多粘菌素重新出现的抗多药耐药革兰阴性细菌的抗生素.docx

1、多粘菌素重新出现的抗多药耐药革兰阴性细菌的抗生素Lancet Infect Dis.2006 Sep;6(9):589-601.Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections.Li J1,Nation RL,Turnidge JD,Milne RW,Coulthard K,Rayner CR,Paterson DL.Author informationAbstractIncreasing multidrug resistance in Gram-neg

2、ative bacteria, in particular Pseudomonas aeruginosa, Acinetobacterbaumannii, and Klebsiellapneumoniae, presents a critical problem. Limited therapeutic options have forced infectious disease clinicians and microbiologists to reappraise the clinical application ofcolistin, a polymyxin antibiotic dis

3、covered more than 50 years ago. We summarise recent progress in understanding the complex chemistry, pharmacokinetics, and pharmacodynamics ofcolistin, the interplay between these three aspects, and their effect on the clinical use of this important antibiotic. Recent clinical findings are reviewed,

4、 focusing on evaluation of efficacy, emerging resistance, potential toxicities, and combinationtherapy. In the battle against rapidly emerging bacterial resistance we can no longer rely entirely on the discovery of new antibiotics; we must also pursue rational approaches to the use of older antibiot

5、ics such ascolistin.Introduction One of the greatest accomplishments of modern medicine has been the development of antibiotics for the treatment of potentially fatal infections. However, this has inevitably been followed by the acquisition of resistance towards their antimicrobial activity. Unfortu

6、nately, the past two decades have seen a marked decline in the discovery and development of novel antibiotics and a remarkable increase in resistance to those currently available.1 In particular, there is substantial concern worldwide with the mounting prevalence of infections caused by multidrug-re

7、sistant Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacterbaumannii, and Klebsiellapneumoniae; for these species, polymyxins are sometimes the only available active antibiotics.28 Since there have been no promising new chemical entities for Gram-negative infections in the dr

8、ug development pipeline,1,4,5 clinicians and microbiologists have been forced to reappraise the clinical value of colistin, a relatively old polymyxin antibiotic. In critically ill patients with such infections, colistin (polymyxin E) is increasingly being used as salvage therapy.2,4,7 Although the

9、novel agent tigecycline has significant activity against multidrugresistantA baumannii,9 it is not active against P aeruginosadue to efflux by MexXY-OprM.10 Colistin is a multicomponent polypeptide antibiotic, comprised mainly of colistin A and B, that became available for clinical use in the 1960s,

10、 but was replaced in the 1970s by antibiotics considered less toxic.2,7,11 There are two forms of colistin commercially available: colistin sulfate for oral and topical use, and colistimethate sodium (sodium colistinmethanesulphonate, colistinsulfomethate sodium) for parenteral use (fi gure 1); both

11、 can be delivered by inhalation. Although there have been a substantial number of clinical reports on the successful use of colistin6,1224 or polymyxin B2527 (which diff ers by only one aminoacid from colistin) against infections caused by multidrug-resistant P aeruginosa, A baumannii, and K pneumon

12、iae, there is a dearth of information on the clinical pharmacokinetics, pharmacodynamics, and toxicodynamics of colistin; such data are essential for establishing optimal dose regimens.2 As a specifi c example, there are no dosing regimens listed in the product information for the drug appropriate f

13、or critically ill patients requiring haemodialysis or continuous renal replacement therapy.2830 Most knowledge on the pharmacokinetics of colistin was obtained at least two decades ago when non-specifi c microbiological assays were used to measure the concentrations of “colistin” in biological fl ui

14、ds.2 Because it is approximately 50 years since its discovery and introduction into clinical use, colistin was never subjected to the drug development processes required for compliance with contemporary regulatory requirements. As a result, the pharmacokinetic and pharmacodynamic information require

15、d to underpin prescribing recommendations in the product information is lacking. This review will focus on the pharmacology of colistin and new clinical fi ndings from the past 10 years that reflect renewed interest in its use. The scarce and heterogeneous data on the use of colistin in the literatu

16、re prevents the quantitative synthesis of the impact of this treatment. For the mechanisms of activity and resistance, spectrum of activity and anti-endotoxin effect of colistin, please refer to our recent review.2 Pharmacology Chemistryimportant diff erences between chemical entities Although widel

17、y used in the literature, the terms colistin and colistimethate are not interchangeable.2,3134 Colistin (usually used as the sulphate salt) is a polycation, whereas colistimethate (used as the sodium salt) is a polyanion at physiological pH (fi gure 1). Colistimethate is prepared from colistin by re

18、action of the free -amino groups of the fi ve,-diaminobutyric acid residues with formaldehyde followed by sodium bisulphite.35 Colistimethate is not stable in vitro32 or in vivo,31,33 and is hydrolysed to a series of methanesulphonated derivatives plus colistin. Colistin is more stable than colistim

19、ethate in human plasma.32 The diff erences in chemistry between colistimethate and colistin also translate into differences in pharmacokinetics and pharmacodynamics. Whereas colistimethate is eliminated mainly by the kidney and the urinary excretion involves renal tubular secretion, colistin is elim

20、inated predominantly by the non-renal route because, at least in part, the compound undergoes very extensive renal tubular reabsorption.33,36 After intravenous administration of colistimethate (sodium), the plasma half-lives of colistimethate are approximately half of those of the colistin generated

21、 from it in vivo in both rats (236 SD 39 min vs 557 193 min)33 and patients with cystic fi brosis (124 52 min vs 251 79 min).31 With respect to antibacterial activity against P aeruginosa, recent studies have indicated that colistimethate is a non-active prodrug of colistin.37 A recent review provid

22、es more details on the considerable diff erences between colistimethate and colistin in their chemistry, pharmacokinetics, and pharmacodynamics.2 Given these diff erences, we recommend that the formulations of colistin should be fully described in all future reports, particularly clinical studies, a

23、s either colistin sulfate or colistimethate sodium, to avoid any confusion in interpretation of studies with one or both substances. Inconsistent dose regimens of two major colistimethate (sodium) products Colistimethate sodium is administered parenterally since it is less toxic than colistin sulfat

24、e.35 The two most common commercially available parenteral formulations of colistimethate sodium are Colomycin (Dumex- Alpharma A/S, Copenhagen, Denmark) and Coly-Mycin M Parenteral (Parkedale Pharmaceuticals, Rochester, USA; table 1). The vials of both formulations contain colistimethate sodium dry

25、 powder for reconstitution before administration. Unfortunately, the two products are labelled diff erently with respect to content. Colomycin is labelled in international units (IU; 500 000 IU, 1 million IU, and 2 million IU per vial);30 since there are approximately 12 500 units per milligram of c

26、olistimethate sodium,38 there are 40, 80, and 160 mg of colistimethate sodium in each vial size, respectively.30 The recommended dose for this product for a patient over 60 kg and with normal renal function is 12 million IU three times daily, equivalent to 240480 mg colistimethate sodium per day. By

27、 contrast, Coly-Mycin M Parenteral is labelled as containing “150 mg colistin base activity per vial”.28,29 Actually, each vial contains approximately 400 mg colistimethate sodium, which is equivalent to about 5 million IU. The recommended doses for this product are 255 mg/kg colistin base activity

28、per day in two to four divided doses; which is equivalent to about 667133 mg/kg of colistimethate sodium per day.28,29 Hence, for a patient with normal renal function and bodyweight of 60 kg, the recommended daily dose of Coly-Mycin (400800 mg) is almost double that of Colomycin (240480 mg). Unfortu

29、nately, despite the fact that this diff erence has important implications for therapeutic doses, it seems to have been ignored in published works, and brand or product type is often not specifi ed. To further confuse matters, there are several other brands of colistimethate sodium described in some

30、recent clinical reports (Bellon, France;39 Norma, Greece;40 Laboratory Bristol-Myers Squibb, Argentina13); however, being generic products, it is very diffi cult to obtain their product information. Considering that colistin is one of the few and most important antibiotics against multidrug-resistan

31、t Gram-negative bacteria, it is crucial that optimal dose regimens be used to maximiseefficacy and minimise the development of resistance.2 Acceptable safety was demonstrated with 69 mg/kg of colistimethate sodium per day (divided into two to three doses) of Colomycin4144 and 255 mg/kg per day colis

32、tin base activity with Coly- Mycin,45 the latter corresponding to an actual daily dose of 667133 mg colistimethate sodium per kg per day. The recommended upper daily dose for the two products (480 mg colistimethate sodium per day and 800 mg colistimethate sodium per day for Colomycin and Coly- Mycin

33、, respectively; table 1) diff er substantially. Therefore, it is possible that there is potential “under-dosing” when Colomycin is used. Clearly, with the multiplicity of terms used to express content of vials and dose information, there is major potential to create confusion in the minds of clinicians wishing to