Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin.

The emergence of antimicrobial resistance is a significant public health issue worldwide, particularly for healthcare-associated infections caused by carbapenem-resistant gram-negative pathogens. Cefiderocol is a novel siderophore cephalosporin targeting gram-negative bacteria, including strains with carbapenem resistance. The structural characteristics of cefiderocol show similarity to both ceftazidime and cefepime, which enable cefiderocol to withstand hydrolysis by ß-lactamases. The unique chemical component is the addition of a catechol moiety on the C-3 side chain, which chelates iron and mimics naturally occurring siderophore molecules. Following the chelation of iron, cefiderocol is actively transported across the outer membrane of the bacterial cell to the periplasmic space via specialized iron transporter channels. Furthermore, cefiderocol has demonstrated structural stability against hydrolysis by both serine- and metallo-ß-lactamases, including clinically relevant carbapenemases such as Klebsiella pneumoniae carbapenemase, oxacillin carbapenemase-48, and New Delhi metallo-ß-lactamase. Cefiderocol has demonstrated promising in vitro antibacterial and bactericidal activity, which correlates with its in vivo efficacy in several animal models. This article reviews the discovery and chemistry of cefiderocol, as well as some of the key microbiological and in vivo findings on cefiderocol from recently conducted investigations.

ß-Lactams and ß-Lactamase Inhibitors: An Overview.

ß-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related ß-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of ß-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to ß-lactams is primarily because of bacterially produced ß-lactamase enzymes that hydrolyze the ß-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum ß-lactamase inhibitors that work against many problematic ß-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of ß-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.

History of antibiotics. From salvarsan to cephalosporins.

Infections have represented for a long time the leading cause of death in humans. During the 19th century, pneumonia, tuberculosis, diarrhea and diphtheria were considered the main causes of death in children and adults. Only in the late 19th century did it become possible to correlate the existence of microscopic pathogens with the development of various diseases. Within a few years the introduction of antiseptic procedures had begun to reduce mortality due to postsurgical infections. Sanitation and hygiene played a significant role in the reduction of the mortality due to several infectious diseases. The introduction of the first compounds with antimicrobial activity succeeded in conquering many diseases. In this review we analyzed, from a historical perspective, the development of antibiotics and the circumstances that led to their discovery. The first compound with antimicrobial activity was introduced in 1911 by Erlich. He focused his research activity on the discovery of a "magic bullet" to treat syphilis. Afterwards, Foley and colleagues brought penicillin to the forefront. Streptomycin represents the first drug discovered for the treatment of tuberculosis, and its development included the first use of clinical trials. Finally, with the development of cephalosporins, the introduction of new antimicrobial compounds with broad activity against gram-positive and also some gram-negative bacteria began.

Historical perspectives in critical care medicine: blood transfusion, intravenous fluids, inotropes/vasopressors, and antibiotics.

Significant progress in critical care medicine has been the result of tireless observation, dedicated research, and well-timed serendipity. This article provides a historical perspective for four meaningful therapies in critical care medicine: blood transfusion, fluid resuscitation, vasopressor/inotropic support, and antibiotics. For each therapy, key discoveries and events that have shaped medical history and helped define current practice are discussed. Prominent medical and social pressures that have catalyzed research and innovation in each domain are also addressed, as well as current and future challenges.

The life and work of Guy Newton (1919-1969).

An account is given of the life and work of G.G.F. Newton (1919-1969), joint discoverer with E.P. Abraham (1913-1999) of cephalosporin C.

Development of the semi-synthetic penicillins and cephalosporins.

Semi-synthetic penicillins and cephalosporins both derive from their respective chemical nuclei, 6-aminopenicillanic acid (6-APA) and 7-aminocephalosporanic acid (7-ACA). Work leading to their isolation was being carried out in parallel, but following very different pathways, during the last half of the 1950s. The development of 6-APA was reviewed recently in this journal, and in the present article I take a closer look at early work on 'penicillin amidase' and revisit the steps that led to 7-ACA.

[The origin of cephalosporins].

The origin of cephalosporins is investigated. In 1945, Giuseppe Brotzu, who was the rector of the University of Cagliari in Sardina, Italy, isolated a cephalosporin-producing strain, Cephalosporium acremonium. Although as many as 48 cephalosporin derivatives have been developed in Japan, how a cephalosporin-producing organism was discovered is not widely known here. This article contains the first Japanese translation of Brotzu's Italian publication entitled "Ricerche su di un nuovo antibiotico (Research on a new Antibiotic)" and reveals how cephalosporin was developed, together with a cross reference to the first report of penicillin, a similar antibiotic compound, which was discovered by A. Fleming in 1928. Brotzu's brief academic and social background is also presented.

Sir Edward Abraham's contribution to the development of the cephalosporins: a reassessment.

This paper is based on an invited lecture given at the 21st International Congress of Chemotherapy in July 1999, as part of a Symposium entitled '50 years of cephalosporins: their use the next 50 years', (Hamilton-Miller JMT, Cephalosporins: from mould to drug. Sardinia to Oxford and beyond, J Antimicr Chemother 1999;44(A):26). Celebration of this Golden Anniversary was made more poignant by the death of the last major participant, Sir Edward Abraham, in May 1999. This history has been told before, but mainly by Sir Edward, who being a very modest man (to which his obituaries graphically attest) consistently underplayed the role that he and Newton had in the discovery of cephalosporin C, that led to all the cephalosporins now in use. I had the privilege of working at the Dunn School from 1967 to 1970, with Abraham and Newton, where I met Brotzu, Florey and Dorothy Hodgkin, all of whom had important roles in this story. Other workers at the Dunn School at that time, e.g. Heatley, Sanders and Jennings (who became Lady Florey), helped develop penicillin. Such a galaxy of stars of the antibiotic firmament will never again be assembled. "Let us now praise famous men... these were honoured in their generation, and were the glory of their times" - Ecclesiasticus XLIV. vv 1.7.

Cephems: fifty years of continuous research.

Since 1964, seven waves of parenteral cephems have been reported. All of them were designed to meet medical needs. The first (group I) and the third (group III) waves were very successful and drugs belonging to group III are widely used in the treatment of severe infections. A new series of compounds (group VII), with a new compound underdevelopment was designed for the treatment of Staphylococcus aureus strain resistant to methicillin but also to glyco- and lipoglycopeptides. By modifying the substituent at position 3 and 7 of the cephems rings optimal moieties have been fixed leading to potent anti-Gram-positive drugs. Alterations of substituents are still in progress to obtain optimal anti-Gram-positive (anti-MRSA) compounds. The first oral cephem cephalexin was introduced in clinical practice in 1967. Since this time, many esterified and non-esterified cephems have been synthesized and introduced in clinics. There are two groups of compounds, alpha-amino and non-alpha-amino cephems which are classified in six groups according to their chemical structure. The absorption route was explored and three transporting systems have been described according to the physico-chemical properties of these compounds, in addition prodrugs are passively absorbed.