How to overcome resistance.

So many pathogens, such ingenious defenses

Resistant organisms are those that will not be inhibited or killed by an antibacterial agent at concentrations of the drug achievable in the body with normal dosage. "Bacteria confronted with something that's going to kill them are either going to get killed or they are going to survive," according to Stuart B. Levy, MD, Professor of Medicine and Director of the Center for Adaptation Genetics and Drug Resistance at Tufts University. "The surviving ones have developed a means to curtail, destroy, run around the antibiotics." [1]

[beta]-lactamases -- the most problematic resistance mechanisms

Antibiotic inactivation occurs through several basic mechanisms. The most common resistance mechanism is the production of beta-lactamase enzymes that destroy the antibiotic. Beta-lactam antibiotics--most of which are either penicillins or cephalosporins--have a beta-lactam ring that is essential to their activity, the inhibition of bacterial cell wall synthesis. Bacterial genes encoding beta-lactamases, which break the beta-lactam ring, have been found in both gram-positive and gram-negative bacteria. The activity of beta-lactamases is variable; some are highly active against penicillins, others against cephalosporins, others against both groups. [2,3]

One strategy for circumventing beta-lactamase-mediated resistance has been to combine the beta-lactam drug with a molecule sometimes referred to as a "suicide inhibitor." [4] These molecules bind with the beta-lactamase, preventing it from inactivating the antibiotic. Unfortunately, there are many classes of beta-lactamase, and the inhibitors do not bind with all of them. No beta-lactam drug or beta-lactamase inhibitor can resist all of these enzymes. [2,3]

Altered antibiotic targets

A second resistance mechanism involves modification of the antibiotic target site in the bacterium, so that the drug no longer binds. An alteration in penicillin-binding sites is the mechanism by which Streptococcus pneumoniae (a common respiratory tract pathogen) has become resistant to penicillins and to some cephalosporins. [5]

Alterations in antibiotic target sites can occur through spontaneous mutation of a bacterium's own genetic material, acquisition of DNA from another bacterium, and acquisition of DNA fragments, known as plasmids, which can travel from one type of bacterium to another. [5]

Permeability alterations [plus or minus] active efflux 

A third mechanism of resistance is the alteration by gram-negative bacteria of their outer membrane transport channels that serve as the bacterium's own transport system, and which also allow the antibiotic to enter the organism. [2,3] This is accomplished by mutations of genes encoding the outer-membrane protein channels called porins. [2] Because the transport systems are essential to bacterial viability, this mechanism of resistance is weak, and may sometimes be overcome by increasing the antibiotic dose. However, in combination with other resistance mechanisms, decreased permeability can result in resistance that cannot be surmounted by increased antibiotic dosage. [3]

Some bacteria are also able to pump antibiotics and other toxins out of the cell faster than they can accumulate by diffusion or active influx, a mechanism referred to as "active efflux." The slow influx of antibiotic through the low-permeability outer membrane, along with the efficient efflux of drug, can result in high-level resistance because the organism is able to survive and mutate in the presence of the antibiotic. [2,3]

Resistance -- a growing challenge

Infections caused by antibiotic-resistant organisms are a growing part of clinical practice. Resistance can produce therapeutic failure, and carries a risk of fatal outcome. National surveillance systems are beginning to monitor and publicize the emergence of resistance to current antibiotics. [6] Increasing microbial resistance clearly demonstrates that the fight against infection is far from over, and that new, highly effective antibiotics are needed.

References:

(1.) Lovy S. cited in Antibiotics, Part 1: The end of the miracle #1039, Television News Service/Medical Breakthroughs, Ivanhoe, Broadcast News, Inc., 1997. http://www.ivanhoe.com/docs/backissues/ antiobioticspart1theendofthemiracle.html Accessed July 8, 1999.

(2.) Archer GL, Polk RE. Treatment and prophylaxis of bacterial infections. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, ads. Harrison's Principles of Internal Medicine, 1998. 14th ed. New York, NY; McGraw-Hill; 1998-856-869.

(3.) Jenkins SG. Mechanisms of bacterial antibiotic resistance. New Horizons, 1996;4:321-332

(4.) Chambers HF, Neu HC. Other B-lactam antibiotics. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone; 1995:264-272.

(5.) Mayer KH, Opal SM, Medeiros AA. Mechanisms of antibiotic resistance. In: Mandell GL, Bennett JE, Dolan R, eds. Principles and Practice of Infectious Diseases. 4th ad. New York, NY: Churchill Livingstone; 1995:212-225.

(6.) Jones RN. Can antimicrobial activity be sustained? An appraisal of orally administered drugs used for respiratory tract Infections. Diagn Microbiol Infect Dis. 1997;27:21-28.