Antimicrobial resistance : The never ending story

THE THERAPEUTIC TRIUMPHS OF ANTIMICROBIALS IN the past decades have been echoed by the successes of microbial resistance to chemotherapy (1). Penicillin G therapy presaged hospital outbreaks of penicillin-resistant Staphylococcus aureus significant enough to lead to the foundation of hospital infection programs. On the heels of the introduction of ampicillin was ampicillin-resistant Haemophilus infiuenzae; optimism in the extended spectrum cephalosporins such as cefotax:ime or ceftriaxone was immediately cooled by chromosomally inducible beta-lactamases produced by Enterobacter doaceae, among others (2): and widespread ciprofloxacin-resistant, methicil lin-resistant S aureus appeared immediately with ciprofloxacin use for this organism. While certain organisms the group A streptococcus and Neis seria meningitidis , for example have remained susceptible to such ·early antibiotics' as penicillin G, there can be no complacency. These bacteria have become resistant to other antimicrobials, such as erythromycin or sulphonan1ides. and we are simply waiting for the other shoe to drop. The increasing use of antiviral and antifungal chemotherapy has broadened the field. Acyclovir-resistant herpes simplex and azidothymidine-resistant human immunodeficiency virus are therapeutic problems; and prophylactic fluconazole therapy has seen the emergence of resistant Candida Jcruzeii. Antimicrobial therapy alters bacterial ecosystems in at least two ways. As the examples above demonstrate, susceptible organisms may become resistant, with most strains being replaced by resistant clones. Today, penicillin-susceptible S aureus is a microbiological dinosaur, and a source

T HE T HERAPEUTIC TRIUMPHS OF ANTIMICROBIALS IN the past decades have been echoed by the successes of microbial resistance to chemotherapy (1).Penicillin G therapy presaged hospital outbreaks of penicillin-resistant Staphylococcus aureus significant enough to lead to the foundation of hospital infection programs.On the heels of the introduction of ampicillin was ampicillin-resistant Haemophilus infiuenzae; optimism in the extended spectrum cephalosporins such as cefotax:ime or ceftriaxone was immediately cooled by chromosomally inducible beta-lactamases produced by Enterobacter doaceae, among others (2): and widespread ciprofloxacin-resistant, methicillin-resistant S aureus appeared immediately with ciprofloxacin use for this organism.While certain organisms -the group A streptococcus and Neisseria meningitidis , for example -have remained susceptible to such •early antibiotics' as penicillin G, there can be no complacency.These bacteria have become resistant to other antimicrobials, such as erythromycin or sulphonan1ides.and we are simply waiting for the other shoe to drop.The increasing use of antiviral and antifungal chemotherapy has broadened the field.Acyclovir-resistant herpes simplex and azidothymidine-resistant human immunodeficiency virus are therapeutic problems; and prophylactic fluconazole therapy has seen the emergence of resistant Candida Jcruzeii.
Antimicrobial therapy alters bacterial ecosystems in at least two ways.As the examples above demonstrate, susceptible organisms may become resistant, with most strains being replaced by resistant clones.Today, penicillin-susceptible S aureus is a microbiological dinosaur, and a source of a musement when idenlified.Alternately, an ecological niche occupied by susceptible organisms is replaced by intrinsically resistant organisms.Health care interventions and widespread use of cephalosporins and related antibiotics have propelled coagulase negative staphylococci and Enterococcus faecalis to the forefront of hospitalacquired pathogens.Now we grapple with the problems of vancomycin-resistant Gram-positive organisms (2).
The contributions of anti-infective chemoU1erapy to health care should not be underestimated.The extraordinary adaptability, diversity and molecular flexibility of microorganisms, however.ensures that resistance will emerge to limit the usefulness of any antimicrobial.We are running hard to stay in the same place, but the treadmill is of our own creation.Societal and economic imperatives dictate that the pharmaceutical industry focus on new drug development, not old drug preservation.A system perpetually requiring 'new and improved' antimicrobials , largely because of emergence of resistance in microorganisms, serves both industry and academia well.
Is there an alten1ate approach?One repeated recommendation , whose proponents point to numerous studies documenting that less than 50% of antimicrobials are used appropriately, is to restrict antimicrobial use (3).Encourage formula ry restriction and control in acute care institutions .No antimicrobials in animal feed.Stop the selling of antimicrobials 'over the counter' in developing countries.
Ecological modification through antimicrobia l limitation has been documented to be effective, especia lly in a cute care institutions (4) .More widespread restriction on a societal basis would.however, be problematic.The restrictive a pproach is inconsistent with our western, 'free market' philosophy, which emphas izes individual rights a nd freedoms.Even if all ina ppropriate use of antimicrobials ceased , the expansion of certain high use patient populations, eg, bon e marrow transplant patients , will r equire increasingly intensive antimicrobial use.In these populations , r esistance will continue to emerge even with a ppropriate antimicrobial thera py.Thus.poten tial gains from the r es trictive approach are n ot guaranteed.This does not mean that efforts to p romote optimal antimicrobial use should not be pursued.It is likely naive, however , to expect even completely op timal use to do more than s low the emergence of resistance.Th e arguments for optimal use of antim icrobials are primarily th ose of clinical care, adverse effects and cost, rather than resistance.
An a lternate approach is to beat the bugs at their own game: to use molecular strategies to reverse or prevent m icrobial resistance.One can envisage the creation of transposon s which provide some benefit to the organism, ensuring their acquisition and dissemination , but which also interfere with resistance m ech anis m s .While this is an attractive a pproach , it remains theoretical.One assumes that microorganisms would develop the means to circu mven t these strategies, a dding another level to the treadmill.A conceptu ally similar approach .the use of s a prophytic organis ms to fill the ecological vacuums created by antimicrobial u se, has a lon g history, but th ere h as b een limited s u ccess and no curren t reason fo r optim ism regar d ing th e ult imate val u e of this a pproach.
The most effective m eans of preventing or d elaying development of antimicrobial resistance must be the prevention of infection.Antimicrobials themselves may be used to preven t infecti on , but this use may lead to em ergen ce of resistant organisms-this approach requires a cost-b en efi t analys is and further study.But th e stage is la rger.
Programs s uch as continued d evelopment and wider use of vaccine, and ensuring optim al h ospital infection control are cru cial to pres erving the efficacy of antimicrobial agen ts .Th er e rem ains r oom for advances in both of th ese areas .Provis ion of a dequate nutrition, sanita tion and h ou s ing should all b e consider ed s trategies to prevent the emergen ce of r esistant organisms.Antimicrobial resistance is one issue in the distribution and appropriate use of r esources in ou r own and oth er s ocieties .This editorial is not an attempt to reduce a complex issue to a s implistic concept.Despite universal problems with antimicrobial r esistance , excellent antimicrobial therapy is still effective in managing most infections.Cure is d et ermined more by host variables rather than the infecting organism.For individu als working in the field of infectious disease, the ch allenges of antimicrobial resistance provide daily intellectual and therapeutic stimulation.issues of antimicrobial resistance are , however, one facet of the larger, u ltima te goal of infectious diseases -prevention.