Pediatric Annals

EDITORIAL: A Pediatrician's View 

Germ Wars

William A Altemeier, III, MD

Abstract

This issue presents the latest developments in pediatrie antibacterial therapy. Because new classes of antibacterials are becoming harder to find and resistance to the ones vfe have is increasing, emphasis is shifting toward preserving existing agents through more judicious use.

THE ORIGIN OF ANTIBIOTICS

Antibiotics are antibacterial agents originally derived from living organisms and they evolved long before humans discovered them. Their existence and possible use for treatment were conceptualized soon after the dawn of bacteriology. Pasteur noted that some organisms interfere with the growth of others and Vuillemin called this process "antibioses" in 1889. However, attempts to treat patients with cultures or crude extracts of such organisms were too toxic or of uncertain benefit.

In search of an antiseptic that damaged organisms more than patients' tissues and leukocytes, Alexander Fleming, a British physician, discovered lysozyme, a bacteriocidal component of human tears, mucous, and skin in 1922. Various attempts to use this for treatment failed, but this prepared Fleming for a chance observation in 1929. Working in his microbiology laboratory at St. Mary's in London, Fleming noticed that a colony of Pénicillium mold that had contaminated a Petri dish caused nearby staphylococcal colonies to become transparent. Fleming put aside other research and found that a crude filtrate of the mold also killed diphtheria, Streptococcus pyogenes, Streptococcus viridans, Streptococcus pneumoniae, Neisseria meningitidis, and Neisseria gonorrhoeae. He noted a low toxicity when the extract was injected into animals or applied to leukocytes. However, Fleming's presentation and publication of this work raised little interest and the development of penicillin was put on hold for a decade. The possibility of systemic use had not occurred to Fleming.1'2

Then Chain came upon Fleming's paper about penicillin while studying lysozyme in England. A culture of Fleming's Pénicillium strain was obtained in 1939 and he began serious work a year later with Flory. Impure penicillin was first injected into mice infected with group A streptococci. All treated animals survived, but all untreated animals died. After further purification, the first clinical trial was conducted in 1941 on an Oxford policeman dying of staphylococcal osteomyelitis and septicemia that followed a prick from a rose thorn. Chain and Flory had only enough penicillin, including that extracted from the patient's urine, to complete 5 days of treatment. Although the policeman eventually died, penicillin temporarily arrested the infection.

Development was then moved to the United States because of the war, and by 1943 enough penicillin was being produced for the allied forces. A search for organisms that made other antibiotics quickly ensued and streptomycin was obtained from Streptomyces griseus in 1944. The discovery of the tetracydines, chloramphenicol, and the remaining classes followed. Since then we have modified side chains and used other chemical methods to tweak antibiotics. However, these agents were originally derived from products that one organism made to gain an advantage over another and this limits the number of classes (including those too toxic for use) to whatever exists in nature. Thus, the rate of identification of new classes has progressively slowed during the past 50 years. There may not be many (or any) more waiting to be discovered. Of course, some gains are still expected through modifying those we have and through synthesizing new antibacterials.

THE HISTORY OF ANTIBIOTIC RESISTANCE: WHAT ARE WE UP AGAINST?

Resistance to penicillin was noted soon after its release for general use following the war. The same then happened for streptomycin. For a time we stayed ahead by discovering new antibiotics. But: "The pattern of discovery, exuberant use, and predictable obsolescence has been repeated after the introduction of each new antimicrobial drug."2 Why has…

This issue presents the latest developments in pediatrie antibacterial therapy. Because new classes of antibacterials are becoming harder to find and resistance to the ones vfe have is increasing, emphasis is shifting toward preserving existing agents through more judicious use.

THE ORIGIN OF ANTIBIOTICS

Antibiotics are antibacterial agents originally derived from living organisms and they evolved long before humans discovered them. Their existence and possible use for treatment were conceptualized soon after the dawn of bacteriology. Pasteur noted that some organisms interfere with the growth of others and Vuillemin called this process "antibioses" in 1889. However, attempts to treat patients with cultures or crude extracts of such organisms were too toxic or of uncertain benefit.

In search of an antiseptic that damaged organisms more than patients' tissues and leukocytes, Alexander Fleming, a British physician, discovered lysozyme, a bacteriocidal component of human tears, mucous, and skin in 1922. Various attempts to use this for treatment failed, but this prepared Fleming for a chance observation in 1929. Working in his microbiology laboratory at St. Mary's in London, Fleming noticed that a colony of Pénicillium mold that had contaminated a Petri dish caused nearby staphylococcal colonies to become transparent. Fleming put aside other research and found that a crude filtrate of the mold also killed diphtheria, Streptococcus pyogenes, Streptococcus viridans, Streptococcus pneumoniae, Neisseria meningitidis, and Neisseria gonorrhoeae. He noted a low toxicity when the extract was injected into animals or applied to leukocytes. However, Fleming's presentation and publication of this work raised little interest and the development of penicillin was put on hold for a decade. The possibility of systemic use had not occurred to Fleming.1'2

Then Chain came upon Fleming's paper about penicillin while studying lysozyme in England. A culture of Fleming's Pénicillium strain was obtained in 1939 and he began serious work a year later with Flory. Impure penicillin was first injected into mice infected with group A streptococci. All treated animals survived, but all untreated animals died. After further purification, the first clinical trial was conducted in 1941 on an Oxford policeman dying of staphylococcal osteomyelitis and septicemia that followed a prick from a rose thorn. Chain and Flory had only enough penicillin, including that extracted from the patient's urine, to complete 5 days of treatment. Although the policeman eventually died, penicillin temporarily arrested the infection.

Development was then moved to the United States because of the war, and by 1943 enough penicillin was being produced for the allied forces. A search for organisms that made other antibiotics quickly ensued and streptomycin was obtained from Streptomyces griseus in 1944. The discovery of the tetracydines, chloramphenicol, and the remaining classes followed. Since then we have modified side chains and used other chemical methods to tweak antibiotics. However, these agents were originally derived from products that one organism made to gain an advantage over another and this limits the number of classes (including those too toxic for use) to whatever exists in nature. Thus, the rate of identification of new classes has progressively slowed during the past 50 years. There may not be many (or any) more waiting to be discovered. Of course, some gains are still expected through modifying those we have and through synthesizing new antibacterials.

THE HISTORY OF ANTIBIOTIC RESISTANCE: WHAT ARE WE UP AGAINST?

Resistance to penicillin was noted soon after its release for general use following the war. The same then happened for streptomycin. For a time we stayed ahead by discovering new antibiotics. But: "The pattern of discovery, exuberant use, and predictable obsolescence has been repeated after the introduction of each new antimicrobial drug."2 Why has this happened? First, resistance to antibiotics and the methods organisms use to get resistance genes from other bacteria (see the article by James in this issue) evolved to some degree before we used antibiotics. This gave pathogens a head start in developing ways to avoid our treatments. For example, in 1968 Gardner et al. studied resistance (R) factors in stools of people living on the remote Solomon Islands, virtually untouched by man-made antibiotics.3 They found R factors to streptomycin and tetracycline that could be incorporated into Escherichia coli by conjugation. Other studies have found R factors for ampicillin and several aminoglycosides from bacteria isolated before we had these antibiotics.3 It is only logical that if some organisms evolved antibiotics to fight others, these others would evolve mechanisms to protect themselves, even before we used antibiotics.

Recent work on colicins, nontherapeutic antibiotics that E. coli produce to kill closely related organisms, provides a model for these offensive and defensive moves. When a new strain begins competing with an older E. coli intestinal resident, both may release colicins. Each has evolved a protective mechanism against its own colicin, so the battle ensues. When one organism evolves a protective defense against the other's antibiotic, it quickly takes over and those with resistance to many colicins become "super-killers." So, there are genes that make the antibiotic and genes that defend against the antibiotics of others. This has helped explain a previous puzzle - why do strains of E. coli differ by 5% of their DNA? This is much more diversity than usual within a species. Individual humans differ by only .05% and humans and chimpanzees differ by only 1% to 2%. The explanation came when the diverse DNA was discovered to be centered on the resistance genes, at the end of the colicin-producing genes. The high diversity apparently evolved to facilitate this resistance.4

Our use of antibiotics has accelerated this resistance tremendously by increasing the selective pressure for pathogens to evolve ways to protect themselves. We help the enemy develop its defenses when we overuse antibiotics, and this issue is primarily about prolonging the years that individual antibiotics are effective by judicious use. But there are other ways we help the enemy.5 Our hospitals, critical care units, and nursing homes are a manmade Garden of Eden for the evolution of bacterial resistance. There we bring weakened hosts with iatrogenic portals for bacterial access together with our latest antibiotics and the most virulent and resistant organisms. What a deal - for the bacteria. Developing countries also breed resistance because of high infection rates and the unrestricted use of low-cost antibiotics. We sabotage ourselves even further by using huge amounts of antibiotics in farm animals.

WHAT CAN WE DO?

The actions that need to be taken are obvious, but doing these is difficult. It is clear that reducing the use of an antibiotic, through hospital or national policies, to meet a resistance problem is generally followed by an increase in sensitivity to that product. There are encouraging signs that this trend is beginning.

REFERENCES

1. Riley HD. The story of penicillin. Oklahoma State Medical Association Journal. 1972;65:107-119.

2. Kunin CM. Resistance to antimicrobial drugs: a worldwide calamity. Ann Intern Mea. 1993;118:557-560.

3. Gardner P, Smith DH, Beer H, Moellering RC Ir. Recovery of resistance (R) factors from a drug-free community. Lancet. 1969;2:774-776.

4. Morell V. Bacteria diversify through warfare. Science. 1997;278:575.

5. Williams RJ, Heymann DL. Containment of antibiotic resistance. Science. I998;279: 1153-1155.

10.3928/0090-4481-19990701-06

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