Antibiotics may rightly be called wonder drugs, but their use over the last 80 years has come at a price. Through evolutionary mechanisms assisted by overuse and misuse, bacteria develop resistance to new antibiotic compounds soon after their introduction. Today, some of the most virulent bacterial pathogens are resistant to all but one or two agents.
Our experience with one topical antibiotic, mupirocin, demonstrates that resistance can emerge even against agents that are not administered systemically.
GlaxoSmithKline’s Bactroban (mupirocin ointment) anti-infective was introduced in 1985 and rapidly adopted into clinical practice for treating topical Staphylococcus infections and colonizations. Numerous studies demonstrated mupirocin’s effectiveness in treating primary skin infections, surgical incisions, and accidental wounds. Bactroban soon became the agent of choice for these indications; within 15 years the drug was registered in 90 countries for eradication of Staphylococcus, including such virulent strains as methicillin-resistant S. aureus (MRSA).
Resistance to mupirocin began to emerge shortly after the drug’s introduction. By 2007 Simor et al. reported that the incidence of mupirocin-resistant Staphylococcus aureus increased from 1.6% during the period 1995–1999, to 7% between 2000 and 2004. Resistance was related to a mutation on a gene coding for the enzyme isoleucyl-tRNA synthetase. Moreover, it became apparent that MRSA could confer resistance to mupirocin through gene transfer to other bacteria treatment.
A more recent study, by Fawley et al, on perioperative patients, confirmed that 7% of Staphylococcus isolates from nasal passages of orthopedic/vascular patients were mupirocin-resistant, a figure that rises to 9% among elderly patients. In 2007, David Warren and coworkers reported that 13.2% of MRSA isolates from patients at Washington University hospital were mupirocin-resistant. These figures have immediate consequences, as Graber et al. noted failures in decolonization in patients infected with mupirocin-resistant MRSA.
Bacterial resistance to antibiotics generally rose throughout the 1990s and 2000s, and will continue to increase despite efforts to introduce “clean” treatment practices in hospitals. The availability of over-the-counter antimicrobial agents, particularly those that were once sold only by prescription, can potentially reverse the positive impact of best hospital practices, and lead to pockets of high bacterial resistance that will be difficult to eradicate.
For example, a study by Upton and coworkers reported that mupirocin resistance in New Zealand hospitals had reached 28% by 1999, due in part to sales of mupirocin over the counter. Upton urged that “current patterns of mupirocin consumption be reviewed and its use rationalized to maximize the chances of this antibiotic retaining beneficial antistaphylococcal activity.”
Mupirocin is a good antibiotic, but therein lies the problem. Bacteria have evolved over hundreds of millions of years to evade and adapt to antibiotic mechanisms, particularly when these agents are administered systemically. It, therefore, makes no sense to expose every organ and system to antibiotic treatment when an infection is localized to one area that is easily accessible to topical agents. An unintended consequence of the overuse of systemic antibiotics has been the rise of resistant strains on the skin, which complicates treatment even in accessible areas of the body.
Antibiotic Discovery Conundrum
Since 1941, when penicillin was introduced in the United States, every antibiotic brought to market has become less effective (or in some cases completely ineffective) thanks to bacterial resistance. Beginning in the early 1990s this unavoidable problem, coupled with low profit margins, made antibiotics an unattractive business proposition. Companies saw little benefit in developing yet another variant of beta-lactam, quinoline, or macrolide antibacterials as these agents were, for want of a better term, “played out.”
That is beginning to change. The sequencing of the first bacterial genome in 1995 presented the opportunity to create new classes of antibiotics that operated through novel mechanisms against both old and new targets. Realizing the full potential of genome mining is still several years off. Thus far, results have been mixed because antibiotic drug discovery, even when based on gene mining, results in only one-fifth of the number of lead compounds per screening program as for other therapeutic areas.
Nevertheless, the rise in resistant super-bugs has created renewed interest in antibiotics. But even those that operate through novel mechanisms share the fatal flaw of first-line agents, namely that bacteria will eventually adapt, and the agents will become less effective.
The intravenous agent Ceftobiprole (zeftera; Johnson & Johnson), currently under FDA review, is a case in point. Ceftobiprole has been hailed as a fifth-generation antibiotic, partly because it short-circuits known resistance mechanisms. For example, Ceftobiprole is active against MRSA and resistant to staphylococcal beta-lactamase, the key mutation that confers resistance to beta-lactam antibiotics. Despite the high billing, researchers have recently discovered Ceftobiprole-resistant strains of S. aureus by simple passaging experiments.