'Old' antibiotics for emerging multidrug-resistant bacteria

Abstract

Purpose of review: Increased emergence of bacterial resistance and the decline in newly developed antibiotics have necessitated the reintroduction of previously abandoned antimicrobial agents active against multidrug-resistant bacteria. Having never been subjected to contemporary drug development procedures, these 'old' antibiotics require redevelopment in order to optimize therapy. This review focuses on colistin as an exemplar of a successful redevelopment process and briefly discusses two other old antibiotics, fusidic acid and fosfomycin.

Recent findings: Redevelopment of colistin led to an improved understanding of its chemistry, pharmacokinetics and pharmacodynamics, enabling important steps towards optimizing its clinical use in different patient populations. A scientifically based dosing algorithm was developed for critically ill patients, including those with renal impairment. As nephrotoxicity is a dose-limiting adverse event of colistin, rational combination therapy with other antibiotics needs to be investigated.

Summary: The example of colistin demonstrated that state-of-the-art analytical, microbiological and pharmacokinetic/pharmacodynamic methods can facilitate optimized use of 'old' antibiotics in the clinic. Similar methods are now being applied to fosfomycin and fusidic acid in order to optimize therapy. To improve and preserve the usefulness of these antibiotics rational approaches for redevelopment need to be followed.

Figure 1

(a) Structures of colistin A and B; (b) structures of colistin A and B methanesulphonate (CMS). Fatty acyl: 6-methyloctanyl for colistin A and 6-methylheptanyl for colistin B; Thr, threonine; Leu, leucine; Dab, α,γ-diaminobutyric acid. α and γ indicate the respective −NH₂ involved in the peptide linkage.

Figure 2

Steady-state plasma concentration–time profiles of (a) CMS or (b) formed colistin in 105 critically ill patients (89 not on renal replacement, 12 on intermittent haemodialysis and 4 on continuous renal replacement therapy) [51■■]. The physician-selected daily dose ranged from 75 to 410 mg colistin base activity; the dosage intervals ranged from 8 to 24 h and hence the inter-dosing blood sampling interval spanned the same range. CMS, colistin methanesulphonate. Reproduced with permission from [51■■].

Figure 3

Relationship of (a) physician-selected daily dose of colistin base activity (CBA) and (b) the resultant average steady-state plasma colistin concentration with creatinine clearance in 105 critically ill patients [51■■]. Reproduced with permission from [51■■].