A brief history of antibiotics

During the month of June, Dr. Gail Demmler-Harrison and I went over antibiotic historical trivia. The systematic and at times serendipitous development of the first antibiotics decisively shifted paradigms in medicine. I’d like to share with you distant facts about current drugs.

More than 80 antibiotics (here meaning antibacterial agents) are available in the United States for use in pediatrics. During a given month on the inpatient service, and without counting antivirals, antiprotozoals or antifungals, I commonly handle some 30 antibiotics, with half of them used in four out of five cases. I find this fact interesting, and I imagine that it should apply to other specialties as well. I’m not aware of any systematic study addressing this issue (do you know of any?).

From A to P (Part 1)

Aminoglycosides

Aminoglycosides derive from soil actinomycetes. Its first member, streptomycin (with a ‘y’), was isolated in 1943 from a strain of Streptomyces griseus. It was the first effective drug against tuberculosis and numerous other infections. The actinomycete Micromonospora gave rise to gentamicin and netilmicin (with an ‘i’). Amikacin and netilmicin are semisynthetic aminoglycosides.

Amphotericin B

Amphotericin B was extracted in 1955 at the Squibb Institute for Medical Research from the actinobacterium Streptomyces nodosus from cultures of soil originating in the Venezuelan Orinoco River area. Its name comes from the amphoteric properties of the compound, ie, the ability to react as an acid or a base. Amphotericin A had inferior in vivo activity, and thus it was abandoned. The amphoterrible infusion reactions have ameliorated with improved drug preparations. Insoluble in water, it comes as a deoxycholate esther (regular ampho B). A lipid complex (ampho B inside miscelles) and a liposomal preparation (ampho B inside liposomes) are available with decreased nephrotoxicity, although reduced renal penetration.

Cephalosporins

Supernatants from Cephalosporium acremonium (now Acremonium chrysogenum), a fungus isolated in 1948 from a sewer in Sardinia by Italian investigator Giuseppe Brotzu, were found to inhibit the in vitro growth of Staphylococcus aureus and beta-lactamase producing Salmonella typhi. Modifications in the seven-aminocephalosporanic ring of cephalosporin C (one of the three antimicrobial extracted) conferred improved antibacterial activity and resulted in the introduction of the first-generation cephalosporin cephalotin in 1964 by Lilly. There are more cephalosporins now than ink on your pen. Corollary: Not all waste is a waste.

Clindamycin

Lincomycins were derived from the Streptomyces lincolnensis in 1962. In 1970, clindamycin — with improved activity and pharmacokinetic properties — was discovered. Probably the least palatable of all, its use has glamorously revamped with the methicillin-resistant S. aureus explosion. Be vigilant to clindamycin resistance and Clostridium difficile colitis.

Macrolides

Erythromycin was isolated in 1952 by McGuire and coworkers at Lilly from the metabolic products of a strain of Streptomyces erythreus originated in Iloilo, the Philippines. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin with improved pharmacokinetic properties.

Penicillin

Although a 23-year-old French medical student, Ernest Duchesne, discovered that molds kill bacteria 32 years before Fleming’s seminal publication, penicillin gained attention thanks to Sir Alexander Fleming.

This story is well known. While working with influenza virus (hot at the time) at St. Mary’s Hospital in London in 1928, he noted that mold grown in a Staphylococcus plate was surrounded by a halo of inhibition. He then grew the mold in pure culture to find that even 800-fold dilutions were inhibitory. The mold belonged to the Penicillium genus, and the substance’s name changed from "mold juice" to "penicillin." His research was published in 1929 and penicillin mass-production was fueled by World War II.