Antibiotic Resistance—Does it Ever go Away?

Abstracts & commentary

Synopsis: Reducing the use of an antibiotic may not inevitably bring a return of susceptibility.

Sources: Enne VI, et al. Persistence of sulphonamide resistance in Eschericia coli in the UK despite national prescribing restriction. Lancet. 2001;357:1325-1328; Cunha BA. Effective antibiotic-resistance control strategies (editorial). Lancet. 2001;357:1307-1308.

Workers at the royal london hospital collected strains of E coli in 1991. A total of 359 remained viable for study in 1999 when a comparable number of strains were collected from similar inpatient and outpatient sources. The organisms were tested for resistance to sulphonamides ("sulfonamides" to Americans) to see the effect of the restrictions of sulfonamide use in the United Kingdom in 1995. This restriction was imposed because of the high incidence of rash with sulfa drugs and the availability of trimethoprim, which seemed as effective as sulfamethoxazole-trimethoprim. The number of prescriptions for sulfa antibiotics fell dramatically from 320,000 in 1991 to 7000 in 1999.

There was no increase in susceptibility to sulfonamides over time. In fact, there was an increase in resistance from 40% to 46% of strains, and those from the community were no better than the hospital. The strains with resistance were also more likely to carry resistance genes to other antibiotics as well. This was particularly true with ampicillin and chloramphenicol. The ampicillin resistance rate rose from 80% to 86% although chloramphenicol fell from 44% to 27%. Upon further analysis, the resistance to sulfa drugs was found to be due to a variety of genes, the most common of which was sul-I (16% in 1991 to 18% in 1999) and sul-II (27% in 1991 to 37% in 1999). These genes are carried on plasmids in combination with genes to a variety of other antibiotics.

The British attribute the failure to regain sulfonamide susceptibility to the plasmids, which carry a packet of multiple antibiotic-resistant genes with either sul-I or sul-II, but they note the possibility that the organisms have developed improved survival mechanisms with the resistance mechanisms. It is also possible that continued sulfa use is playing some role in persistence as they still use about 80 tons of sulfonamides per year for animals.

In the related editorial, Burke Cunha takes the issue of antibiotic resistance further. He ascribes the problem with resistance to antibiotics largely to the use of specific drugs that are more likely to select for resistance than others. He thinks it is not an antimicrobial class effect but rather an individual antibiotic defect. He considers the main culprits to be ciprofloxacin (plus nalidixic acid and norfloxacin) among the quinolones, tetracycline among the tetracyclines (not minocycline or doxycycline), cefamandole among the second-generation cephalosporins, ceftazidime among the third-generation cephalosporins, and imipenem among the carbapenems. These drugs can be recognized by the development of resistance during therapy, even in phase III studies. He notes the high-resistance antibiotics are much more likely in the hospital and in the intensive care units, where they may well share genes with other resistant bacteria.

Comment by Alan D. Tice, MD, FACP

The findings at the London hospital are most interesting. The presumption that reducing antibiotic usage changes the microbial environment and encourages the return of susceptible organisms is called into doubt. It seemed to have worked in Finland with erythromycin, but the result is different in the United Kingdom. Sulfonamides have been around for more than 50 years and have been used in the community as much as in the hospital. There must be a huge reservoir of resistant organisms out there from their use in the 1960s, 1970s, and 1980s, and that reservoir is only contributed to by continuing to add sulfa drugs to animal feed.

In addition, it may be that the resistant organisms that have survived may now offer some selective advantages over the old, antibiotic-susceptible ones. Are we now producing superbugs in addition to antibiotic-resistant ones? It could also be, as postulated, that the genes responsible for resistance have found a survival team to join and are along for the ride. The continued antibiotic pressure has made a variety of armaments necessary for bacteria to survive in the antibiotic-rich hospitals and even the community. The plasmids that carry these teams can defend themselves from a variety of antibiotics including ampicillin, chloramphenicol, tetracycline, and trimethoprim.

What do the E coli findings mean? Can we regain what has been lost? Is the cow out of the barn and never to return despite the most prudent use of antimicrobials? It is difficult to know, but the situation we have created may not be reversible for some antibiotics. Which ones? Sulfonamides and E coli seem to be a problem but others may not. Will the same thing happen with the cephalosporins and quinolones?

The theories of Cunha are additional food for thought. The idea of antibiotics being different in their ability to develop resistance in bacteria is a relatively new one and threatens the simple concept of less antibiotics are better. The ability of bacteria to produce resistance genes to some antibiotics more easily than others is certainly of concern, but it may not be translated into a general problem. Not all resistant genes escape the hospital and establish themselves in the community. On the other hand, resistance may develop rapidly in some situations such as with staphylococci and the quinolones.

It should be noted that the mechanism for antibiotic resistance may not simply be developing smarter or better-equipped bacteria. It may be from replacing one strain with another—such as Enterococcus faecium with E faecalis when vancomycin is applied. There is also a note of the importance of infection control when resistance genes appear. This has recently been highlighted by the "Siouxland" study.

Obviously, we need to know more about how and why antibiotic resistance develops and what can be done to prevent and reduce it. The insight gained into sulfonamide and E coli in the United Kingdom brings up many questions that need answers soon.