Afterword: A Course of Action

The continuing hope of many infectious disease experts is that the pharmaceutical industry will temporarily stave off the inevitable by producing new classes of antibiotics. That would keep us one step ahead of the pathogens. However, three fundamental problems stand in the way. First, if new, highly effective compounds were produced, the medical community would restrict their use to avoid loss of efficacy through emergence of resistance. In the absence of sales, little profit can be made. Second, staying only one step ahead of the pathogens is not enough. Pathogen populations are often so large that subpopulations have already moved that first step toward resistance. A third problem is that as a community our antibiotic treatment protocols are not set to restrict the emergence of resistance. Consequently, it is unlikely that new antibiotics will solve the resistance problem without major changes in our philosophy about antibiotic use.

Overuse

One change would be to correct policies that enable the selective enrichment of resistant subpopulations. The medical community is in general agreement that we use many antibiotics when they are not needed. Excess prescription writing and self-medication are medical aspects of overuse that can be controlled. For example, half of the 100 million annual prescriptions in the United States for respiratory infections may be unnecessary. Part of the effort needs to be education of medical professionals at the earliest stages of their training. Another part is education of the public concerning the dangers of poor compliance and improper use of antibiotics. The educational message can be reinforced by legislation and enforcement in cases where antibiotics are sold outside the prescribing process. Reducing the abuse of prescriptions will probably become easier as the potential harm to the individual consumer becomes better documented (refer to Table 12-5): Less pressure placed on doctors to prescribe will reduce the number of prescriptions. But cultural issues are difficult to overcome with education when grocery stores offer free antibiotics.

The agricultural community must also do its share. Use of growth promoters and massive drug treatment to combat disease stemming from overcrowding apply selective pressure to a vast community of microbes that reaches the human food supply. Indeed, agricultural use of antibiotics is so much larger than medical use that one could argue that most of the emphasis on resistance should be directed at agriculture. Astute farmers and managers of agribusinesses will see that the days of massive antibiotic use are limited, and they will begin shifting to other strategies.

The argument for limiting use is also clear at the molecular level. Efflux mutations are readily obtained that lower susceptibility to many agents simultaneously (refer to Table 12-3); consequently, use of one type of antibiotic can start others on the climb to resistance. Moreover, antibiotic use favors cells containing integrons that have assembled resistance cassettes: Environmental contamination with antibiotics selects resistant organisms that can spread resistance genes to pathogens. Thus, an effort is required to lower environmental levels of antibiotics by controlling use and disposal at all levels.

Dosing

Changing dosing concepts is also important. We argued that when antibiotics are needed, doses are too low. Placing drug concentrations inside the mutant selection window allows selective amplification of mutant subpopulations. The suggestion that higher doses be used is often countered by the question, “Are the higher doses safe?” Safety issues are so firmly entrenched in the medical community and in the minds of the public that they override all other considerations. Indeed, the Food and Drug Administration was founded in the 1930s to protect the public from unscrupulous medicine men and their snake oils. There is no doubt that safety needs to remain a critical factor for drug development; however, safety issues need to be re-evaluated. Higher doses for many antibiotics would help limit the emergence of resistance. Some antibiotics can be used safely at higher levels. For example, penicillin doses have been increased substantially over time, and recently the dose of levofloxacin, a fluoroquinolone, was increased by 50% for some indications.

Drug Discovery and Surveillance

From an industry perspective, the question of resistance needs to enter the drug discovery process at an early stage. Drug resistance discussions currently come into serious play after a drug is introduced into the market. We argue that the criteria for developing new compounds should make prevention of resistance equal to considerations of safety and efficacy. For new drugs, a combination of creative chemistries and new performance criteria should lead to better antibiotics that last longer in the clinic. Indeed, in the future, only compounds that seriously restrict the emergence of resistance will experience widespread use because the others will be held back for “emergencies.”

Some hope for short-term, local solutions can be seen in the aggressive effort being mounted with MRSA in several small European countries. The effort is best described by the “search and destroy” policy that Dutch and Danish health authorities have taken against MRSA. In Denmark, all MRSA-positive persons are offered eradication treatment, and guidelines recommend that they be issued personal MRSA identification cards. These cards must be shown at each contact with healthcare workers. Moreover, physicians are required to report all MRSA cases.²⁹⁸ Such policies appear to be keeping the prevalence of hospital-associated MRSA low. Whether these policies will continue to contain the MRSA problem is uncertain, because a large reservoir is being generated in farm animals. Also unknown is whether aggressive policies will work in larger countries that have a higher prevalence of drug resistance or with diseases spread by routes other than direct contact. We are encouraged that many states in the United States now require reporting of pathogens such as MRSA. Moreover, individual institutions are beginning to assess the value of patient and healthcare worker decolonization strategies to prevent infection.

We still place hope in basic research. For example, we know that a compromised immune system can contribute to emergence of drug resistance. But is the effect simply due to higher levels of infecting organisms, or are other factors at play? Might human hormones, produced during stress, facilitate pathogen growth?²⁹⁹ Those hormones could be manipulated. On the microbial side, we now realize the need to have a much better understanding of integrons. These DNA elements gather large numbers of resistance genes into a single DNA locale from which they can move to other bacteria. That makes the recipient microbe multidrug resistant in a single step. We have no way to stop this process. Moreover, it is unlikely that we could put together combinations of drugs in a way that would provide a long-term control over integron-mediated resistance. Perhaps we will find small-molecule inhibitors that will block the action of the integron integrase enzymes.

Resistance as a Side Effect

We close Antibiotic Resistance by reiterating that we collectively created a resistance problem that cannot be easily corrected. A major flaw in our approach has been to treat antibiotics like other drugs, to assume that side effects are the main features to guard against rather than resistance. By ignoring pathogen evolution, we lost control over malaria and pneumonia caused by Acinetobacter; we may soon lose the battle with gonorrhea. Perhaps a way to move forward is to emphasize that resistance is a harmful side effect of antibiotic use when that use predisposes us to future resistance problems.