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Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The issue of poor absorption is a result of the dipolar nature of the molecule, which arises from the free amino acid group and carboxylic acid functionalities. The solution is to use a pro-drug approach, where one of the polar groups is masked by a protecting group that can be removed metabolically once the pro-drug has been absorbed. For example, the use of acyloxymethyl esters, which are susceptible to esterases. A nucleophilic residue in the active site of the esterase cleaves the carbonyl part of the ester from the pro-drug, and, in a second step, the penicillin molecule is unveiled. A curly arrow mechanism for this process is given in Figure 1 of the Supporting Material∗. This can be any analogue mentioned previously, for example ampicillin protected in this way is called pivampicillin.
Mecillinam (Amdinocillin) and Pivmecillinam
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Mecillinam, developed by Leo Pharmaceutical Laboratories (Ballerup, Denmark), has a beta-lactam structure and is derived from the penicillin nucleus, 6-aminopenicillinic acid (6-APA). Natural and semisynthetic penicillins are acylamino-penicillinates, but mecillinam is a different penicillin, being a 6-beta-amidinopenicillanic acid, which contains a substituted amidino group (Lund and Tybring, 1972; Matsuhashi et al., 1974). Mecillinam, in its hydrochloride dihydrate form, is suitable for i.m. or i.v. administration, but it is not absorbed when given orally. A pivaloyloxymethyl ester of the drug, pivmecillinam hydrochloride, is readily absorbed from the gastrointestinal tract. After absorption, it is hydrolyzed by enzymes with the liberation of mecillinam, the active form of the drug (Roholt et al., 1975). A combination of pivmecillinam and the pivaloyl ester of ampicillin, pivampicillin, was used during the 1980s, but is not available today. The chemical structure of mecillinam is shown in Figure 11.1.
Blood culture useful only in selected patients with urinary tract infections – a literature review
Published in Infectious Diseases, 2018
Stamatis Karakonstantis, Dimitra Kalemaki
Whether the presence of bacteremia should alter the duration of treatment remains unclear. Our review did not identify any published clinical trial specifically designed to assess the duration of treatment in patients with bacteremic UTIs. In a meta-analysis of studies comparing ≤7days of treatment to a longer course in patients with pyelonephritis or urosepsis, no difference was found between the two arms regarding clinical failure, even in the subgroup of bacteremic patients [11]. However, this subgroup analysis was possible for only four studies [36–39], including only few patients (n = 35 in the short duration treatment arm and n = 51 in the long duration arm). Furthermore, treatment durations of a variety antimicrobial regimens were compared (ciprofloxacin 7 days versus ciprofloxacin 14 days [36], levofloxacin 750 mg once daily for 5 days versus ciprofloxacin 500 mg twice daily for 10 days [37], ciprofloxacin for 7 days versus trimethoprim–sulfamethoxazole for 14 days [39], pivampicillin–pivmecillinam for 7 versus 21 days [38]). In a recently published multi-centre randomized controlled trial comparing a 7-day course to a 14-day course in patients with pyelonephritis, including men and cases with complicated pyelonephritis, the clinical cure rate was not statistically significantly different in the bacteremic subgroup compared to non-bacteremic patients [27]. However, non-inferiority was not shown, the number of patients with positive blood cultures was small (n = 35), and men treated with the 14-day regimen had significantly higher clinical cure rates.
Modeling percutaneous absorption for successful drug discovery and development
Published in Expert Opinion on Drug Discovery, 2020
Hanumanth Srikanth Cheruvu, Xin Liu, Jeffrey E. Grice, Michael S. Roberts
However, the use of penetration modifiers may alter the absorption of undesired solutes along with the active drug that may cause skin damage or irritancy. Consequently, it may be preferable to modify a poorly penetrating drug by a chemical reaction to produce a better penetrant. This enables an inactive parent drug to be readily partitioned into the skin and subsequently converted into an active metabolite drug by skin metabolism. This delivery technique is known as prodrug therapy. For instance, pivampicillin (logP: 1.43), a pivaloyloxymethyl ester of ampicillin, is used as a prodrug for ampicillin (logP: 0.88). Here, the parent prodrug is more lipophilic than the active drug, resulting in enhanced permeation.
Successes, failures, and future prospects of prodrugs and their clinical impact
Published in Expert Opinion on Drug Discovery, 2019
Prodrugs have been developed for the treatment of microbial and protozoal infections. Bacampicillin and pivampicillin are ester penicillin-class prodrugs. Bacampicillin is 1ʹ- ethoxycarbonyloxyethyl ester prodrug of ampicillin and possesses no antimicrobial activity. During absorption, bacampicillin is rapidly and completely hydrolysed to ampicillin. Bacampicillin produces faster and higher serum concentrations of ampicillin than non-prodrug ampicillin [56]. Similarly, pivampicillin, the pivaloyloxymethyl ester prodrug of ampicillin has a higher absorption than ampicillin, but to a lesser extent [57,58].