingly. If the patient's renal function is stable or stabilises, monitoring can be reduced to every 2–3 days.
| Colistin Minimum Inhibitory Concentration Measurement and Breakpoints: Update 2015|| |
Like many antibiotics, the susceptibility breakpoint for Colistin is yet to reach a consensus. International guidelines developed by the European Committee on Antimicrobial Susceptibility Testing and Clinical and Laboratory Standards Institute (CLSI) differ widely according to the breakpoint values which depend on the organisms tested showed in [Table 6].
|Table 6: Minimum inhibitory concentrations for Colistin according to Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing|
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| Antibacterial Activity|| |
Colistin has very good antimicrobial activity against Enterobacteriaceae, but many non-fermentative GNB were found to be naturally resistant or have variable susceptibility to Colistin [Table 7].
|Table 7: The microbial susceptibility profile of different groups of microorganisms when treated with Colistin|
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| Minimum Inhibitory Concentration Measurements: Dos and Don'ts|| |
Currently, broth microdilution is the primary reference method for Colistin MIC testing, but the drawback of this method is the rapid adherence of Colistin to the plastics used for broth dilution panels. This effect is most apparent at low concentrations of the drug. Addition of certain surfactant (Tween 80) directly either to the bacterial inoculum suspension or to the Mueller-Hinton broth for reducing the adsorption of Colistin to polystyrene has been proposed, but the guidelines for broth dilution may not encourage the use of surfactant for Colistin testing.
| Cost of Treatment|| |
In the absence of any central procurement policy in India, CMS is sourced from different manufacturers. The multiplicity of brands, manufacturers, marketing companies, units per pack, prices, and per day cost is a challenge to the prescribers with regard to fair and optimal prescribing [Table 8].
| Effect of Use of Colistin in Animal Live Stock and Human Health|| |
The use of Colistin for veterinary use, particularly for the treatment of poultry, pig, and calves, has been common for decades. Most of the Colistin used for the treatment of animals is mainly by oral administration. Globally, Colistin is used in both hospital and community settings and the total annual consumption (which includes all of the possible routes of administration or combination) of Colistin widely varies between countries. Developed country-based data on rapid emergence of CRB showed its association with increased mortality. A study by Meletis et al., 2011 showed the rate of Colistin resistance rose from 0% to 24.3% within three years in one Greek hospital, while the use of Colistin for selective digestive tract decontamination (SDD) in an ICU of another developed country's hospital was actually associated with increase of Colistin resistance including cases of bacteraemia-associated Colistin-resistant strains.,
As of now, in many developing countries, including India, there are no statutory guidelines for the use of antibiotics in animal feeds or in agriculture. The use of different antimicrobials for agricultural purposes will also increase the chance of resistance level in the general population. A study conducted by the WHO and UN Food and Agricultural Organization in 2003 showed the direct association of community-based antimicrobial resistance with usage of different antimicrobial product in agricultural field.
| Colistin Assay Methods (Therapeutic Drug-Level Monitoring)|| |
A number of assays for Colistin have been developed which include high-performance liquid chromatography (HPLC) and mass spectrometry-based assays. Both methods require sophisticated instrumentation and technical expertise which is very often found to be lacking in general diagnostic laboratories. On the other hand, more simple microbiological assays use Bordetella bronchiseptica or Escherichia More Details coli as an indicator organism and Difco Number 10 agar. However, this method suffers from the difficulty in obtaining indicator organism, agar, and lack of sensitivity. Major limitation of the microbiological methods are their inability to distinguish different Colistin components. More recently, a rapid HPLC tandem mass spectrometry (LC-MS/MS) spectrometry based method has also been used for the analysis of Colistin, but this method also requires extensive sample purification, with multiple potential problems. After the administration of Colistin (CMS) to the patients, it hydrolyses spontaneously in aqueous solutions. This hydrolysis process is strongly dependent on in vivo temperature and pH. Colistin also has low native fluorescence and absorbance, so it needs to be derivatised to use fluorescence or absorbance for low-level detection. Finally, Colistin binds easily to labware, both plastics and glass, causing loss of the analyte (CMS). Although the adsorption of CMS to polystyrene can be alleviated by the addition of a surfactant, such as Tween80, either to the bacterial inoculum suspension or directly to the cation-adjusted Mueller-Hinton broth (CAMHB).
| Conclusion|| |
Clinical use of Colistin started in 1959 but was never subjected to a battery of drug development procedures which are mandatory now. This has led to the dearth of pharmacological information on the drug. Analytical methods for drug assays, such as HPLC and LC-MS, have only been developed over the last few decades. Previously used microbiological assays could not separately quantify CMS (pro-drug) and active Colistin moieties. The previous knowledge about pharmacokinetics and guidelines for dosing were based on those microbiological assays. Even now, pharmacokinetics of aerosolised preparations has not been studied in details. Most of the studies are retrospective outcome studies. Till very recently, it was rare to find prospective studies and data about Colistin use and clinical outcomes. There are also relatively less data in paediatric (neonatal) population. Carbapenem resistance in GNB is a major issue in developing world, where MIC methods may not be readily available and there are no standardised recommendations for disc diffusion method from CLSI for Enterobacteriaceae and Acinetobacter. The failure to analyse local antibiogram and reporting bias (under-reporting of resistance studies from developing countries) also makes standardisation of the dosages difficult. Over-the-counter availability of Colistin (like other antibiotics) makes the situation worse. The results of Colistin sulphate AST may or may not always translate into the actual in vivo response of CMS (used as a pro-drug). It is presumed that previous relatively higher incidence of nephrotoxicity was related to greater proportion of Colistin sulphate in older formulations. Better supportive care and monitoring of nephrotoxicity in the present era makes it possible to allow larger doses. The methods of in vitro synergy testing such as time-kill test, checkerboard assay and modifications of E-test are not always available and employed in clinical practice. Hence, prospective controlled trials to generate data on synergy testing and clinical outcomes are needed.
Globally, alarming rise of Colistin resistance, especially among the K. pneumoniae, is a matter of serious concern. Recently, Liu et al., in 2015 have reported the emergence of plasmid-mediated Colistin resistance mechanism MCR-1 in animals and human beings in China. The emergence of MCR-1-mediated and plasmid-associated resistance to Colistin represents a serious threat to one of the last remaining antibiotic (namely Colistin) in the treatment of extensively drug-resistant GNB infections. Contamination of the human food chain by Colistin or Colistin-resistant microorganisms can become a major driver for Colistin resistance. Appropriate poultry and animal husbandry practices along with safe drinking water and appropriate waste disposal are essential.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]