How it began
At the end of the 1970s a team at the research institute of the pharmaceutical company PLIVA in Zagreb worked on derivatives of the antibiotic erythromycin. The core team was Slobodan Đokić, Gabrijela Kobrehel, Gorjana Lazarevski and Zrinka Tamburašev. A priority patent application for the precursor compound was filed in Yugoslavia in 1979, and PLIVA protected azithromycin itself with a Yugoslav patent application in March 1981, naming Kobrehel and Đokić as inventors.
Before it existed
Erythromycin had a wider spectrum of antibacterial activity than penicillin, but it was less well tolerated and was unstable in acid. PLIVA researchers had studied the macrolides since the 1960s and tried to make erythromycin more stable in an acidic medium through chemical changes, focusing on the carbonyl group at position 9 of the macrolide ring, which was thought to be responsible for the instability.
How it works
The chemists took erythromycin A through a Beckmann rearrangement, which expanded the ring, and after reduction obtained a cyclic amine with a nitrogen atom at position 9a. A further modification of that ring gave azithromycin, the first member of a new class called azalides. Its name replaces the er- of erythromycin with az- for nitrogen. Studies showed that it passed quickly from the blood into tissues and stayed at the site of infection for a long time, and that it inhibits bacterial protein synthesis.
How it spread
Yugoslavia was in economic crisis and PLIVA was state owned, so it looked for a partner. Pfizer had filed its own United States applications in 1982 and 1983, but could not make or sell the drug without a PLIVA license. Agreements were negotiated between 1982 and 1987. PLIVA kept sales rights in Eastern Bloc countries and some Asian countries, and Pfizer paid royalties on sales in its markets. PLIVA registered the drug in Yugoslavia in 1988 as Sumamed, the first registration globally, and Pfizer launched Zithromax in 1991.
What lasted
By the end of the 20th century azithromycin had become the leading macrolide antibiotic in the world, and the authors of a 2024 history in the journal Pharmazie call it one of the most successful and best-selling antibiotics. Kobrehel and Đokić, the latter posthumously, were named Heroes of Chemistry for the year 2000. The same history presents the drug as an example of how patent protection let a small state-owned company bargain with a large one.
