note: the following refers to bacteria, but would no doubt apply to fungal pathogens as well

QUOTED MATERIAL:

At the risk of attack from purist colleagues, the generic term “antibiotic” is used here to denote any class of organic molecule that inhibits or kills microbes by specific interactions with bacterial targets, without any consideration of the source of the particular compound or class. Thus, purely synthetic therapeutics are considered antibiotics; after all, they interact with receptors and provoke specific cell responses and biochemical mechanisms of cross-resistance in pathogens. The fluoroquinolones (FQs), sulfonamides, and trimethoprim are good examples. 

As in any field of biological study, antibiotic history is replete with misconceptions, misinterpretations, erroneous predictions, and other mistakes that have occasionally led to the truth. This account aspires to focus on the truth. 

In the 60 years since their introduction, millions of metric tons of antibiotics have been produced and employed for a wide variety of purposes. Improvements in production have provided increasingly less expensive compounds that encourage nonprescription and off-label uses. The cost of the oldest and most frequently used antibiotics is (probably) mainly in the packaging. The planet is saturated with these toxic agents, which has of course contributed significantly to the selection of resistant strains.

Only in the past few years has it been appreciated that gene exchange is a universal property of bacteria that has occurred throughout eons of microbial evolution. The discovery of the presence of putative bacterial gene sequences in eukaryotic genomes has heightened awareness of the great importance of horizontal gene transfer (HGT) in genome evolution.

An example of bacterial genetic jugglery comes from the recent appearance of a novel FQ resistance mechanism. When the highly potent FQs were introduced in 1987, a few foolhardy experts predicted that resistance to this new class of gyrase inhibitors was unlikely, since at least two mutations would be required to generate a significant resistance phenotype. It was also suggested that horizontally transmitted FQ resistance was unlikely to occur. However, mutants of the tar get bacterial gyrase genes and efflux of the FQs from the cell have increasingly been encountered. More unexpectedly, a transmissible mechanism of FQ inactivation has made its appearance. We have not heard the end of the quinolone resistance saga. The moral of the story . . . one should not try to second-guess microbes! If resistance is biochemically possible, it will occur.

Obtaining accurate figures on the quantities of antimicrobials produced by the pharmaceutical industry is difficult (it is not in the best interest of pharmaceutical companies to provide this information), but it can be estimated that many millions of metric tons of antibiotic compounds have been released into the biosphere over the last half-century.

Some alternative uses of antimicrobial agents are as follows: (i) growth promotion/prophylactic use in animals; (ii) therapeutic/prophylactic use in humans; (iii) therapeutic/prophylactic use in aquaculture; (iv) therapeutic/prophylactic use in household pets; (v) pest control/cloning for plants and agriculture; (vi) use as biocides in toiletries and in hand care and household cleaning products; and (vii) culture sterility, cloning, and selection in research and industry. It should be noted that therapeutic use in humans accounts for less than half of all applications of antibiotics produced commercially.

* Numerous types of anthropogenic activity, including antibiotic use in agriculture and aquaculture, other nonhuman applications of antibiotics, and waste disposal, create major environmental reserves of resistance and, quite probably, of virulence genes and the organisms that harbor them.

* It is worth noting that antibiotics, especially at subinhibitory concentrations, may facilitate the process of antibiotic resistance development. For example, they have been shown to enhance gene transfer and recombination, in part through activating the SOS system. 

* Given the increasing knowledge of environmental reservoirs of resistance, it should now be possible to have early warning of potential resistance mechanisms to new or old antibiotics and thus prepare for problems in the clinic in a proactive manner.

Origins and Evolution of Antibiotic Resistance
Julian Davies and Dorothy Davies
Microbiol. Mol. Biol. Rev.September 2010 vol. 74 no. 3417-433
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