Essay: Cephalosporins – discovery, use, future

Health Sciences researcher Carolina Campos Muniz states that from their observation and discovery in 1945 by Italian professor of hygiene Giuseppe Brotzu, cephalosporins have led to remarkable successes against many strains of bacteria. Once he first isolated cephalosporin from a fungus growing in sewage-contaminated seawater on the Italian coast, Brotzu recognized the predecessor of modern cephalosporins to be effective in treating typhoid fever as well as other infections (90). S.J. Dancer, specialist of Microbiology states cephalosporins’ hypoallergenic nature, lack of toxicity, and deadliness across a large spectrum of microorganisms has made them popular for a wide range of disease prevention methods and treatment options. According to Lorenzo Zaffri, researcher at Michigan State University, as the successor to the incredible victories of penicillins, cephalosporins have been frequently prescribed to treat both infections of gram negative and gram positive bacteria (73-74). Although cephalosporin antibiotics have been instrumental in safely eradicating infections caused by a variety of bacteria, they have become perhaps too popular: overprescribing and overuse in the hospital setting has led to much of the multidrug resistant bacteria medicine is struggling with today (Dancer).
Oddly enough, a sewage contamination problem led to Brotzu’s curiosity and subsequent isolation of the fungus that produces cephalosporin (Campos et. al. 90). Professor of preventative medicine at University of Pavia G. Bo states that in Brotzu’s home city of Calgari, he researched salmonella bacteria presence in the sewage system, which cause typhoid fever. However, he discovered that these bacteria were no longer infective once the sewer water merged with the sea (6-8). Interestingly, the young people of Calgari had a habit of swimming in “Su Siccu” Bay, where the city’s sewage system drained, with no ill effects (Campos et. al. 90). Brotzu noticed that as a whole Calgari was remarkably low in typhoid fever outbreaks compared to the rest of Italy and that swimming in the sewage polluted water did not seem to negatively affect swimmers later. This piqued Brotzu’s interest, as it seemed swimmers should be afflicted by the multitudinous diseases borne by feces and sewage (Zaffiri et. al. 73). In fact, those who both swam in and drank the water never came down with typhoid fever and were resistant to skin diseases as well (Bo 7). Edward Abraham, the Oxford researcher responsible for isolating the form of cephalosporin used today, states Brotzu was inspired to research the possible antibiosis properties of this fungus due to the recent popularity of penicillin. The self-purification process of the seawater captured his curiosity, and Brotzu took a seawater sample to try to isolate the fungus (99-100). He named the fungus Cephalosporium acremonium but couldn’t take research further without funding. Brotzu wasn’t shy about experimentation: he injected the fungus culture into multiple patients and animals infected with typhoid fever in an effort to learn more (Bo 7). He tried unsuccessfully to procure a research grant from an Italian pharmaceutical company, but was denied; without funding his experiments had to come to a close. However, as E.P. Abraham states in the introduction of Chemistry and Biology of Beta-Lactam Antibiotics, Brotzu wanted others to continue his work as he saw the potential of the fungus. He published his experimentation on the antibiotic in hopes his work efforts would be continued by someone else (Gorman and Morin xxix). Additionally, he sent his research and the fungus culture to Oxford; after the advent of cephalosporins he was nominated for a Nobel Prize for his work in isolating the antibiotic producing fungus (Campos et. al. 90). Brotzu’s inquisitiveness as to how Calgari’s seawater self-purified led to preliminary isolation and research of how cephalosporins worked.
Once Brotzu’s work was sent to Oxford, cephalosporin was further studied and eventually isolated (Campos Muniz et. al. 90). As professor of microbiology J.M.T. Hamilton-Miller states, researcher Edward Abraham was instrumental in this progress. Abraham was no stranger to antibiotic research. During the period when extensive investigation was being done on penicillin, he had proposed a structure for the drug, but two of the most respected organic chemists of the time disagreed. Years later, his structure was eventually proven right; due to the structural similarity of cephalosporins to penicillins, his investigation of penicillin’s structure likely helped him in his cephalosporin research (Hamilton-Miller). As Abraham describes, the first antibiotic he and other Oxford researchers isolated from the fungus was cephalosporin P, which was effective against only gram positive bacteria; Abraham did not believe this antibiotic was responsible for the data Brotzu provided, so research continued (100-101). The second compound they subsequently discovered and purified, cephalosporin N, proved to be a variant of penicillin and was named penicillin N. This form was effective against both gram negative and gram positive bacteria, and was very different from other known forms of penicillin known at the time. Further research of penicillin N led to the discovery of cephalosporin C, which was a byproduct of the purification process for penicillin N (101). Because penicillin N did not show huge promise, research moved in the direction of the researchers’ accidental discovery: cephalosporin C (Gorman and Morin xxix).  This new compound, isolated in 1953 by Abraham and colleagues, proved active against a far greater range of bacteria than penicillin (Campos Muniz et. al. 90). Abraham devised a structure for the newly discovered compound, but again, it was slandered by other chemists. X-ray crystallography, however, soon demonstrated Abraham right once more (Abraham 103). Abraham’s cephalosporin C had incredible potential, but the method he had for obtaining it produced unrealistically low yields that would never succeed commercially (105). A new strain of the fungus yielded higher levels of product; however, it was still very difficult to isolate in large quantities, which limited experimentation (Hamilton-Miller). Abraham was eager to improve on the structure by modifying side chains, and his advances attracted the attention of several pharmaceutical companies (Abraham 104-105). He published his findings as well as cephalosporin’s structure in 1961(Zaffiri et. al. 73). Soon, the company Eli Lilly in the United States began experimentation (Abraham 104-105).
Lilly was successful in devising an effective isolation method that gave a much higher yield of cephalosporin C, allowing clinical trials to begin (Abraham 105). In 1964, Lilly introduced the first cephalosporin drug, in parenteral form, to the public (Zaffiri et. al. 73). Multiple forms of the drug continued to be synthesized and produced for different purposes. A method for creating cephalosporin from penicillin was also developed (Abraham 105). In just under a decade, cephalosporin had gone from an undiscovered factor in seawater self-purification to a prescribed antibiotic.
Throughout history, the majority of human deaths have been a result of infections of some kind (Zaffiri et. al. 67). As World War II drew to a close, penicillin was the primary antibiotic used in treatment of nearly all infections. The same year as the discoverers of penicillin received their Nobel Prize, Brotzu started his research on the fungus that created cephalosporin. As research continued at Oxford, the huge possibilities for modification and the broad spectrum effectiveness of cephalosporin were recognized and attracted the attention of pharmaceutical companies (Campos Muniz et. al. 95-96). As the website eMedExpert describes in their article “Cephalosporins,” among the benefits of cephalosporins is their versatility. Allergies to cephalosporins are rare, but when side effects occur, they are normally mild and affect the digestive system primarily (“Cephalosporins”). Because of their safety and breadth of effectivity, they are prescribed as the antibiotic of choice in the hospital setting, especially for surgeries (Dancer). Patients with penicillin allergies can typically be given cephalosporin, as the likelihood of cross-reaction is very low. This flexibility allows for a whole different demographic to be treated outside of the much smaller population able to be treated by penicillin. In addition, each successive generation of cephalosporins kill a wider range of bacteria than the last (“Cephalosporins”). The Best Practice Journal’s article “Appropriate Use of Cephalosporins” states that over the course of their history in medical practice, these antibiotics have been used to treat anything from meningitis to cellulitis to gonorrhea. There can be no doubt of the countless lives cephalosporin use has spared. Their multitudinous benefits have made them popular, but perhaps their fame has not been entirely beneficial. Overprescribing has proved a dangerous adversary; as Dancer aptly states, “It is the popularity of the cephalosporins, perhaps, that has become their downfall.”
The reasons for cephalosporins’ popularity, their safety and ability to kill a wide range of bacteria, have resulted in overuse. In cephalosporins’ more recent history, their popularity has shifted away from improving public heath to actually hindering it. Physicians have prescribed cephalosporin liberally in hospitals for years, causing selection for multidrug resistant bacteria that can cause epidemics. The greater the cephalosporin usage, the higher the mutation rate and subsequent resistance. Once the bacteria have mutated and are resistant, they can cause deadly epidemics for which there are few treatments. Cephalosporins are partially to blame for the spread of MRSA: widespread epidemics began shortly after cephalosporin became prevalent in the early 1980s. MRSA was largely inactive during the 60s and 70s. As cephalosporins were introduced to practice in the 80s, MRSA incidences increased exponentially: cephalosporin use and MRSA are directly correlated (Dancer).
Failure of physicians to prescribe adequate dosage to rid the patient completely of infection as well as failure of the patient to follow usage directions will only exacerbate MRSA’s spread (Dancer). Dancer conveys the seriousness of the situation by citing a study that showed “patients who had received treatment for >5 days with cephalosporins were three times more likely to acquire MRSA than those who had not received these agents.” To regulate the incidence of MRSA, cephalosporin use must also be regulated. Dancer argues that evidence points to cephalosporins not only allowing MRSA to take over, but facilitating its success. It has only been in recent years, with the increase in knowledge regarding how bacteria mutate and drug resistance occurs, that the effect of overzealous cephalosporin prescribing has been observed and studied. The precise impact cephalosporins will have on deadly epidemics such as MRSA will remain to be seen in the years to come (Dancer). Overprescribing has led to mutation, resistance, and MRSA: without significant reduction in cephalosporin use, the problem will only get worse.
Bacterial overgrowth is another drawback of cephalosporin use. Cephalosporins kill a broad spectrum of organisms, but those it does not kill have the opportunity to take over. When bacteria susceptible to cephalosporin are killed off, other bacteria can increase far above normal levels and even thrive in the absence of competition. These unaffected bacteria are often resistant to other antibiotics as well and although they may not be a threat in the absence of cephalosporin, they can cause epidemics such as MRSA. Fungal infections are also common after cephalosporin treatment. Candida yeast infections frequently occur because of the wide range of bacteria that are killed and the opportunity for overgrowth this affords (Dancer). Although correlation does not necessarily equal causation, Dancer argues the 500% increase in Candida infection in the 1980s occurred in conjunction with cephalosporin usage increase. Gonorrhea has possibly began to develop resistance as well following widespread treatment with cephalosporins (“Appropriate Use of Cephalosporins”). By destroying most of the types of bacteria, both good and bad, cephalosporin antibiotics allow for the remaining bacteria to take over and even thrive, with disastrous effects (Dancer).
How then, should cephalosporins be regulated? Dancer explores both sides of the situation by highlighting arguments from opposing viewpoints. The case for controlling prescribing states that cephalosporin use is unarguably correlated with higher levels of resistant bacteria, and hospitals and countries where use is restricted have lower levels of multidrug resistant bacteria, while those that do not restrict use are afflicted by epidemics such as MRSA much more heavily. Experts on this trend argue that cephalosporins alone are the “key players in the link between antibiotic usage and prevalence of multiply-resistant organisms” (Dancer). The question of how to regulate prescribers is difficult to address, with no one right answer. Enforcing antibiotic usage is made more problematic by the lack of a precise understanding of how antibiotic use works to encourage bacterial resistance. There is also the issue of educating most of the medical profession about why cephalosporin use should be monitored. As the power to kill infection is removed from general practitioners, dentists, and the like, an increased responsibility would be given to specialists in infectious disease and other similar areas. Pharmacists would hold a more important position in antibiotic prescription review to reduce use (Dancer). The evidence points to the need for cephalosporin regulation, but the method for doing so is unclear and difficult to implement.
In opposition to prescriber regulation, should the mutation and resistance process be allowed to run its course as it has with previous antibiotics? Dancer argues that while cephalosporins have caused an inordinate increase in multidrug resistant bacteria, if they wouldn’t have been discovered, another popular antibiotic would likely have produced similar effects. In other words, “Resistance inevitably follows the introduction of a new antimicrobial.” Resistance to cephalosporin, once the drug is restricted, would move to combat another antibiotic. Multidrug resistant organisms are inevitable, and in the place of cephalosporins, another type of antibiotic would produce similar results. Perhaps the best strategy is to allow resistance to cephalosporins to run its course, as in cephalosporins’ absence, bacteria would likely do the same with another antibiotic (Dancer). With both arguments, the path forward remains unclear.
Cephalosporins, from their humble discovery in the polluted water on Calgari’s coast in 1945, have undoubtedly played a major role in keeping the modern antibiotic using population relatively infection free since their introduction. Their activity against a broad spectrum of bacteria, lack of toxicity, and potential for modification have made them one of the most heavily prescribed drugs of the modern medical world. However, cephalosporins have also encouraged the evolution of multidrug resistant organisms with far-reaching and disastrous effects: MRSA and other resistant organisms have thrived like never before (Dancer). The question for this century is what action, if any, needs to be taken to prevent further prosperity of resistant entities? Cephalosporin regulation would prove difficult to enforce, and merely allowing the resistance process to continue would bring unforeseen effects on global health. Cephalosporins have been used in practice for only two decades, yet their consequences have already been experienced and their future remains unclear.