Category:Antibacterials

An antibacterial is a medicine that kills or inhibits the growth of bacteria. The term antibiotic, in its original sense, meant a substance produced by one microorganism that suppresses the growth of another, and excluded the synthetic agents; in current clinical use the two words are interchangeable. The category encompasses the natural-product fermentation antibiotics (the penicillins, the cephalosporins, the aminoglycosides, the tetracyclines, the macrolides, and several others), the semi-synthetic derivatives that extended their spectrum and stability, and the wholly synthetic classes (the sulfonamides, the fluoroquinolones, the nitroimidazoles, the nitrofurans, the oxazolidinones).

The clinical era began with a synthetic agent. In 1909 Paul Ehrlich and his Japanese collaborator Sahachiro Hata, working at the Frankfurt Royal Institute for Experimental Therapy, identified compound number 606 in their methodical screen of arsenical dyes against the syphilis spirochete; arsphenamine (Salvarsan) was the first medicine of any kind shown to cure a specific bacterial infection, and the prototype of what Ehrlich called the magic bullet.^[1] Its toxicity and parenteral administration limited its use; its conceptual importance was immense. A quarter century later Gerhard Domagk at IG Farbenindustrie in Wuppertal-Elberfeld found that the red azo dye sulfamidochrysoidine, given under the trade name Prontosil, protected mice from lethal streptococcal infection; he reported the work in 1935 after a private trial in his own daughter, who had a streptococcal arm infection that was about to be amputated.^[2] Within a year the Bovet group at the Pasteur Institute showed that the active metabolite was the colourless aminobenzenesulfonamide, sulfanilamide, whose patent had expired in 1908; a class of inexpensive synthetic antibacterials, the sulfonamides, became available worldwide within months. Domagk was awarded the Nobel Prize in 1939 and was forced by the Nazi regime to decline it.

The natural-product era opened, more famously, with Alexander Fleming's observation in September 1928 at St Mary's Hospital in London that a stray contaminant Penicillium colony on a discarded staphylococcus plate had cleared a halo around itself.^[3] Fleming named the active substance penicillin but did not pursue its purification, and it lay essentially dormant for a decade. In 1940 Howard Florey, Ernst Chain, and Norman Heatley at the Sir William Dunn School of Pathology in Oxford concentrated enough penicillin from mould broth to test in mice, and in February 1941 they treated their first human patient, the Oxford policeman Albert Alexander, who recovered briefly before the supply ran out.^[4] Production at the scale required for clinical use was solved in 1942-1944 by a U.S. War Production Board collaboration with the Northern Regional Research Laboratory in Peoria, Illinois, where Mary Hunt's mouldy cantaloupe yielded the high-producing strain Penicillium chrysogenum and deep-tank submerged fermentation replaced the surface cultures of the Oxford team. By D-Day in June 1944 there was enough penicillin to treat every Allied casualty. Fleming, Florey, and Chain shared the 1945 Nobel Prize.

The decade after penicillin was the most productive in the history of antibacterial chemistry, and the man at the centre of it was the Russian-born American microbiologist Selman Waksman at the Rutgers Agricultural Experiment Station. Waksman had spent his career studying soil actinomycetes and had coined the term antibiotic for their secondary metabolites in 1942. In 1943 his graduate student Albert Schatz isolated streptomycin from Streptomyces griseus, the first medicine effective against Mycobacterium tuberculosis; Waksman received the Nobel Prize in 1952 and Schatz, after years of dispute, was credited as co-discoverer.^[5] Chloramphenicol (1947, Burkholder, then Parke-Davis), chlortetracycline (Aureomycin, 1948, Benjamin Duggar at Lederle, from Streptomyces aureofaciens), neomycin (1949), erythromycin (1952, Lilly, from a soil sample from the central Philippine island of Iloilo), vancomycin (1956, Lilly, from a sample of Borneo soil sent in by a missionary), and the cephalosporins (1948, Giuseppe Brotzu at the University of Cagliari, from a Sardinian sewage outflow, developed in Oxford and brought to clinical use by Lilly in 1964 as cephalothin) followed in steady succession.

The synthetic antibacterials of the second half of the century filled in gaps the natural products did not cover. The nitroimidazole metronidazole was developed at Rhône-Poulenc in 1959 for trichomoniasis and was found to be active against anaerobic bacteria as well. The first quinolone, nalidixic acid, was isolated by George Lesher at Sterling-Winthrop in 1962 as a side product of chloroquine synthesis; the introduction of a fluorine atom at the 6-position of the quinolone nucleus in the late 1970s yielded norfloxacin (1980) and then ciprofloxacin (1987), broad-spectrum oral agents with a respiratory- and urinary-tract niche the natural-product antibiotics had filled poorly.^[6] The carbapenems, beginning with imipenem in 1985, extended the beta-lactam spectrum to most Gram-negative pathogens including Pseudomonas, and the oxazolidinone linezolid (2000) and the cyclic lipopeptide daptomycin (2003) restored activity against vancomycin-resistant Gram-positive bacteria when no other option remained.

The phenomenon of bacterial resistance is as old as the medicines themselves. Penicillinase from Staphylococcus aureus was reported by Abraham and Chain in 1940, before penicillin had ever been given to a patient.^[7] By 1944 a third of the staphylococci in the wards at Hammersmith Hospital were penicillin-resistant; methicillin was introduced in 1959 specifically to evade the staphylococcal beta-lactamase, and methicillin-resistant S. aureus (MRSA) was reported in 1961, two years later. Vancomycin-resistant enterococci appeared in 1988, the Klebsiella pneumoniae carbapenemase in 1996, the New Delhi metallo-beta-lactamase in 2008. The accumulation of resistance mechanisms has steadily compressed the useful pharmacopoeia in some clinical settings, particularly the intensive-care unit and the long-term-care facility, and the rate at which new antibacterial classes are developed has not kept pace; only the oxazolidinones, the lipopeptides, the lipoglycopeptides, and, more recently, the siderophore cephalosporin cefiderocol, represent genuinely novel mechanisms reaching clinical use since 2000.^[8]

The contemporary use of an antibacterial in a person who is acutely ill is, in principle, a question of three judgments: which organism is likely, which medicines retain activity against it in this population at this time, and what dose and duration deliver enough medicine to the site of infection. The first is the work of clinical reasoning and laboratory diagnosis; the second is the work of local antibiogram surveillance; the third is the work of pharmacokinetics and the drug-metabolising enzyme pages indexed elsewhere in this wiki. The antibacterials are also the class most often given inappropriately, and antimicrobial stewardship, the structured limitation of unnecessary prescribing, is now a recognised hospital and outpatient discipline.

By mechanism and structure:

• Beta-lactam antibiotics: the penicillins (Penicillin G, Penicillin V, the aminopenicillins including amoxicillin) and the cephalosporins (cephalexin, cefuroxime, cefdinir, and successively broader-spectrum generations)
• Macrolides and the related azalides: erythromycin, azithromycin, clarithromycin
• Tetracyclines: doxycycline, tetracycline, minocycline
• Aminoglycosides: tobramycin, gentamicin, amikacin
• Fluoroquinolones: ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin
• Lincosamides: clindamycin
• Nitroimidazoles: metronidazole
• Nitrofurans: nitrofurantoin
• Glycopeptides and lipoglycopeptides (where built): vancomycin, telavancin, dalbavancin
• Antifolates (sulfonamides combined with trimethoprim are the principal antibacterial application of this class)
• Topical antibacterials are collected separately under topical antibiotics and include mupirocin

The boundary of this category is "medicine that kills or inhibits bacterial pathogens in the human host." Antiviral agents, antifungal agents, and antiparasitic agents are collected separately. Antiseptics and disinfectants (chlorhexidine, povidone-iodine, hypochlorite) act on bacterial surfaces but are not administered systemically and are collected under antiseptics. Antimycobacterial agents (isoniazid, rifampin, ethambutol, pyrazinamide, the fluoroquinolones when used for tuberculosis) belong taxonomically here but are listed under a dedicated subcategory when their principal indication is mycobacterial. Topical preparations whose principal indication is dermatologic or ophthalmic are also listed under the appropriate route-specific category in addition to this one.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.