Review
Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria

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Abstract

Infections caused by multi-resistant Gram-negative bacteria, particularly Pseudomonas aeruginosa, are increasing worldwide. In patients with cystic fibrosis (CF), resistance in P. aeruginosa to numerous anti-pseudomonal agents is becoming common. The absence since 1995, of new substances active against resistant Gram-negative bacteria, has caused increasing concern. Colistin, an old antibiotic also known as polymyxin E, has attracted more interest recently because of its significant activity against multi-resistant P. aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, and the low resistance rates to it. Because its use as an anti-pseudomonal agent was displaced by the potentially less toxic aminoglycosides in 1970s, our knowledge of this drug is limited. However, there has been a significant recent increase in the data gathered on colistin, focussing on its chemistry, antibacterial activity, mechanism of action and resistance, pharmacokinetics, pharmacodynamics and new clinical application. It is likely that colistin will be an important antimicrobial option against multi-resistant Gram-negative bacteria, for some years to come.

Introduction

The widespread resistance of microorganisms to antibiotics threatens to be a future medical disaster [1], [2]. Pseudomonas aeruginosa is one such difficult-to-treat organism, and reports from the National Nosocomial Infections Surveillance (NNIS) in 1998 indicated that it then ranked second among the most commonly isolated Gram-negative pathogens [3], [4], [5]. Chronic pulmonary infections with P. aeruginosa are a major clinical problem for patients with cystic fibrosis (CF) [4], [6], and a public health threat [7]. More importantly, multi-resistant P. aeruginosa isolated from the infected lungs of these patients have a significantly higher mutation rate than those from other clinical sources [8].

Numerous anti-pseudomonal antibiotics are used currently for the treatment of bronchial infections, including ticarcillin, carbenicillin, piperacillin, tazobactam, tobramycin, gentamicin, amikacin, ciprofloxacin, ceftazidime, imipenem, cilastatin and aztreonam. However, resistance to these agents is becoming more prevalent [9], [10], [11]. Surveillance conducted from 1997 to 2000 in the United States showed that approximately 16% of clinical isolates of P. aeruginosa were resistant to at least 3 of the core anti-pseudomonals (amikacin, ceftazidime, ciprofloxacin, gentamicin, imipenem, and piperacillin) and 1% were resistant to all of these antimicrobials [12]. Outbreaks of P. aeruginosa resistant to most available β-lactams, aminoglycosides and fluoroquinolones have been reported among CF patients, as well as in burns units and cancer centres [13], [14], [15], [16]. The annual frequency of studies examining the resistance of P. aeruginosa to currently used antibiotics is increasing, (Fig. 1) and this highlights the growing concerns regarding effective treatment of infections caused by this microorganism. Unfortunately, there has been no new anti-pseudomonal agent released since meropenem in 1995 and significant levels of resistance to meropenem have already been reported in clinical isolates of P. aeruginosa [17].

Multi-resistance in other Gram-negative bacteria, including strains resistant to carbapenems, is also emerging as a global health issue [18], [19]. Now clinical isolates with mutational fluoroquinolone resistance and metallo-β-lactamases are being seen with increasing frequency worldwide [20]. Some species such as Acinetobacter baumannii strains only susceptible to polymyxins, have become a common problem especially in intensive care units [21].

Colistin, also known as polymyxin E, is an old antibiotic with significant in vitro activity against some multi-resistant Gram-negative pathogens, including P. aeruginosa, A. baumannii and Klebsiella pneumoniae. When the use of a β-lactam, aminoglycoside, or quinolone is ineffective, the polymyxins, particularly colistin, remain drugs of last resort [12]. Furthermore, resistance to colistin is seldom observed in spite of a daily selective pressure in patients receiving colistin by inhalation [22], [23], [24], [25]. Hence, in recent years it has attracted considerable interest as an antibiotic for use against multi-resistant strains of P. aeruginosa, Acinetobacter species and Klebsiella species [17], [24], [26], [27], [28], [29]. This trend is demonstrated in Fig. 1. The present review will focus mainly on chemical aspects of colistin, its antibacterial activity, mechanism of action and resistance, pharmacokinetics and pharmacodynamics, and recent clinical experience. Recent advances in development and validation of analytical methods for quantitation in biological fluids have enabled new insights into the pharmacokinetics and pharmacodynamics of colistin [30], [31].

Section snippets

Discovery of colistin and early clinical experiences

Colistin is one of the polymyxin antibiotics produced by Bacillus colistinus. Polymyxins were discovered in 1947 [32], [33], [34]. ‘Colistin’, first reported by Koyama and coworkers [35], was originally thought to be distinct from polymyxins, but was later proven to be identical to polymyxin E [36]. It has been available since 1959 for the treatment of infections caused by Gram-negative bacteria [37]. However, when early clinical reports suggested a high incidence of toxicity [38], [39], its

Chemistry

Colistin contains a mixture of d- and l-amino acids arranged as a cyclic heptapeptide ring with a tripeptide side-chain. The side-chain is covalently bound to a fatty acid via an acyl group (Fig. 2a). Sodium colistin methanesulphonate (Fig. 2b) is prepared from colistin by reaction of the free γ-amino groups of the Dab residues with formaldehyde followed by sodium bisulphite.

At least 30 components have been isolated from colistin and 13 identified [54], [55], [56]. They differ in the

Mechanism of action

Most investigations into the mechanism of antibacterial action of polymyxins have been conducted with polymyxin B, which is regarded as a model compound of polymyxins. Colistin, with its similar structure to polymyxin B, is believed to have an identical mechanism of action [71]. Polymyxin B interacts electrostatically with the outer membrane of Gram-negative bacteria and competitively displaces divalent cations (calcium and magnesium) from the negatively charged phosphate groups of membrane

Clinical uses

Colistin sulphate is administered orally for the treatment of bacterial diarrhoea in infants and children and applied locally for conditions such as otitis externa and eye infections due to P. aeruginosa [106].

For parenteral use, colistin is administered as colistin methanesulphonate. Early experience showed it to be an effective antimicrobial agent for the treatment of septicaemias, wound infections, urinary tract infections and respiratory system infections caused by P. aeruginosa [24], [126]

Pharmacokinetics of colistin (sulphate or base) and colistin methanesulphonate

As noted above, a greater understanding of the pharmacokinetics of colistin methanesulphonate and colistin (base) in humans should offer considerable scope for improving the use of colistin for infections. However, in only two published pharmacokinetic studies, have more specific methods such as HPLC been used to measure concentrations in the plasma of humans following doses of colistin methanesulphonate [46], [70]. Most data reported previously on the concentrations of ‘colistin’ in plasma and

Pharmacodynamics of colistin sulphate and colistin methanesulphonate

Apart from the considerable data on the MICs of colistin sulphate and colistin methanesulphonate (see Section 4), very little work has been conducted on the pharmacodynamics of colistin sulphate and colistin methanesulphonate, particularly against the multi-resistant P. aeruginosa. Recently, the in vitro pharmacodynamic properties of colistin sulphate and colistin methanesulphonate were comprehensively investigated in our laboratory by determining the MICs, time-kill kinetics, and

Conclusion

While colistin has been established as an effective agent against P. aeruginosa for several decades, its clinical use has been limited by the reported toxicities. However, much of these toxicities may be traced to its inappropriate use before the 1980s. There is an increasing appreciation of the potential value of colistin in patients infected with P. aeruginosa, especially with the alarming emergence of resistance to the currently available anti-pseudomonal agents. A better understanding of

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