The Pneumococcus: Learning to Tolerate Antibiotics

Streptococcus pneumoniae is the most common bacterial cause of meningitis, community acquired pneumonia, otitis media, and sinusitis, and a pathogen whose infections often result in morbidity and mortality (1). The success of the Haemophilus influenzae serotype b vaccine has almost eliminated invasive disease in those countries where it has been incorporated into vaccination programs (2). In contrast, the prevalence of invasive disease due to S. pneumoniae has remained high and there are even suggestions that it may be increasing. Of even greater concern has been the recent rapid emergence of multidrug resistance in pneumococci (3-5). In the June 10th issue of Nature Medicine (6) , researchers from St. Jude's Hospital in Memphis, Tennessee, and the Karolinska Institute in Stockholm, Sweden, report the results of investigations that may not only have helped unravel the mystery of why some strains are able to accumulate foreign DNA which allows them to develop resistance, but also provided insights on how certain strains are able to survive exposure to antibiotics.

In the report, Novak and his colleagues describe a group of strains of penicillin-resistant pneumococci which are also tolerant to a number of other antibiotics, including vancomycin. Tolerance and resistance are somewhat different. Antibiotic-resistant microorganisms are insensitive to the antibiotic, and continue to grow in its presence. Antibiotic-tolerant strains stop growing but do not die in the presence of the antibiotic. In neither case does antibiotic therapy eliminate the infective agent, meaning that the infection can continue once therapy is stopped. Antibiotic tolerance is particularly insidious because it cannot be detected using conventional susceptibility tests -- tolerant strains remain sensitive to antibiotics in in vitro testing.

Novak and colleagues have also pinned down the genetic basis for the vancomycin tolerance: a mutation in a two-component signal-transduction system. Two-component systems control a variety of responses in bacteria by allowing the microorganisms to sense their environment and to respond to it by adjusting gene expression. Penicillin and vancomycin are bactericidal for S. pneumoniae because the presence of the antibiotic activates an autolytic system which digests the cell wall exoskeleton and kills the cell. The strains Novak described have a mutation in the signal transduction system which normally activates autolysis. In these strains, the presence of the antibiotic no longer results in autolysis. The presence of vancomycin inhibits their growth, but the organisms survive, and start to grow again when the antibiotic is gone. This type of tolerance to vancomycin, b-lactams, aminoglycosides, and quinolones was found in roughly 3% of the clinical S. pneumoniae isolates studied.

Of particular interest, Novak et al also found that these tolerant strains were better able to take up DNA than other pneumococci. This raises the real possibility that, through DNA uptake and recombination in nature, new strains of pneumococci will continue to arise that are increasingly difficult to treat with existing drugs.

What does this all mean? It suggests that possibly there are some strains of pneumococci out there that are able to survive the insult of antibiotics and live to tell about it. Since the ability to survive appears to be linked to the ability to acquire foreign DNA (e.g., resistance genes), this may explain why strains develop resistance to multiple drugs, and why we have seen the rapid emergence of multi-drug resistant strains worldwide. If these findings are confirmed by other groups, we may have to reconsider therapeutic endpoints. Successful therapy may not only require symptomatic relief, but also complete bacteriologic eradication.

Reference List

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2. Scheifele DW. Recent trends in pediatric Haemophilus influenzae type B infections in Canada. Immunization Monitoring Program, Active (IMPACT) of the Canadian Paediatric Society and the Laboratory Centre for Disease Control [published erratum appears in Can Med Assoc J 1996 May 1;154(9):1319]. CMAJ. 1996;154:1041-47.

3. Davidson RJ, Canadian Bacterial Surveillance Network, Low DE. A Cross Canada Survillance of Antimicrobial Resistance in Respiratory Tract Pathogens. Cand J Infect Dis. 1999;10:128-33.

4. Lovgren M, Spika JS, Talbot JA. Invasive Streptococcus pneumoniae infections: serotyype distribution and antimicrobial resistance in Canada, 1992-1995. CMAJ. 1999;158:327-31.

5. Anonymous. Geographic variation in penicillin resistance in Streptococcus pneumoniae -- Selected sites, United States, 1997. Morbid Mortal Weekly Rep. 1999;48:656-61.

6. Novak R, Henriques B, Charpentier E, Normark S, Tuomanen E. Emergence of vancomycin tolerance in Streptococcus pneumoniae [In Process Citation]. Nature. 1999;399:590-593.